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abcd Clinical Study Report • • • • Information will be excluded in order to protect the privacy of patients and all named persons associated with the study Patient data listings will be completely removed to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. Aggregate data will be included; with any direct reference to individual patients excluded We will only redact information for the purpose of protecting the privacy of individuals, and not for any other purpose Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 3 U12-2466-01 Clinical Trial Protocol Doc. No.: U10-1634-03 EudraCT No.: 2009-018004-18 BI Trial No.: 205.418 BI Investigational Product(s): Tiotropium bromide Inhalation Solution Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Clinical Phase: III Trial Clinical Monitor: Boehringer Ingelheim bv, Medical department Comeniusstraat 6, 1817 MS Alkmaar, The Netherlands Phone: , Fax: , MD Co-ordinating Investigator: The Netherlands Phone: , Fax: Status, Version, and Date of Protocol: Final Protocol, Version 1.0, 15 April 2010 Status, Version, and Date of Revised Protocol: Revised Protocol (based on modification 2) Version 3.0, 5 December 2011 Page 1 of 147 149 Proprietary confidential information. © 2011 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. TITLE PAGE Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 4 U12-2466-01 5 Dec 2011 Page 2 of 149 Trial Protocol CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.418 I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Name: MD Signature:__________________________ Signed signature page is located in the electronic Clinical Trial Master File Affiliation: The Netherlands Date: ___________________________ Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 5 Page U12-2466-01 5 Dec 2011 Page 3 of 149 Trial Protocol LOCAL SIGNATURES (PRINCIPAL INVESTIGATOR OF SITE AND LOCAL CLINICAL MONITOR (CML)) Local Clinical Monitor <optional, delete if not applicable>: Date Name Full name Organisation/Department <Add other signatories if applicable.> I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Principal Investigator (site): Date Name Full name Organisation/Department Signed signature page is located in the electronic Clinical Trial Master File Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 6 U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 Trial Protocol 5 Dec 2011 Page 4 of 149 CLINICAL TRIAL PROTOCOL SYNOPSIS Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 15 April 2010 Title of trial: Trial number: 205.418 Revision date: 5 December 2011 A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma , MD, Co-ordinating Investigator : , The Netherlands Trial site(s) : Multi-centre, Multi-national Clinical phase: III Objective(s): Evaluate the long term efficacy and safety of tiotropium (2.5 and 5 µg once daily administered in the evening) inhalation solution delivered by the Respimat® inhaler compared to placebo and salmeterol (administered twice daily) in patients with moderate persistent asthma Methodology: Randomised, double-blind, placebo- and active-controlled, parallel-group design comparing tiotropium versus placebo and salmeterol over 24 weeks on top of maintenance therapy with an inhaled corticosteroid controller medication No. of patients: total entered: 1000 each treatment: 250 Diagnosis : Asthma Main criteria for inclusion: Outpatients of either sex, age 18 - 75 years, never-smokers or ex-smokers with < 10 pack years and smoking cessation at least one year prior to enrolment. Patients must have at least a 3-month history of asthma that was diagnosed before the age of 40, and a current diagnosis of moderate persistent asthma (according to GINA guideline). Patients need to be still symptomatic, i.e. not fully controlled with their current maintenance treatment (assessed by ACQ mean score and pulmonary lung function tests). Maintenance treatment with medium dose of inhaled corticosteroids (Appendix 10.4) is required. Test products : Tiotropium inhalation solution 2.5µg (2 actuations of 1.25 µg) and 5 µg (2 actuations of 2.5 µg) once daily in the evening mode of admin. : Oral inhalation via Respimat® inhaler dose: Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 7 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 5 of 149 Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 15 April 2010 Trial number: 205.418 Revision date: 5 December 2011 Comparator product 1: Salmeterol hydrofluoroalkane (HFA 134a) metered dose inhaler (MDI) dose: 50 µg (2 actuations of 25 µg per actuations) twice daily (morning and evening) mode of admin. : Oral inhalation from HFA MDI Comparator product 2: Placebo inhalation solution dose: Not applicable mode of admin. : Oral inhalation via Respimat® inhaler Comparator product 3: Placebo MDI dose: Not applicable mode of admin. : Oral inhalation via HFA MDI Duration of treatment: 24 weeks Criteria for efficacy: Co-primary endpoints: peak FEV1 response (within 3 hours post evening dosing) and trough FEV1 response after 24 weeks treatment Secondary endpoints: Peak FVC; trough FVC; FEV1 (AUC0-3h); FVC (AUC0-3h); individual in-clinic FEV1/FVC/PEF measurements; Asthma Quality of Life Questionnaire (AQLQ (S)); Home assessment: PEF am/pm (last weekly mean of treatment period), use of PRN rescue medication; daytime and nocturnal symptoms; asthma symptom free days, control of asthma (Asthma Control Questionnaire; ACQ) after 24 weeks treatment. In a subset of patients: FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h) Other endpoints: Home assessments during treatment period PEF am/pm; FEV1 am/pm; PEF variability Meta-analysis on combined data from the two twin trials 205.418 and 205.419. Primary endpoint: Control of asthma (Asthma Control Questionnaire) after 24 weeks treatment. Secondary endpoints: time to first exacerbation; time to first severe asthma exacerbation. ACQ at each visit. Criteria for pharmacokinetics: Plasma and urine samples for the quantification of tiotropium will be obtained in a subset of patients following the administration of the first dose and following administration of tiotropium for 4 weeks (i.e., at steady state). Additionally, a predose and 5 minute post-dose blood sample will be obtained on study days 7, 14 and 21 to confirm the achievement of steady-state. Enough patients will be included in this subset to ensure at least 80 patients will complete the PK sampling visits. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 8 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 6 of 149 Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 15 April 2010 Trial number: 205.418 Revision date: 5 December 2011 Criteria for health economics: Health care resource utilisation (HCRU) and Quality of Life assessed by EQ-5D Criteria for pharmacogenomics: Unspecified pharmacogenetic testing Criteria for safety: Adverse events, vital signs, vital status information Other criteria: In a subset of patients: patient satisfaction and preference questionnaire (PASAPQ) Statistical methods: For the two co-primary FEV1 endpoints: restricted maximum likelihood (REML)based mixed effects model with repeated measures (MMRM) with terms for treatment, investigative site, visit, and treatment by visit interaction as fixed categorical effects, and baseline and fixed covariates baseline by visit interaction. The comparisons with salmeterol are not part of the inferential analysis. Standard statistical parameters (number of non-missing values, mean, standard deviation (SD), median, quartiles, minimum, and maximum) or frequency tables will be calculated where appropriate for all parameters. Meta analysis: primary endpoint (ACQ): pooled analysis of the twin trials with trial numbers 205.418 and 205.419. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 9 Page U12-2466-01 5 Dec 2011 Page 7 of 149 Trial Protocol FLOW CHART Trial periods Treatment* Screening Visit 0 1 2 Week Day Time window** -1 -4 -28 ±4 0 1 Informed consent1 Instruct patient on washout/restrictions1 Demographics Medical History/Baseline conditions2 Physical examination (incl. vital signs) Review smoking status ECG, laboratory and pregnancy test4 Inclusion/exclusion criteria Dispense rescue medication Respimat® and MDI training Randomisation Dispense trial medication Administration of trial medication in clinic5 Collect trial medication Drug accountability Blood sample for pharmacogenetics6 Pharmacokinetic sampling7 Training eDiary with PEF-meter Issue eDiary with PEF-meter Download eDiary with PEF-meter Collect eDiary with PEF-meter Issue paper diary card Review/collect paper diary card ACQ9 AQLQ (S)9 EQ-5D9 PASAPQ9 Review exacerbation and HCRU Medication washout check11 Pulmonary function test12 Vital signs (seated) Adverse events Concomitant therapy Termination of trial medication Vital status collection18 Completion of trial X X X X X X X X X X X X X1 X X X X X X10 X X13 X X 2A7 2B7 2C7 3 4 5 6 7 7 ±1 14 ±1 21 ±1 4 28 ±2 8 56 ±2 16 112 ±4 24 168 ±4 27 189 +7 X X X X X X X X3 X3 X3 X X X X X X 16 Follow up X X X X X X 16 X X X X X X X X X X X X X X X X X X X X X X X X3 X3 X3, 8 X3 X8 X8 X8 X X X10 X X X X X X X X X X X X X X X X X X X X14 X15 X X X X X14 X15 X X X X X14 X15 X X X X X14 X15 X X X X X X X X X X X16 X X8 X X X3 X X X X17 X3 X X14 X15 X3 X3 X3 X X X18 X Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 8 of 149 * ** Visit 0 and 7 may be conducted during business hours. Visits 1 to 6 will always start in the evening. Each Respimat® inhaler and MDI contains drug supply for 30 days which must be obeyed regarding visit flexibility after randomisation. 1 All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions (see Section 4.2.2). A separate consent for pharmacokinetic sampling should be signed if patients are participating in the pharmacokinetic substudy. A separate consent for pharmacogenetic sampling should be signed if patients are participating in the pharmacogenetic substudy. The interval between Visit 0 and Visit 1 may be between 1 and 28 days depending on medication washout requirements and restrictions. A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid unnecessary washout procedures in non-eligible patients. Including asthma background characteristics. To be completed by all patients who took at least one dose of trial medication including those who discontinue early. Vital status information has to be collected on the originally planned follow up visit date (Visit 7). Haematology and blood chemistry (local laboratory). White bloodcell count, eosinophil count (absolute and relative), total serum IgE and creatinine levels will be documented in eCRF at Visit 1. Urine pregnancy test required for all women of child-bearing potential. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (LTRA) (if applicable), 2. trial medication from assigned MDI, 3. trial medication from assigned Respimat®. Patient’s ICS should be administered without change in posology (bid/qd; am/pm), i.e. as prescribed by patient’s treating physician prior to trial entry. Blood sample for pharmacogenetics will be drawn from all randomised patients that received at least one dose of trial medication and that gave a separate informed consent. Participation in the pharmacogenetic subset is not a pre-requisite for participation in the trial. The blood sample will be drawn at preferably Visit 2 or at any other subsequent visit after randomisation. PK in a subset of patients at selected sites (separate informed consent should be obtained first). e-Diary compliance check (see Section 4.3 and Section 6.1). First ACQ, then AQLQ (S), then EQ-5D and then PASAPQ will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. ACQ at screening will be used for assessment of degree of asthma control. If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). Refer to Section 4.2.2.1. Pre-bronchodilator FEV1 at Visit 1 and pre-dose FEV1 at Visit 2 must be within ± 30% variation prior to randomisation based on absolute FEV1 values. If the variation of FEV1 in the screening period exceeds ± 30%, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). 10 minutes pre- and 15 to 30 minutes post-bronchodilator PFT after inhalation of 4 puffs (100 µg/puff) salbutamol/albuterol. 10 minutes prior to trial drug administration (pre-dose) and until 3 hours post-dose. In a subgroup of patients at selected sites at Visit 6: 10 minutes prior to trial drug administration and until 24 hours post-dose. In conjunction with pulmonary function testing until 3 hours post-dose (measured immediately before PFT). Rescue medication only. Only in selected countries. After any premature withdrawal of patients who took at least one dose of trial medication, vital status information should be collected (see Section 6.2.3). 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 11 Page U12-2466-01 5 Dec 2011 Page 9 of 149 Trial Protocol TIMING OF TRIAL PROCEDURES DURING THE TREATMENT PERIOD 3 hour pulmonary function test without pharmacokinetic sampling1 Timing related to evening inhalation of study drug -1h -30’ -15’ -10’ Administer patient’s usual ICS medication followed by trial medication2 5' 15' 4 4 30’ 1h 2h 3h X X X X X X X X X AM3 Å ------ Æ Patient self-administration of questionnaires3 Å -------------- Æ Vital signs (seated) X Pulmonary function test 1 0 X X X Order of procedures if performed at the same time point: - Vital signs followed by pulmonary function testing - Use of AM3 device followed by filling out questionnaires Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat®). ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. At Visit 6, the PASAPQ will be patient self-administered as fourth questionnaire in selected countries. Only at Visit 5 and only in a subset of patients at selected sites. 2 3 4 Pharmacokinetic plasma sampling at Visits 2A (day 7), 2B (day 14), and 2C (day 21)1 Timing related to evening inhalation of study drug -1h -30’ -15’ 0 5’ Administer patient’s usual ICS medication followed by trial medication2 Å --------------------- Æ AM3 PK plasma sampling 1 2 X X X At selected sites only. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat®). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments 12 Page U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 5 Dec 2011 Page 10 of 149 Trial Protocol 3 hour pulmonary function test with 24 hour pharmacokinetic sampling at Visit 2 and Visit 31, 2 Timing related to evening inhalation of study drug -1h Administer patient’s usual evening ICS medication followed by trial medication3 Administer patient’s usual morning ICS medication followed by trial medication4 AM3 Patient self-administration of questionnaires6 PK plasma sampling PK urine collection 1 2 3 4 5 6 7 8 9 7 -30' -15' -10' 0 2' 5' 7' 10' 15' 30' 1h 2h 3h 6h 12h 24h8,9 X X X5 Å ----- Æ Å -------------- Æ X X Å ----------------------- Æ X X X X X X Å ---------------------------------------------------- Æ X X Å --- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X X X Å --------------- Æ Order of procedures if performed at the same time point: - PK plasma sampling (as close to planned time point as possible!), vital signs and pulmonary function testing - Use of AM3 device followed by filling out questionnaires At selected sites only. Patients may stay overnight. Refer to Section 5.5.2 for more information. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat ®). Morning trial drug administration will occur between 06.00 and 08.00 am and 12 hours (± 5 minutes) after the time of the pm administration. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI. Patient should use AM3 device immediately upon arising and prior to inhalation of medication. ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. Patients must empty bladder at the end of each urine collection interval. All urine voided during the sampling intervals -1 to 0 pre-dose and 0 to 2, 2 to 6 and 6 to 24 hours post-dose will be collected in containers. Patients should continue urine collection at home. Urine fraction must be kept cold at all times. Patient should return 30 minutes prior to last PK sample. Refer to Section 5.5.2 and Investigator Site File (ISF) chapter 10 for instructions. PK blood sample should be collected 15 minutes prior to the administration of next dose ICS and trial medication, i.e., at time point 23:45. Patients must void urinary bladder into the 6-24 container up to 5 minutes prior to the inhalation of the next day ICS and tiotropium doses (i.e., up to 23:55 hours after last dosing). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments 13 Page U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 5 Dec 2011 Page 11 of 149 Trial Protocol 24 hour pulmonary function test after 24 weeks (Visit 6)1, 2 Timing related to evening inhalation of study drug -1h -30' -15' -10' 0 30' 1h 2h 3h 4h 11h10' 11h50' 12h 12h30' 13h 14h 15h 16h 18h 20h 22h 23h 23h50' Administer patient’s usual evening ICS medication followed by trial medication3 Administer patient’s usual morning ICS medication followed by trial medication4 AM3 Patient self-administration of questionnaires6 1 2 3 4 5 6 X X X5 Å -Æ Å -------- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X X X X X X X X X X X X X Order of procedures if performed at the same time point: - Vital signs followed by pulmonary function testing - Use of AM3 device followed by filling out questionnaires At selected sites only. Requires overnight stay. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat ®). Morning trial drug administration will occur between 06.00 and 08.00 am and 12 hours (± 5 minutes) after the time of the pm administration. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI. Patient should be woken 40 minutes (± 10 minutes) prior to the start of the initial morning PFT (11h50’ time point). Patient should use AM3 device immediately upon arising and prior to inhalation of medication. ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. The PASAPQ will be patient self-administered as fourth questionnaire in selected countries. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 14 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 12 of 149 TABLE OF CONTENTS TITLE PAGE ...................................................................................................... 1 CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................ 4 FLOW CHART ................................................................................................... 7 TABLE OF CONTENTS ................................................................................. 12 ABBREVIATIONS ........................................................................................... 16 1. INTRODUCTION................................................................................ 20 1.1 MEDICAL BACKGROUND ............................................................................ 20 1.2 DRUG PROFILE ............................................................................................... 21 1.2.1 Inhalation solution and Respimat® Inhaler ................................................ 25 2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT ..................................................................................... 26 2.1 2.2 2.3 3. RATIONALE FOR PERFORMING THE TRIAL ........................................ 26 TRIAL OBJECTIVES ....................................................................................... 27 BENEFIT - RISK ASSESSMENT.................................................................... 28 DESCRIPTION OF DESIGN AND TRIAL POPULATION.......... 29 3.1 OVERALL TRIAL DESIGN AND PLAN ...................................................... 29 3.1.1 Administrative structure of the trial ........................................................... 30 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S) ..................................................................................... 31 3.3 SELECTION OF TRIAL POPULATION ...................................................... 31 3.3.1 Main diagnosis for study entry .................................................................... 32 3.3.2 Inclusion criteria............................................................................................ 32 3.3.3 Exclusion criteria ........................................................................................... 34 3.3.4 Removal of patients from therapy or assessments ..................................... 36 3.3.4.1 Removal of individual patients ................................................................... 36 3.3.4.2 Discontinuation of the trial by the sponsor ................................................. 37 4. TREATMENTS .................................................................................... 39 4.1 TREATMENTS TO BE ADMINISTERED .................................................... 39 4.1.1 Identity of BI investigational product and comparator product(s) .......... 39 4.1.2 Method of assigning patients to treatment groups ..................................... 40 4.1.3 Selection of doses in the trial ........................................................................ 41 4.1.4 Drug assignment and administration of doses for each patient ................ 41 4.1.5 Blinding and procedures for unblinding ..................................................... 44 4.1.5.1 Blinding ...................................................................................................... 44 4.1.5.2 Procedures for emergency unblinding ........................................................ 45 4.1.6 Packaging, labelling, and re-supply ............................................................. 45 4.1.7 Storage conditions ......................................................................................... 47 4.1.8 Drug accountability ....................................................................................... 47 4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT .................................................................................................... 48 4.2.1 Rescue medication, emergency procedures, and additional treatment(s) 49 4.2.1.1 Rescue medication ...................................................................................... 49 4.2.1.2 Emergency procedures ............................................................................... 49 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 15 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 13 of 149 4.2.1.3 Additional treatments ................................................................................. 49 4.2.2 Restrictions..................................................................................................... 51 4.2.2.1 Restrictions regarding concomitant treatment ............................................ 51 4.2.2.2 Restrictions on diet and life style ............................................................... 55 4.3 TREATMENT COMPLIANCE ....................................................................... 55 5. VARIABLES AND THEIR ASSESSMENT ..................................... 56 5.1 EFFICACY - CLINICAL PHARMACODYNAMICS ................................... 56 5.1.1 Endpoint(s) of efficacy .................................................................................. 56 5.1.1.1 Primary Endpoints ...................................................................................... 56 5.1.1.2 Secondary Endpoints .................................................................................. 56 5.1.1.3 Other Endpoints .......................................................................................... 58 5.1.2 Assessment of efficacy ................................................................................... 58 5.2 SAFETY .............................................................................................................. 63 5.2.1 Endpoint(s) of safety ..................................................................................... 63 5.2.2 Assessment of adverse events ....................................................................... 63 5.2.2.1 Definitions of adverse events ..................................................................... 63 5.2.2.2 Adverse event and serious adverse event reporting.................................... 65 5.2.3 Assessment of safety laboratory parameters .............................................. 66 5.2.4 Electrocardiogram......................................................................................... 67 5.2.5 Assessment of other safety parameters ....................................................... 67 5.3 OTHER ............................................................................................................... 68 5.3.1 Other endpoints ............................................................................................. 68 5.3.2 Other assessments.......................................................................................... 68 5.3.3 Pharmacogenetic evaluation......................................................................... 70 5.3.3.1 Methods of sample collection ..................................................................... 70 5.3.3.2 Analytical determinations ........................................................................... 70 5.4 APPROPRIATENESS OF MEASUREMENTS ............................................. 70 5.5 DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS .................................................................................. 71 5.5.1 Pharmacokinetic endpoint(s)........................................................................ 71 5.5.2 Methods of sample collection........................................................................ 73 5.5.3 Analytical determinations............................................................................. 74 5.6 BIOMARKER(S) ............................................................................................... 75 5.7 PHARMACODYNAMICS ................................................................................ 75 5.8 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP...... 75 6. INVESTIGATIONAL PLAN ............................................................. 76 6.1 VISIT SCHEDULE ............................................................................................ 76 6.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................ 78 6.2.1 Screening and run-in period(s) .................................................................... 78 6.2.2 Treatment period(s) ...................................................................................... 79 6.2.3 End of trial and follow-up period ................................................................ 83 7. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................................................................................... 85 7.1 7.2 7.3 STATISTICAL DESIGN - MODEL ................................................................ 85 NULL AND ALTERNATIVE HYPOTHESES .............................................. 86 PLANNED ANALYSES .................................................................................... 88 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 16 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 14 of 149 7.3.1 Primary analyses ........................................................................................... 88 7.3.2 Secondary analyses ........................................................................................ 89 7.3.3 Safety analyses ............................................................................................... 90 7.3.4 Interim analyses............................................................................................. 91 7.3.5 Pharmacokinetic analyses ............................................................................. 91 7.3.6 Pharmacodynamic analyses.......................................................................... 91 7.3.7 Pharmacogenetic analyses ............................................................................ 91 7.3.8 Health economic analyses ............................................................................. 91 7.3.9 PASAPQ analysis .......................................................................................... 91 7.4 HANDLING OF MISSING DATA .................................................................. 91 7.5 RANDOMISATION .......................................................................................... 92 7.6 DETERMINATION OF SAMPLE SIZE ........................................................ 93 8. INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS ............................................................................................ 95 8.1 8.2 8.3 8.3.1 8.3.2 8.3.3 8.4 8.4.1 8.4.2 8.5 8.6 8.7 8.8 9. STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT .......................................................................................................... 95 DATA QUALITY ASSURANCE ..................................................................... 97 RECORDS .......................................................................................................... 97 Source documents .......................................................................................... 97 Direct access to source data and documents ............................................... 97 Storage of records .......................................................................................... 98 LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS .............................................................................................................................. 98 Listedness ....................................................................................................... 98 Expedited reporting to health authorities and IECs/IRBs ........................ 98 STATEMENT OF CONFIDENTIALITY ....................................................... 98 COMPLETION OF TRIAL .............................................................................. 99 PROTOCOL VIOLATIONS ............................................................................ 99 COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL RELATED INJURY............................................................................. 99 REFERENCES ................................................................................... 100 9.1 9.2 10. 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 PUBLISHED REFERENCES ......................................................................... 100 UNPUBLISHED REFERENCES ................................................................... 102 APPENDICES .................................................................................... 104 INSTRUCTIONS FOR THE USE OF THE RESPIMAT INHALER ........ 105 INSTRUCTIONS FOR THE USE OF THE MDI ........................................ 111 INSTRUCTIONS FOR RETURN OF MALFUNCTIONING RESPIMAT INHALERS ....................................................................................................... 113 ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA ........ 114 ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S)) ............. 116 ASTHMA CONTROL QUESTIONNAIRE (ACQ) ..................................... 122 EQ-5D HEALTH QUESTIONNAIRE........................................................... 125 PAPER PATIENT DIARY CARD ................................................................. 128 AM3 PATIENT INSTRUCTION CARD ...................................................... 129 DEFINITION ASTHMA EXACERBATION ............................................... 133 CLINICAL LAB PARAMETERS ................................................................. 135 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 17 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 15 of 149 10.12 PHARMACOKINETIC METHODS ............................................................. 136 10.12.1 Planned analyses for pharmacokinetic evaluations ................................. 136 10.12.2 Handling of missing data ............................................................................ 136 10.12.3 Derivation of PK parameters ..................................................................... 137 10.13 PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE .. 140 11. SUMMARY OF CLINICAL TRIAL PROTOCOL MODIFICATIONS ............................................................................ 145 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 18 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 16 of 149 ABBREVIATIONS °C °F µg ACQ ACRN Ae AE Aet1-t2,ss Degree Celsius Ddegree Degree Fahrenheit Microgram Asthma Control Questionnaire Asthma Clinical Research Network Amount of analyte that is eliminated in urine Adverse Event Amount of analyte that is eliminated in urine from the time point t1 to time point t2 (Ae0-2, Ae2-6 at steady state) ALT Alanine aminotransferase am Ante meridiem AM3 Asthma Monitor® 3 ANCOVA Analysis of Variance AQLQ(S) Standardised Asthma Quality of Life Questionnaire AST Aspartate aminotransferase ATS American Thoracic Society AUC Area under the curve Area under the plasma concentration-time curve at steady AUCτ,ss state over a uniform dosing interval τ at steady state AUCt1-t2,ss Area under the concentration time curve of analyte in plasma over the time interval t1 to t2 at steady state AUMCss Area under the first moment curve at steady state b.i.d. Bis in die (twice daily) BAC Benzalkonium chloride BARGE trial Beta-Adrenergic Response by Genotype trial BDI Baseline Dyspnoea Index BI Boehringer Ingelheim BLQ Below the limit of quantification CA Competent Authority CCDS Company Core Data Sheet CFC Chlorofluorocarbon CL/F,ss Apparent clearance of analyte in the plasma after extravascular administration Renal clearance of analyte in plasma from the time point t1 to CLR,t1-t1 time point t2 Cmax [pg/mL] Maximum measured concentration of the analyte in plasma Cmax,ss Maximum measured concentration of analyte in plasma at steady state Cmin,ss Minimum concentration of analyte in plasma at steady state CML Clinical Monitor Local COPD Chronic obstructive pulmonary disease Cpre,ss Predose concentration of analyte in plasma at steady state CRA Clinical Research Assistant/Associate CRO Contract Research Organisation Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 CTMF CTP CTR CVA CZ DNA DPI DSMB ECG eCRF ECSC EDC EDTA EEC EQ-5D ERS ERT EU FAS FDA fet1-t2 FEV1 [L] FVC [L] GCP gCV GINA gMean h HCRU HFA HPLC/MS/MS ICH ICS IEC IgE INN IRB ISF IVRS IWRS kg L LABA LARGE trial 19 Page U12-2466-01 Trial Protocol Clinical Trial Master File Clinical Trial Protocol Clinical Trial Report Cerebrovasculair accident Climate Zone Deoxyribonucleic acid Dry powder inhaler Drug safety monitoring board Electrocardiogram Electronic Case Report Form European Community for Steel and Coal Electronic Data Capture Ethylenediaminetetraacetic acid European Economic Community Quality of life questionnaire developed by EuroQol group European Respiratory Society eResearch Technology European Union Full Analysis Set Food and Drug Administration Fraction of analyte eliminated in urine from time point t1 to time point t2 Forced expiratory volume in one second Forced vital capacity Good Clinical Practice Geometric coefficient of variation Global Initiative for Asthma Geometric mean Hour(s) Health Care Resource Utilization Hydrofluororalkane High Performance Liquid Chromatography/ Mass Spectrometry/Mass Spectrometry International Conference on Harmonisation Inhaled CorticoSteroids Independent Ethics Committee Immunoglobulin E International Non-proprietary Name Institutional review board Investigator Site File Interactive Voice Response System Interactive Web Response System Kilogram Litre(s) Long-acting beta-adrenergic Long-Acting Beta Agonist Response by Genotype trial 5 Dec 2011 Page 17 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 LDH LI LOCF LTRA max MCID MD MDI MedDRA mg min mL MMRM MRTih NA NC nnACh No. NOA NOP NOR NOS OPU PASAPQ PEF(R) [L/sec] PFT pg PK pm pMDI PRN q.d. RA RDC REML ROW SABA SAE SD SGOT SGPT SNP SOMS SOP SPC SUSAR 20 Page U12-2466-01 Trial Protocol Lactate dehydrogenase Lineary Index Last observation carried forward Leukotriene Receptor Antagonist (leukotriene modifier) Maximal Minimum clinically important difference Multiple dose Metered dose inhaler Medical Dictionary for Regulatory Activities Milligram Minimal; minute Millilitre(s) Mixed effect model with repeated measures mean residence time of analyte in the body after inhalation Not applicable Not calculated Non-neuronal acetylcholine Number Not analysed No peak detectable No valid result No sample Operative Unit (of BI) Patient satisfaction and preference questionnaire Peak expiratory flow (rate) Pulmonary function test Picogram Pharmacokinetic(s) Post meridiem Pressurized Metered Dose Inhaler As occasion requires Quaque die (once daily) Accumulation ratio Remote Data Capture (eCRF) Restricted maximum likelihood Rest of World Short-acting beta-adrenergic Serious Adverse Event Standard deviation or single dose Serum glutamic oxaloacetic transaminase Serum glutamic pyruvic transaminase Single nucleotide polymorphisms Summary of Clinical Trial Protocol Modifications Sheet Standard Operating Procedure Summary of product characteristics Suspected Unexpected Serious Adverse Reaction 5 Dec 2011 Page 18 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 T, t [h or min] t.b.d. t½,ss t1/2 TCM TDMAP TinA tmax tmax,ss TNF TSAP ULN USA USPI Vz/F γ-GT 21 Page U12-2466-01 Trial Protocol Time To be determined Terminal half-life of analyte in plasma at steady state Terminal half-life of analyte in plasma Trial Clinical Monitor Trial data management and analysis plan Tiotropium in Asthma Time from dosing to the maximum concentration of the analyte in plasma Time from dosing to the maximum concentration of analyte in plasma at steady state Tumor Necrosis Factor Trial Statistical Analysis Plan Upper Limit of Normal United States of America US prescribing information Apparent volume of distribution of analyte during the terminal phase following an extravascular dose Gamma glutamyltransferase 5 Dec 2011 Page 19 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 22 Page U12-2466-01 Trial Protocol 1. INTRODUCTION 1.1 MEDICAL BACKGROUND 5 Dec 2011 Page 20 of 149 Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular products play a role. The overall worldwide prevalence of asthma is about 5%, affecting 300 million people worldwide with over 60 million affected in the United States and Europe and high variability from country to country. Researchers estimate that an additional 100 to 150 million persons are likely to have asthma by 2025 with the projected increase of world’s urban population from 45% to 59% [P10-03196]. Central to the various phenotypic patterns of asthma is the presence of chronic underlying airway inflammation. The inflammatory cell components involved are variable, but with overlapping patterns that reflect the different phenotypes of the disease, such as intermittent versus persistent or acute versus chronic manifestations.The inflammation causes airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment [P10-03196]. According to the worldwide accepted guidelines of GINA (Global Initiative for Asthma 2009) [P10-03196] asthma is categorised into different severity categories and three levels of asthma control. The severity assessment is based on level of symptoms, airflow limitation, and lung function variability. Asthma severity can be intermittent, or it can be persistently mild, moderate or severe. The classification of asthma by severity is useful for initial assessment of the patient and initial treatment decisions. Due to the variability of asthma severity over time and individual patient’s response to treatment, a periodic assessment of the achieved asthma control is more relevant for ongoing treatment decisions. Asthma control is categorized into three levels based on daytime and nocturnal symptoms, limitations of activities, need for reliever treatment, lung function and exacerbations. Asthma can be controlled, partly controlled or uncontrolled. The aim of any asthma treatment is to achieve and maintain control for prolonged periods, thereby considering the safety of treatment, potential for adverse effects, and the cost of treatment required to achieve this goal. Asthma severity can be classified into so called GINA steps 1 to 5. The severity of asthma determines the treatment to be required. For many patients, medication must be taken everyday to control symptoms, to improve lung function and to prevent exacerbations. Medications are optionally also required to relieve acute symptoms such as wheezing, chest tightness, and cough. The role of long-acting anticholinergics as controller medication remains still to be eludicated in the treatment of asthma but appears to be promising based on preclinical findings and a successful proof-of-concept trial with tiotropium in patients with severe persistent asthma who were not fully controlled despite adequate treatment with at least high-dose ICS and LABAs. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 23 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 21 of 149 In this present study we will investigate if patients with moderate persistent asthma who are not fully controlled despite treatment with medium doses inhaled corticosteroids would benefit from tiotropium. The effects on pulmonary function and patient-reported outcomes of two different doses of tiotropium will be compared to placebo and salmeterol. 1.2 DRUG PROFILE Please refer to the "Investigator’s Brochure" [U92-0551] for the detailed outline of the existing quality, non-clinical and clinical data of tiotropium. Tiotropium is a quaternary ammonium compound developed as a long-acting orally inhaled anticholinergic bronchodilator and approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Two product formulations have been investigated in clinical trials. The first formulation is a single-dose capsule containing 18 µg of tiotropium (equivalent to 22.5 µg of tiotropium bromide monohydrate) formulated in a powder blend with lactose monohydrate. The inhalation powder formulation has been registered in about 100 countries (Spiriva® Handihaler®) and is presently being used in Phase IV clinical studies. The second product is an aqueous solution of tiotropium formulated with the excipients benzalkonium chloride and EDTA (2.5 µg tiotropium per actuation, 2 actuations per dose), which is intended for oral inhalation only via the Respimat® inhaler. The Respimat® inhaler is a novel propellant-free inhaler, which may prove to be an alternative to metered-dose and dry powder inhalers (MDIs and DPIs). The Respimat®inhaler is designed to deliver a single dose of Spiriva® in two actuations. Tiotropium in the Respimat® inhaler has been tested in a set of Phase III clinical studies, has been registered in several countries of the European Union and filed for New Drug Application in the United States of America. The beneficial effect of tiotropium on bronchoconstriction is well established and clinically used for years in the treatment of chronic obstructive pulmonary disease (COPD). The following text describes the pharmacological properties of tiotropium on a molecular level. Investigations on mucus (hyper-) secretion, potential anti-inflammatory effects as well as on anti-remodelling properties of tiotropium are reviewed. Receptor binding In vitro studies with human and animal muscarinic receptor subtypes (M1, M2, and M3) and with human and animal isolated tracheal preparations established tiotropium as a potent, selective and reversible muscarinic receptor antagonist. No other receptor interactions were detected at relevant concentrations. Association and dissociation from muscarinic receptors (M1, M2, and M3) were slow compared to ipratropium. The dissociation half-life of tiotropium-M3-complexes at 23°C was 34.7 hours compared to 0.26 hours for ipratropiumM3-complexes. Tiotropium-M2-complexes and ipratropium-M2-complexes dissociate more rapidly than M3- or M1-receptor-complexes. This pattern suggests a “kinetic receptor subtype selectivity” of occupation and blockade of M3>M1>M2-receptors [U99-1004]. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 24 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 22 of 149 Mucus modifying effects In a model of ovalbumine-induced asthma in guinea pigs [P05-05129] tiotropium prevented goblet cell hyperplasia and reduced the histologically assessed mucus gland area. In particular, the ovalbumine-stimulated increase in mucus gland area was reduced to baseline by inhalative treatment with tiotropium. These effects may positively influence mucus hypersecretion and airway plugging, and may thus improve lung function in asthma patients. Anti-inflammatory properties First in vitro investigations on the inflammatory potential of acetylcholine, the endogenous ligand of muscarinic receptors, were performed by Sato et al. [R05-0813]. Acetylcholine induced the release of neutrophil and monocyte chemotactic activity in bovine airway epithelial cells. Furthermore, acetylcholine stimulated alveolar macrophages to release eosinophil chemotactic mediators [R05-2327]. In a similar trial [P07-12448] acetylcholine stimulated different primary airway cells and cell lines to release inflammatory chemotactic factors. The acetylcholine-induced release of neutrophil chemotactic factors was abolished by tiotropium bromide suggesting an effect mediated by M3 receptors. Anti-inflammatory effects have also been shown for oxitropium bromide, another antimuscarinic, by Profita et al. in sputum cells derived from COPD patients [P05-11064]. In vivo investigations in an asthma model in guinea pigs have shown that eosinophilic inflammation was in part prevented by tiotropium [P07-10315]. Anti-remodeling effects In the above mentioned guinea pig asthma model ovalbumine induced an increase in airway smooth muscle mass measured morphometrically as well as on the alpha smooth muscle myosin heavy chain expression level. This may reflect airway smooth muscle hyperplasia observed in asthma patients. This pathophysiological proliferative effect on airway smooth muscles in guinea pigs was significantly reduced by inhaled tiotropium [P05-05129]. The above mentioned non-bronchodilating effects may contribute to beneficial long-term effects of tiotropium in the treatment of chronic airway diseases, including asthma. Comprehensive information about the development program of tiotropium is provided in the "Investigator´s Brochure" [U92-0551]. Renal impairment Tiotropium is mainly excreted renally. Increased plasma concentrations were described in patients with moderate to severe renal impairment (creatinine clearance ≤ 50mL/min). A dose reduction based on renal dysfunction cannot be recommended. Tiotropium should only be used in patients with moderate to severe renal impairment if the expected benefit outweighs the potential risk. As with all predominantly renally excreted drugs, tiotropium use should be monitored closely in patients with moderate to severe renal impairment. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 25 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 23 of 149 Drug-Drug Interaction Drug interactions of tiotropium with other drugs are unlikely due to the small dose and very low steady state plasma levels of tiotropium and the lack of inhibition of cytochrome P 450 isoenzymes by tiotropium [U97-2651]. The Respimat® Inhaler The Respimat® is a multi-dose inhaler differing from currently marketed dry powder and pressurized metered dose inhalers (pMDIs) by several features, including: (1) relatively slow aerosol delivery (1.5 seconds spray duration) that facilitates a better inhalation coordination for the patient, (2) high fine particle fraction of the spray permitting increased efficiency of drug delivery to the target organ, (3) a delivered dose independent of patient’s inspiratory flow, (4) propellant-free environment-friendly formulation, (5) convenience of a multidose inhaler, and (6) technological advances that enhance the proper use by the patient (e.g. a dose indicator and a locking mechanism that prevent tail-off of dosing after the declared number of doses). Tiotropium inhalation powder/HandiHaler® in Patients with Asthma Four randomized clinical trials have been conducted in patients with asthma using the inhalation powder capsule formulation of tiotropium [U96-0240, U98-3174, U98-3274, U991019]. These trials in the general (and exercise-induced) asthma population have demonstrated that tiotropium provides some degree of bronchodilation in asthmatic patients. Dose-dependency and convincing pharmacodynamic duration of action were not shown. Tiotropium did provide dose-related protection against methacholine induced bronchoconstriction in patients with mild to moderate asthma. The incidence of adverse events was low in all four asthma trials using doses up to 36 µg inhalation powder/HandiHaler® over 21 to 28 days of treatment. The type and rate of events were not different from those seen in the trials with COPD patients, aside from “asthma exacerbation”. The most common events were asthma exacerbation, upper respiratory infection, headache and dry mouth. Tiotropium inhalation solution/Respimat® in Patients with Asthma Three trials have been conducted with Spiriva® Respimat® in patients with asthma: Trial 205.248 [U02-1222]: local tolerability of Spiriva® Respimat® placebo formulation in hypersensitive asthmatic patients Trial 205.248 was a Phase II, single-dose, randomised, double-blind (within-device), fourway crossover trial conducted to evaluate the local tolerability of an acidic solution (pH = 2.7) for inhalation with the Spiriva® Respimat® placebo solution. This trial was conducted in 34 hypersensitive asthmatic patients. No adverse effects were attributed to the acidic solution, which was well tolerated. Neither spirometric parameters nor vital signs were changed by study treatment. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 26 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 24 of 149 Trial 205.341 [U08-2081]: Phase II proof-of-concept, severe persistent asthma This trial was an 8-week randomised, placebo-controlled, double-blind, 3-way crossover comparison of 5 µg and 10 µg Spiriva® Respimat® and placebo Respimat® administered once daily in the morning as add-on therapy in 100 adult asthmatics with maximized controller medication, who were still symptomatic. The primary endpoint of peak FEV1 response showed statistically significant superiority for both doses of Spiriva® Respimat® compared to placebo, with these results supported by the analysis of secondary endpoints. Thus, clinical proof of concept has been demonstrated for the 5 and 10 µg doses of Spiriva® Respimat® as add-on therapy in a population of patients with symptomatic severe persistent asthma. The 5 µg Spiriva® Respimat® administered as once daily in the morning was shown to be well tolerated with a comparable safety profile to placebo. Treatment with 10 µg Spiriva® Respimat® was similarly effective, generally well tolerated with comparable safety profile to placebo too; however, the higher occurrence of dry mouth is interpreted as sensitive indicator of a systemic anticholinergic reaction. Trial 205.342 [U09-1701]: Phase II proof-of-concept, moderate persistent asthma This trial was a 16-week randomised, placebo- and active-controlled, double-blind, doubledummy, parallel-group study comparing the efficacy and safety of Spiriva® Respimat® (5 µg once daily) in the evening with that of salmeterol HFA MDI (2 puffs of 25 µg twice daily) both in addition to maintenance ICS in moderate persistent asthma patients homozygous for arginine at ADRB2. The primary endpoint of this study, the change in mean weekly morning PEF from baseline to the last week of treatment,demonstrated the statistical non-inferiority of 5 µg Spiriva® Respimat® versus salmeterol and its superiority versus placebo. Thus, 5 µg Spiriva® Respimat® was as effective as salmeterol in the treatment of patients homozygous for arginine at the 16th amino acid position of the β2-adrenergic receptor (B16-Arg/Arg) with moderate persistent asthma. Spiriva® Respimat® showed an acceptable safety profile with no marked differences compared to salmeterol or placebo. Relevance of the B16-Arg/Arg genotype for the adrenergic or anticholinergic response The implications of selecting this subgroup of patients by receptor genotype are discussed extensively in the Investigator's Brochure [U92-0551]. Trial 205.342 [U09-1701] investigated the effect of Spiriva® Respimat® in B16-Arg/Arg patients with moderate persistent asthma for whom previously published studies suggested that they might not benefit from a LABA such as salmeterol therapy [P04-11193 and P0907838]. There is currently no evidence or mechanistic rationale to assume that the anticholinergic response is different in asthma patients homozygous for arginine at ADRB2. For this reason, the efficacy profile shown in patients homozygous for B16-arginine is most likely relevant for the general population with moderate persistent asthma. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 27 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 25 of 149 In conclusion: Two BI trials 205.341 [U08-2081] and 205.342 [U09-1701] showed a significant efficacy signal and a favourable safety profile for tiotropium administered via the Respimat® inhaler in moderate or severe persistent asthma in patients adequately treated with ICS according to current treatment guidelines. All trials for tiotropium Respimat® in asthma were and will be conducted only with an appropriate maintenance treatment with an ICS. 1.2.1 Inhalation solution and Respimat® Inhaler Active ingredient solution The tiotropium inhalation solution is aqueous based. The pH value is adjusted to pH 2.9 ± 0.2, near the stability optimum of the active substance. Administration of tiotropium inhalation solution is achieved with the Respimat® inhaler in combination with a drug reservoir/cartridge. The drug is delivered from the Respimat® inhaler as two actuations per dose. As a multi-dose device and solution, the drug formulation contains ethylenediaminetetraacetic acid, disodium salt (EDTA) and the bacteriostatic agent benzalkonium chloride (BAC), which have been reported to induce bronchospasm in some patients inhaling such solutions from a nebulizer. However, the doses of EDTA and BAC administered with two actuations of the Respimat® are well below the amounts for which bronchospasm has been reported with nebulized solutions. Additionally, clinical data for the Respimat® inhaler with a variety of drug substances (including tiotropium) indicates that it is unlikely that patients using the Respimat® inhaler will experience an EDTA or preservativerelated bronchospasm (see Section 6.2.4.4.4 of the tiotropium Investigator's brochure for further information) [U92-0551]. Details of the Respimat® device and the cartridge for active ingredient solution and the instructions for use are found in Appendix 8.2 of the tiotropium Investigator's Brochure [U92-0551] and in this protocol (Section 10.1). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 28 Page U12-2466-01 Trial Protocol 2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT 2.1 RATIONALE FOR PERFORMING THE TRIAL 5 Dec 2011 Page 26 of 149 Airway smooth muscle tone is controlled by sympathetic and parasympathetic influences as well as a range of other mediators. The predominant neural constrictor pathway is cholinergic but its impact depends on the influence of a range of other involved mediators. As consequence, anticholinergics have been explored as anti-obstructive therapies with variable responses in the different obstructive airway diseases. Neuronally released acetylcholine stimulates M3 muscarinic receptors on the airway smooth muscle and mucus glands causing bronchoconstriction and mucus (hyper-) secretion. Classically regarded as a neurotransmitter of the parasympathetic nervous system, acetylcholine is suggested to be also synthesized in many other cell types found in the airways as concluded from the expression of choline acetyl transferase, the enzyme responsible for the acetylcholine synthesis. Acetylcholine produced by these non-neuronal cells is commonly referred to as non-neuronal acetylcholine (nnACh). Additional components of the cholinergic system, in particular muscarinic receptors have been detected in nearly all cell types present in the lungs. Consequently, increasing evidence suggests that non-neuronal acetylcholine may play a role in various pathophysiological processes relevant in the course of chronic airway diseases. Taken together, these effects suggest that tiotropium, an anticholinergic, might have (beside its well characterized bronchodilatory mode of action) additional important characteristics which could be of potential therapeutic benefit for the patient. Preclinical in vivo studies in a guinea pig asthma model revealed that tiotropium attenuates airway inflammation as well as remodelling processes in these models [P05-05129 and P07-10315]. A published Cochrane Database review concluded that “the role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma” [P05-01207]. Anticholinergics are considered as a first-line therapy in COPD and there is a large body of evidence demonstrating its efficacy and safety, whereas, the place of anticholinergics in the treatment of asthma is less well-defined, particularly in patients with not optimally controlled or uncontrolled asthma. Patients with severe persistent asthma who are inadequately controlled despite treatment with a combination of inhaled steroids/long- acting ß2-agonists therapy are a therapeutic challenge with significant unmet medical need. An additional anticholinergic bronchodilator may provide added benefits for these patients. For some patients still symptomatic on maintenance therapy with an ICS alone, treatment with a longacting anticholinergic could be an alternative bronchodilator controller medication instead of a long-acting ß2-agonist. Short-acting anticholinergic agents such as ipratropium bromide, alone or in combination with ß2-agonists, are used in the management of chronic asthma in many countries. They are recognized particularly as alternative bronchodilators for patients who experience adverse effects such as tachycardia, arrhythmia and tremor from rapid-acting ß2-agonists (Global Initiative for Asthma (GINA) (2009) [P10-03196]). A meta-analysis of trials in which nebulized ipratropium bromide was added to a nebulized ß2-agonist [P99-02952] showed that Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 29 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 27 of 149 ipratropium bromide has an additional effect when nebulized together with a rapid-acting ß2agonist for exacerbations of asthma.The anticholinergic not only produced a statistically significant improvement in pulmonary function, but also significantly reduced the risk of hospital admission. According to the results of Beck R, et al. [P86-0614] a beneficial effect of ipratropium inhalation added to the standard care could be shown. Therefore clinical efficacy of inhaled tiotropium as a long acting anticholinergic can be expected. As tiotropium offers a superior time-response profile as a bronchodilator to ipratropium in COPD, tiotropium also likely will be more effective and have sustained antiobstructive effects for 24 hours in asthma. The 24-hour duration of action profile may be of special value in a population suffering from nocturnal events of, e.g., shortness of breath, which is the case in moderate and severe but still not optimally controlled asthma. Two completed phase II proof-of-concept trials (205.341 and 205.342) confirmed clinically relevant effectiveness of the 5 µg dose of tiotropium inhalation solution in patients with severe and moderate persistent asthma. Two identical 1-year phase III trials (205.416 and 205.417) are currently in conduct to confirm the safety and efficacy of 5 µg tiotropium inhalation solution (on top of at least ICS and LABA) in patients with severe persistent asthma. Trials 205.418 and 205.419 will be performed to evaluate the safety and efficacy of 2.5 and 5 µg tiotropium inhalation solution (on top of ICS) in patients with moderate asthma. Comprehensive information about the development program of tiotropium is provided in the "Investigator’s Brochure" [U92-0551]. Refer to Section 4.1.3 for the selection of doses in the trial. Please refer to Section 3.2 for a discussion on the trial design, including the choice of control groups, and to Section 4.1.3 for information on the selection of doses in the trial. 2.2 TRIAL OBJECTIVES This is one of two confirmatory phase III trials with identical protocols (twin trials with BI trial numbers 205.418 and 205.419). The primary objective of each trial is to evaluate the long term (24 weeks) efficacy and safety of two doses (2.5 µg and 5 µg) of tiotropium inhalation solution (administered once daily) compared to placebo and to salmeterol (50 µg; administered twice daily) on top of maintenance therapy with inhaled corticosteroid controller medication in patients with moderate persistent asthma. The comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. A 24 hour PK profile of tiotropium is only available for COPD patients. In this trial PK samples will be collected from 80 patients to confirm this 24 hour profile in asthma patients. A substudy will be done to explore the onset of action of the study medication. The substudy will comprise of 2 additional PFTs (5 and 15 minutes post-dose) at Visit 5 only and will be completed in approximately 480 patients. Refer to Section 5 for the endpoints. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 2.3 30 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 28 of 149 BENEFIT - RISK ASSESSMENT The favourable benefit-risk ratio based on the so far acquired knowledge about inhaled tiotropium is the rationale to conduct further studies with tiotropium in asthma. The incidence of adverse events was low in all four asthma trials using doses up to 36 µg inhalation powder/HandiHaler® over 21 to 28 days of treatment. The type and rate of events were not different from those seen in the trials with COPD patients, aside from “asthma exacerbation”. The most common events were asthma exacerbation, upper respiratory infection, headache and dry mouth. Single doses of placebo inhalation solution/Respimat® were well tolerated, as evaluated in 32 mild asthmatic patients. During a crossover efficacy and safety evaluation trial (205.341) of 8-week treatment periods of two doses (5 and 10 µg ) tiotropium inhalation solution delivered by the Respimat® inhaler as add-on therapy in patients with severe persistent asthma the overall occurrence of adverse events was similar between the placebo and 5 µg tiotropium groups (39.8% and 42.3% of patients, respectively, reported at least one adverse event), but slightly higher in the 10 µg tiotropium group (49.5% of patients reported at least one adverse event). The most common treatment-emergent adverse events were nasopharyngitis and asthma (MedDRA preferred term classification including aggravated asthma and exacerbation of asthma), with both being reported overall by 28 patients (26.2%). The only treatment-emergent adverse event reported in more than one patient was dry mouth, which was considered drug-related in 4 patients (3.9%) only in the 10 µg tiotropium group [U08-2081]. During the double-blind treatment and follow-up period of trial 205.342, mean (standard deviation) duration of double-blind exposure to trial medication was 109.6 (21.3) days (placebo), 110.9 (16.2) days (tiotropium), and 111.8 (16.8) days (salmeterol). During the double-blind treatment and follow-up periods, the overall incidence of AEs was similar in the active treatment and placebo groups: 52 (41.3%) placebo patients; 51 (39.8%) tiotropium patients; 56 (41.8%) salmeterol patients. Few AEs were considered drug-related and the incidences of such AEs were also similar across groups: 4 (3.2%) placebo patients, 6 (4.7%) tiotropium patients, and 3 (2.2%) salmeterol patients. The most common AEs by preferred term were asthma exacerbation (including preferred term asthma) and nasopharyngitis [U091701]. In conclusion, the studies conducted in asthmatic patients provided no evidence of serious adverse effects with suspected causal relationship to tiotropium treatment. The administration of tiotropium can be considered as safe for patients. For detailed information regarding the safety of tiotropium in COPD, please refer to the "Investigator’s Brochure" [U92-0551]. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 31 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 29 of 149 3. DESCRIPTION OF DESIGN AND TRIAL POPULATION 3.1 OVERALL TRIAL DESIGN AND PLAN This is a randomised, double-blind, double-dummy, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of 2.5 and 5 µg of tiotropium inhalation solution delivered by the Respimat® inhaler (once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in moderate persistent asthma patients treated with medium doses of inhaled corticosteroids. After signing informed consent and an initial screening visit, patients will enter a 28-day screening period. Patients who meet all inclusion and none of the exclusion criteria will be randomised into the 24-week treatment period in which they will receive either 2.5 µg tiotropium (2 puffs of 1.25 µg) once daily, 5 µg tiotropium (2 puffs of 2.5 µg) once daily, 50 µg salmeterol (2 puffs of 25 µg) twice daily or placebo in a double-dummy fashion. Patients will be evaluated for an additional 21 days following completion of the randomised treatment period. Visit 0 and Visit 7 may be conducted during business hours. Visit 1 to Visit 6 will always start in the evening. Patients who withdraw prematurely from the randomised treatment period will be followed up regarding their vital status. They will be contacted at their predicted normal exit date from the trial, i.e. completion of the 24 week treatment period plus 21 days follow-up period. Pulmonary function testing will be conducted at the screening visit (Visit 1) and vital signs will be measured in conjunction with pulmonary function tests until three hours post-dosing at all visits (except at Visits 2A, 2B and 2C) during the randomised treatment period. Asthma exacerbations according to protocol-specific definition (see Appendix 10.10) will be documented together with additional observations including utilisation of healthcare resources, adverse events and concomitant therapies. Three paper-based questionnaires (ACQ, AQLQ (S) and EQ-5D) will be patient self-administered during the treatment period. In selected countries a fourth questionaire (PASAPQ) will be patient self-administered at V6. The ACQ will also be self-administered at Visit 1. The ACQ mean score at Visit 1 and Visit 2 will be used to determine the patient's eligibility. The patient will record morning and evening PEF and FEV1 and use an electronic diary throughout the screening and treatment period. Physical examination will be performed together with an evaluation of the patient's smoking status and asthma background characteristics at Visit 1. Blood samples for clinical laboratory testing will be obtained and a 12-lead ECG will be recorded at Visit 1 to evaluate the patient's eligibility. Urine pregnancy testing will be done at Visit 1 in females of childbearing potential. The physical examination, laboratory testing, pregnancy testing, ECG and evaluation of the patient's smoking status will be repeated on completion of patient's participation in the randomised treatment period of the trial. Analysis of clinical laboratory samples will be performed by the local laboratory of each site. Depending on patient's informed consent, a blood sample for pharmacogenetics will be drawn at Visit 2 (or any subsequent visit) from all randomised patients that received at least one dose of trial medication. If a patient signed an informed consent for participation in the PK substudy, blood samples for pharmacokinetic evaluation will be drawn over 24 hours at Visits Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 32 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 30 of 149 2 and 3 and pre- and post-dose at Visit 2A, 2B and 2C (in a subset of patients at selected sites). Pulmonary function testing over 24 hours will be performed at Visit 6 in a subset of patients at sites capable of performing 24 hour measurements. Adverse events will be documented throughout the trial, i.e. starting with informed consent and ending 21 days after last administration of trial medication. All trial relevant documentation will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). Trial relevant documentation for the trial sites will be filed in the Investigator Site File (ISF) at the investigator sites. 3.1.1 Administrative structure of the trial Sponsor: Clinical trial drug supplies including trial, training and rescue medication will be provided by the sponsor. Co-ordinating Investigator: The co-ordinating investigator was selected by the sponsor. He will review the trial protocol, any subsequent amendments to the protocol and the (draft) Clinical Trial Report (CTR). He will provide his signature on the final protocol signature page and amendments and will provide his signature on the (draft) Clinical Trial Report (CTR) indicating that, to the best of Co-ordinator’s knowledge, the final CTR accurately describes the conduct and results of the Trial. Targeted group of Investigators: Pulmonologists/qualified sites with access to the requested patient population. The following local facilities/equipment are required at the investigational site: clinical laboratory, ECG, scale and sphygmomanometer. The sites have to be able to perform the 3 hour PFT measurements in the evening. Selected sites have to be able to perform the (24 hour) PK and/or 24 hour PFT measurements. DSMB: A DSMB will not be implemented on trial level, but might be implemented on project level. If so, safety review meetings will be held as per separate DSMB charter Central laboratory: The sample transport logistics (from site to sponsor) for PK and pharmacogenetic samples will be the responsibility of the central lab. The central lab will provide sampling and shipment materials. IVRS: An interactive voice response system (IVRS) will be used for randomisation to a treatment group in this trial and for appropriate re-supply of medication to patients. The ability to unblind will be available to the investigator via the IVRS. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 33 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 31 of 149 CROs: A CRO will provide MasterScope® CT and AM3® devices for the complete duration of the trial. All contracts and relevant meeting minutes will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S) The trial design has been selected to allow comparison of the effects on pulmonary function and patient-reported outcomes of different doses of tiotropium to placebo and salmeterol in patients with moderate persistent asthma that is not fully controlled although the patients are treated with medium doses inhaled corticosteroids. The selection of evening administration in this patient subgroup was mainly to consider nocturnal control of airway patency. In trials 205.341 [U08-2081] and 205.342 [U09-1701] no untoward events happened to patients treated with placebo and the overall incidence of AEs and the incidence of asthma exacerbations were similar in active treatment and placebo arms. Based on these data, a 'placebo' (i.e. no second controller medication) treatment group in this trial could be considered safe, because all patients are at least on a maintenance treatment with a stable dose of an anti-inflammatory medication (inhaled corticosteroid). Moreover, all patients will be provided with so-called rescue medication (open-label salbutamol (albuterol) HFA MDI). Boehringer Ingelheim intends to conduct a Phase 3 program that will fulfil global registration requirements. According to EU regulations, inclusion of an active comparator treatment arm is required. BI decided to use Serevent® HFA MDI as approved and commercially available in the EU as the active comparator. Washout requirements prior to pulmonary function testing and other medication restrictions (see Section 4.2.2) are given to reduce possible influences on pulmonary function testing and ensure patient's safety during the trial. The permitted concomitant asthma medication (see Section 4.2) should be kept stable during the complete trial period with the exception of acute treatment of asthma exacerbations. The data collected in a controlled, double-blind, randomised and placebo-controlled trial will provide useful information to health care providers and patients regarding the efficacy and safety of 2 doses of tiotropium inhalation solution delivered by the Respimat® inhaler added to inhaled corticosteroids in the treatment of not fully controlled moderate asthma in comparison to placebo and salmeterol. 3.3 SELECTION OF TRIAL POPULATION A sufficient number of patients of either sex with a diagnosis of moderate persistent asthma will be enrolled in the study to ensure approximately 1000 adult patients are entered (randomised) in the trial. Additional sites may be initiated and 'non-productive' sites may be closed to ensure sponsor's timelines. Randomisation will end when the trial clinical monitor has determined that enough patients are evaluable. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 34 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 32 of 149 Participation in the PK part of the trial is optional and not a prerequisite for patients to participate in the trial. Several sites capable of performing 24 hour PK sampling will be selected to participate in the PK part of the trial. All participating patients at these sites will be asked to consent to the PK visits until at least 80 patients have completed the PK substudy. Participation in the 24 hour PFT visit (at Visit 6) is optional and not a prerequisite for patients to participate in the trial. All sites capable of performing 24 hour PFT measurements will be selected to perform the 24 hour PFT visit. All participating patients at these sites will be asked to consent to the 24 hour PFT visit. The number of patients participating in the 24 hour PFT measurements is not limited. Several sites will be selected to perform a PFT at 5 and 15 minutes post-dose at Visit 5. A total of approximately 480 patients will be asked to participate (120 patients in each treatment arm). The Patient satisfaction and preference questionnaire (PASAPQ) will be patient selfadministered in selected countries at Visit 6. Every effort should be made to keep patients in the trial until they complete all trial procedures. Patients who discontinue after randomisation may not be re-enrolled at a later date. A record will be kept of all patients who fail to complete all trial visits and their reason for discontinuation. A log of all patients included into the study (i.e. having given informed consent) will be maintained in the ISF at the investigational site irrespective of whether they have been treated with investigational drug or not. 3.3.1 Main diagnosis for study entry Outpatients with a history of asthma and a current diagnosis of moderate persistent asthma (according to GINA guideline) and who are symptomatic (partly controlled) despite their current maintenance treatment with at least a medium dose of inhaled corticosteroids are eligible for inclusion if they fulfil all the inclusion criteria (Section 3.3.2) and none of the exclusion criteria (Section 3.3.3). 3.3.2 Inclusion criteria 1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1). 2. Male or female patients aged at least 18 years but not more than 75 years. 3. All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5. 4. The initial diagnosis of asthma must have been made before the patient's age of 40. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 35 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 33 of 149 If the patient is > 40 years and the diagnosis has not yet been recorded in the patient's medical files, the investigator should assess whether the patient's medical history (e.g. symptoms and prescribed medications) confirms the patient suffered from asthma since before the age of 40. If so, this patient may be considered for inclusion after consultation with the Clinical Monitor Local (CML). 5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 to 30 minutes after 400 µg salbutamol (albuterol)) resulting in a FEV1 increase of ≥ 12% and ≥ 200mL (see Appendix 10.4). NOTE: If this criterion is not met, the reversibility test may (in combination with the ACQ) be repeated once within two weeks (see Section 6.1). 6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (see Appendix 10.4) (alone or in a fixed combination with a LABA or SABA) for at least for 4 weeks prior to Visit 1. 7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ (see Appendix 10.6) mean score of ≥ 1.5. NOTE: If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). 8. All patients must have a pre-bronchodilator FEV1 ≥ 60% and ≤ 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to ECSC [R94-1408] (see Appendix 10.4). 9. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30% (see Appendix 10.4 for calculation). NOTE: If this criterion is not met, the patient’s Visit 2 may be repeated once within two weeks (see Section 6.1). 10. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years (see Appendix 10.4 for calculation). 11. Patients must be able to use the Respimat® inhaler (Appendix 10.1) and metered dose inhaler (Appendix 10.2) correctly. 12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter (diary compliance of at least 80% is required; refer to Section 6.1 for instructions). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 3.3.3 36 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 34 of 149 Exclusion criteria 1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial. 2. Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion 1. 3. Patients with a recent history (i.e. six months or less) of myocardial infarction. 4. Patients who have been hospitalised for cardiac failure during the past year. 5. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. 6. Patients with lung diseases other than asthma (e.g. COPD). 7. Patients with known active tuberculosis. 8. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed. 9. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1. 10. Patients with significant alcohol or drug abuse within the past two years. 11. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening). 12. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA, salmeterol xinafoate or any other components of the study medication delivery systems. 13. Pregnant or nursing woman. 14. Women of childbearing potential not using a highly effective method of birth control. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner. Barrier methods of contraception are accepted if condom or occlusive cap are used together with spermicides (e.g. foam, gel). Female patients will be considered to be of childbearing potential unless surgically sterilised by Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 37 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 35 of 149 hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years. 15. Patients who have taken an investigational drug within four weeks prior to Visit 1. 16. Patients who have been treated with beta-blocker medication - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed. 17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 18. Patients who have been treated with oral or patch beta-adrenergics - within four weeks prior to Visit 1 and/or - during the Screening period (period between Visit 1 and Visit 2) 19. Patients who have been treated with oral corticosteroids - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 20. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), - within 6 months prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 21. Patients who have been treated with cromone - within two weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors - within two weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 23. Patients who have been treated with other non-approved and according to international guidelines not recommended ’experimental’ drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 24. Patients with any asthma exacerbation or any respiratory tract infection - in the four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 to Visit 2). Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection. Refer to Section 6.1 for information on re-scheduling of visits. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 38 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 36 of 149 25. Patients who have previously been randomised in this trial or in the respective twin trial (205.419) or are currently participating in another trial. Precautionary statement Tiotropium As an anticholinergic drug, tiotropium may potentially worsen symptoms and signs associated with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction and should be used with caution in patients with any of these conditions. As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min) treated with tiotropium should be monitored closely. Salmeterol Salmeterol should be administered with caution in patients predisposed to low levels of serum potassium, patients with thyrotoxicosis or pre-existing cardiovascular disease, or patients with a history of diabetes mellitus. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A4 inhibitors (e.g. ketoconazole, atazanavir, ritonavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir) is not recommended. Both non-selective and selective beta-blockers should be avoided, unless there are compelling reasons for their use. 3.3.4 Removal of patients from therapy or assessments 3.3.4.1 Removal of individual patients An individual patient is to be withdrawn from the trial if any of the following criteria apply: • • • • The patient withdraws consent, without the need to justify the decision. The patient is no longer able to participate for medical reasons (e.g. pregnancy, surgery, adverse events, or other diseases). Administrative reasons (protocol violations, persistent non-compliance). Decision by Boehringer Ingelheim to discontinue a specific patient (e.g. in case of SAEs). No patient should be discontinued from the trial for a protocol violation before discussion with the clinical monitor. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 39 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 37 of 149 Withdrawal from the trial of an individual patient may be considered if any of the following criteria apply: • • • • • Intercurrent illness or an adverse event, which requires discontinuation of treatment per protocol. Investigators should check carefully if this applies for patients who experience any of the following criteria: More than 3 courses of systemic corticosteroids are required to treat asthma exacerbations. Twelve or more puffs of rescue medication (salbutamol/albuterol MDI) per day are used for more than 2 consecutive days (use of 12 or more puffs of rescue medication for at least 2 consecutive days will be alerted by the AM3®) A drop of patient’s pre-bronchodilator FEV1 (clinic assessment) below 40% predicted. A decrease of patient's best morning PEF of ≥ 40% from the patient's mean morning PEF for more than 2 consecutive days (a decrease of ≥30% for at least 2 consecutive days will be alerted by the AM3®). During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. Data of patients who discontinue or withdraw prior to randomisation will be entered in the trial database and will be listed. Data of patients who discontinue or withdraw after randomisation must be documented and the reason for withdrawal must be recorded in the eCRF. The data must be included in the trial database and must be reported. Refer to Section 6.2.3 for procedures to be followed for patients prematurely terminating the trial. Pregnancy If a patient becomes pregnant during the trial the investigational product needs to be stopped and the patient should be followed up until birth or otherwise termination of the pregnancy. The data of the patient will be collected and reported in the clinical trial report until patients last visit and any events thereafter will be reported in the BI drug safety database. Refer to Section 5.2.2.2 for detailed information on event reporting in case of pregnancy. 3.3.4.2 Discontinuation of the trial by the sponsor Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial site at any time for the following reasons: • • Failure to meet expected enrolment goals overall or at a particular trial site. Emergence of any efficacy/safety information that could significantly affect continuation of the trial. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • 40 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 38 of 149 Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the appropriate conduct of the trial. The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of trial termination (except in case of the third reason). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 41 Page U12-2466-01 Trial Protocol 4. TREATMENTS 4.1 TREATMENTS TO BE ADMINISTERED 5 Dec 2011 Page 39 of 149 Patients will be randomized 1:1:1:1 to 2.5 µg tiotropium inhalation solution, or 5 µg tiotropium inhalation solution, or salmeterol HFA-MDI, or placebo over the 24-week treatment period. The double-blind, double-dummy design of the study is realized by the use of matching placebos. During the treatment period the patients inhale two puffs from the MDI (salmeterol or placebo) every morning and every evening. In addition, the patients inhale two puffs from the Respimat® inhaler (tiotropium or placebo) every evening. Patients randomised to 2.5 µg tiotropium (treatment A) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations of tiotropium from the 1.25 µg Respimat® inhaler. Patients randomised to 5 µg tiotropium (treatment B) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations of tiotropium from the 2.5 µg Respimat® inhaler. Patients randomised to salmeterol (treatment C) inhale the following medication In the morning: two actuations of 25 µg salmeterol from the salmeterol MDI, In the evening: two actuations of 25 µg salmeterol from the salmeterol MDI followed by two actuations from the placebo Respimat® inhaler. Patients randomised to placebo (treatment D) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations from the placebo Respimat® inhaler. Boehringer Ingelheim Pharma GmbH & Co. KG will supply the investigational product. 4.1.1 Identity of BI investigational product and comparator product(s) Investigational product - 2.5 µg tiotropium bromide Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Tiotropium bromide Inhalation solution 2.5 µg (1.25 µg per actuation) delivered dose ex mouthpiece Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 42 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 40 of 149 Investigational product - 5 µg tiotropium bromide Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Tiotropium bromide Inhalation solution 5 µg (2.5 µg per actuation) delivered dose ex mouthpiece Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Comparator - 50 µg salmeterol xinafoate Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Salmeterol xinafoate Hydrofluoroalkane (HFA 134a) metered dose inhaler 50 µg (25 µg per actuation) Pressurised metered dose inhaler 2 actuations of 25 µg twice daily (in the morning and the evening) Oral inhalation Placebo - inhalation solution Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Placebo Inhalation solution NA Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Placebo - metered dose inhaler Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Placebo Metered dose inhaler NA Pressurised meter dose inhaler 2 actuations twice daily (in the morning and the evening) Oral inhalation Instructions for use of the Respimat® and metered dose inhaler are provided in Appendix 10.1 and Appendix 10.2 respectively. 4.1.2 Method of assigning patients to treatment groups When a patient is qualified for entry into the randomised treatment period, treatment assignment will be by means of a third-party phone/web-based randomisation on Visit 2. This Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 43 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 41 of 149 will involve the use of an Interactive Voice Response System (IVRS/Interactive Web Response system, IWRS). To facilitate the use of IVRS, the investigator will receive an IVRS/IWRS worksheet for each patient with the complete IVRS/IWRS dialogue and all necessary instructions for using the IVRS/IWRS. Upon signing informed consent, patients will be assigned a unique patient number. At each visit (Visit 2 - 5), the IVRS/IWRS will assign medication numbers to each patient. Refer to Section 4.1.6 for details on packaging and labelling, Details on the IVRS/IWRS system are provided in the ISF. 4.1.3 Selection of doses in the trial Two completed Phase 2 proof-of-concept trials (205.341 and 205.342) provide evidence that the 5 µg dose of Spiriva® Respimat® is effective in severe persistent asthma on top of ICSLABA and provide clinically effective bronchodilation in patients with severe and moderate persistent asthma. Trial 205.341 also evaluated the 10 µg dose and established the therapeutic plateau for the higher dosing level. The lower dose of 2.5 µg has been added to the Phase III trials in moderate persistent asthma (205.418 and 205.419) to assess whether a lower dose may still offer sufficient response. The selection of evening administration in this patient subgroup was mainly to consider nocturnal control of airway patency. 4.1.4 Drug assignment and administration of doses for each patient Dispensing of trial medication Patients will be randomised at Visit 2 to one of the four treatment groups. Trial medication will be dispensed to the patient by the investigator/pharmacist at Visits 2 to 5. The amount of trial medication dispensed will be recorded on the drug accountability forms. Priming of the Respimat® inhaler Each newly assembled Respimat® inhaler has to be primed. The inhaler should be primed by actuating it until an aerosol is visible plus three additional actuations. All priming actuations should be directed to the ground. Priming should NOT take place in the same room where the patient is inhaling trial medication nor where samples for PK analyses are drawn or processed (to avoid undue contamination of the environment). Once assembled, the shelf-life of the Respimat® is 3 months (study medication and training devices). Therefore it is important to ALWAYS enter the date of first priming on the medication label of the Respimat® immediately after first priming. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 44 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 42 of 149 Testing of the MDI Before using for the first time, four actuations should be released into the air to make sure the device is working properly. This testing should NOT take place in the same room where the patient is inhaling trial medication (to avoid undue contamination of the environment). Instructing the patient Detailed instructions and training for the use of the Respimat® inhaler and MDI will be given to the patient at Visits 1 and 2 (see Appendix 10.1 and 10.2). Patients should NOT inhale from a training device on Visit 2. At all subsequent visits (Visit 3, 4, 5 and 6) the investigator or qualified study personnel will observe the inhalation procedure and will reinforce a correct inhalation technique. Patients will be instructed to contact the site should they need to use their reserve inhaler and the site will document this. Patients will be instructed at each visit to retain and return all used and unused medication and devices at the subsequent visit. If the patient forgot to take the evening dose of patient’s own ICS, LTRA (if applicable) and trial medication within the specified time window, the patient is allowed to administer the evening dose until 12:00 am (midnight). After 12:00 am the patient should skip the evening dose and take the next dose at the next scheduled time. The evening dose on the day before the clinic visit should be taken at the specified time window to avoid influence on the data collected on the clinic visit day. If the patient took the evening dose after 08:00 pm on the day before the clinic visit, the clinic visit should be re-scheduled. If the patient forgot to take the morning dose of patient’s own ICS, LTRA (if applicable) and trial medication (MDI only) within the specified time window, the patient is allowed to administer the morning dose until 12:00 pm (noon). After 12:00 pm the patient should skip the morning dose and take the next dose at the next scheduled time. The morning dose on the day of the clinic visit should be taken at the specified time to avoid influence on the data collected on the clinic visit day. If the patient took the morning dose (at home) after 08:00 am on the day of the clinic visit, the clinic visit should be re-scheduled. Trial medication administration at clinic visits Patients will be instructed to withhold their evening dose of study medication and the evening dose of their usual ICS (if regular posology) and their leukotriene modifier (LTRA) (if applicable) on the day of clinic visits. The administration of the evening doses of ICS, LTRA (if applicable) and trial medication should be done in the clinic only after the pre-dose procedures (which include AM3 PEF/FEV1 measurement and eDiary, questionnaires, vital signs and pulmonary function test, and PK if applicable). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 45 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 43 of 149 At each clinic visit during the treatment period medication administration will be conducted in a fixed sequence (1. ICS (if regular posology) and LTRA (if applicable), 2. from MDI, 3. from Respimat®). Patient’s ICS should be administered without change in posology (bid/qd; am/pm), i.e. as previously prescribed by patient’s treating physician. Study medication must be inhaled within 5 minutes after the inhalation of the patient's own ICS medication and the patient should inhale from the Respimat® immediately after inhaling from the MDI. The patient should be in a seated position under the direct supervision of the investigator or his/her delegate. Trial medication will be administered in the evening between 06.00 - 08.00 pm and within ± 30 minutes of time of administration at Visit 2 at all visits during the treatment period: 1. Patient will inhale own ICS (if patient usually administrates in the evening) and take their LTRA (if applicable) 2. Patient will inhale 2 actuations of the trial medication from the assigned MDI 3. Patient will inhale 2 actuations of the trial medication from the assigned Respimat® inhaler On the 24 hour visits (PK and PFT), trial medication (MDI only) will also be adminstered on the following morning between 06.00 - 08.00 am and this should be 12 hours (± 5 minutes) after the time of pm administration the previous evening: 1. Patient will inhale own ICS (if patient usually administrates in the morning) and take their LTRA (if applicable) 2. Patient will inhale 2 actuations of the trial medication from the assigned MDI On all clinic visits the start time of the first inhalation and end time of the second inhalation from the Respimat® will be captured with the MasterScope® CT spirometer provided by Boehringer Ingelheim, except on PK Visits 2A, 2B and 2C where no pulmonary function testing is planned. On Visits 2A, 2B and 2C both, the start and end time of the inhalation from the Respimat® will be recorded on the eCRF. For patients participating in the PK measurements, on Visits 2, 2A, 2B, 2C and 3, the end time of the evening administration from the Respimat® device on the evening preceeding the visit will be recorded on the eCRF. A PK Visit Card will be provided to the patients to record the end time of inhalation at home. On 24 hour PFT visit days the start time of the first inhalation and end time of the second (inclinic) inhalation from the MDI in the morning of the visit will also be captured with the MasterScope® CT spirometer. Trial medication administration at home Patients will self-administer the morning and evening doses of trial medication between clinic visits and will record the administration of each dose of trial medication in the electronic diary. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 46 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 44 of 149 The evening dose of patient's own ICS, LTRA (if applicable) and trial medication should be administered within ± 30 minutes of the time of evening administration at Visit 2 and between 06.00 and 08.00 pm. The morning dose of patient's own ICS, LTRA (if applicable) and trial medication (MDI only) should be administered 12 hours (± 30 minutes) after the time of pm administration and between 06.00 - 08.00 am. Medication must be taken immediately after the eDiary questions have been answered and the PEF measurements have been performed. Respimat® and MDI Inhaler Return Patients should return all dispensed trial medication (including reserve and rescue medication) to the clinic at all visits. Study medication dispensed at Visit 2, will be used for the trial medication administration at Visit 2 and will be returned at Visit 3. Study medication dispensed at Visit 3, will be used for the trial medication administration at Visit 3 and will be returned at Visit 4. Study medication dispensed at Visit 4, will be used for the trial medication administration at Visit 4 and will be returned at Visit 5. Study medication dispensed at Visit 5, will be used for the trial medication administration at Visit 5 and at Visit 6 and will be returned at Visit 6. No study medication will be dispensed at Visit 6. Any Respimat® inhaler that has been reported as malfunctioning by a patient or investigator will be returned to the Department of Drug Delivery, Boehringer Ingelheim Pharma GmbH & Co. KG (Germany), for investigation. A detail of the procedure for the return of used inhalers is provided in Appendix 10.3. See Section 4.1.8 for details regarding drug accountability requirements. 4.1.5 Blinding and procedures for unblinding 4.1.5.1 Blinding Patients, investigators and everyone involved in analysing or with an interest in this doubleblind study will remain blinded with regard to the randomised treatment assignments until after database lock. Boehringer Ingelheim will generate the randomisation schedule, and prepare and code the medication in a blinded fashion. Trial supplies will be assigned to the patients via IVRS. The randomisation codes will be provided to bioanalytics prior to database lock to allow them to exclude PK samples taken from placebo and salmeterol patients from the bioanalytical Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 47 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 45 of 149 analyses. Bioanalytics will not disclose the randomisation code or the results of their measurements until the study is officially unblinded. Refer to Section 4.1.5.2 for rules of breaking the code for an individual or for all patients in emergency situations. 4.1.5.2 Procedures for emergency unblinding The ability to unblind will be available to the investigator via the IVRS. Unblinding must only be used in emergency situations when the identity of the study drug must be known by the investigator to provide appropriate medical treatment. Each site receives a manual from the IVRS provider that contains instructions on how to unblind the treatment of a patient via the IVRS (via 24-hour Emergency helpline). If possible, the Clinical Monitor Local (CML) and Trial Clinical Monitor (TCM) must be contacted prior to the site unblinding a patient's treatment. Patients unblinded to treatment will be withdrawn from the trial. 4.1.6 Packaging, labelling, and re-supply All study medication will be contained in individual patient treatment boxes identified with the trial number and a medication number. The boxes will have a two-part tear-off label. One part of each tear-off label will remain on the box, and the other part will be attached to a special drug dispensing log which will be part of the ISF. Examples of the labels are provided in the ISF. The investigator or designee should fill out the following information on the medication label prior to dispensing the medication to the patient: • • investigator's name (should be entered at time of dispense) date of first priming (Respimat® only; should be entered at time of first priming) For details of packaging and the description of the label, refer to the ISF. Respimat® treatment box The 1-month Respimat® treatment box will contain one Respimat® inhaler plus one drugfilled cartridge. The 1-month treatment box will contain sufficient medication for 30 days of treatment. The 2-month Respimat® treatment box will contain two Respimat® inhalers plus two drugfilled cartridges. The 2-month treatment box will contain sufficient medication for 60 days of treatment. The Respimat® inhaler will lock after 60 actuations have been administered and will no longer actuate any medication. Each Respimat® device and treatment box label will be identified by a moon indicating evening administration. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 48 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 46 of 149 MDI treatment box The 1-month MDI treatment box will contain one MDI. The 1-month treatment box will contain sufficient medication for 30 days of treatment. The 2-month MDI treatment box will contain two MDIs. The 2-month treatment box will contain sufficient medication for 60 days of treatment. Each MDI device and treatment box label will be identified by a sun and a moon indicating morning and evening administration. Medication dispensing The allocation of treatment boxes dispensed at each visit will be handled by an IVRS/IWRS system. At Visit 2, patients will be dispensed a 2-month Respimat® treatment box and a 2-month MDI treatment box. One Respimat® and one MDI (labeled with R1 and M1 respectively) will contain a sufficient amount of study medication to last the patient until Visit 3. The second Respimat® and the second MDI (labeled with R2 and M2 respectively) are reserve medication. This is to allow the patient the flexibility of not having to return to the clinic immediately to replace a lost Respimat® inhaler or MDI. The reserve Respimat® and drugfilled cartridge should NOT be assembled prior to leaving the clinic. The patient must assemble and prime the reserve device at home if needed. At Visits 3, patients will be dispensed a 1-month Respimat® treatment box and a 1-month MDI treatment box which will contain a sufficient amount of study medication to last the patient until the next clinic visit. At Visits 4 and 5, patients will be dispensed a 2-month Respimat® treatment box and a 2month MDI treatment box which will contain a sufficient amount of study medication to last the patient until the next clinic visit. The second Respimat® and drug-filled cartridge in the Respimat® treatment box should NOT be assembled prior to leaving the clinic. The patient must assemble and prime this device at home after the first cartridge is emptied. Additional 1-month Respimat® and additional 1-month MDI treatment boxes are available at the investigational site for issuing on an as needed basis. Patients should always have a reserve Respimat® (plus drug-filled cartridge) and a reserve MDI in their possession. At each visit, site staff should assess whether the reserve medication can be re-dispensed to the patient (considering remaining puffs and shelf-life) or if dispense of a new (replacement) reserve Respimat® inhaler plus drug-filled cartridge and/or MDI is needed. New reserve Respimats® and drug-filled cartridges should NOT be assembled prior to leaving the clinic. The patient must assemble and prime the reserve device at home if needed. Allocation of new reserve medication boxes will be handled by the IVRS/IWRS system. Re-supply One or more re-supplies are currently planned for this trial. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 49 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 47 of 149 Open-label supplies Boehringer Ingelheim will provide the following open-label supplies: • • 4.1.7 Respimat® inhalers, placebo cartridges and disposable mouthpieces for training purposes. A training device may be used for more than one training session. The training Respimat® can be used until 3 months after priming or until the device is empty. The date of first priming should be entered on the medication label of the Respimat®. A new mouthpiece should be used for each patient. Salbutamol (albuterol) HFA MDI inhalation aerosol (100 µg per actuation) for use as rescue medication during screening, treatment and follow-up periods (Visit 0 to V7). It will also be used for reversibility testing at Visit 1. Salbutamol (albuterol) will be dispensed to the patient at clinic visits as needed. Storage conditions All clinical trial supplies must be stored in a locked, secure cabinet and must be kept in their original packaging under the recommended storage conditions and may only be dispensed to trial subjects according to protocol. A temperature log must be maintained at the site. If the storage conditions are found to be outside the specified range, immediately contact the local clinical monitor. Further details are provided in the IB and on the country-specific labels, a sample of which will be part of the ISF. 4.1.8 Drug accountability Drug supplies, which will be provided by the sponsor, must be kept in a secure, limited access storage area under the storage conditions defined by the sponsor. A temperature log must be maintained to make certain that the drug supplies are stored at the correct temperature. The investigator / pharmacist / investigational drug storage manager will receive the investigational drugs delivered by the sponsor when the following requirements are fulfilled: • approval of the study protocol by the IRB / ethics committee, • availability of a signed and dated clinical trial contract between the sponsor and the Head of Trial Centre, • approval/notification of the regulatory authority, e.g. competent authority, • availability of the curriculum vitae of the principal investigator, • availability of a signed and dated clinical trial protocol or immediately imminent signing of the clinical trial protocol, • if applicable, availability of the proof of a medical licence for the principal investigator, • for USA only: availability of the Form 1572. The investigator / pharmacist / investigational drug storage manager must maintain records of the product’s delivery to the trial site, the inventory at the site, the use by each patient, and Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 50 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 48 of 149 the return to the sponsor or alternative disposition of unused product(s). Any discrepancies in drug supplies will be noted and explained. These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and the unique code numbers assigned to the investigational product(s) and trial patients. The investigator / pharmacist / investigational drug storage manager will maintain records that document adequately that the patients were provided the doses specified by the CTP and reconcile all investigational product(s) received from the sponsor. At the time of return to the sponsor, the investigator / pharmacist / investigational drug storage manager must verify that all unused or partially used drug supplies have been returned by the clinical trial patient and that no remaining supplies are in the investigator’s possession. For non-investigational medicinal products (salbutamol/albuterol) specific drug accountability requirements need to be fulfilled. Refer to Section 4.2.1.1 for details. ADDITIONAL INFORMATION FOR JAPAN ONLY The investigator / pharmacist / investigational drug storage manager should return the unused and collected investigational drugs (including empty boxes) to the sponsor (OPU) after unblinding the trial. In case investigational drugs are returned before unblinding of the trial, the investigator / pharmacist / investigational drug storage manager should seal the opened box (excluding empty boxes) for the patient, and before returning the unused and collected investigational drugs (including empty boxes) to the sponsor. When returning the investigational drugs, the investigator / pharmacist / investigational drug storage manager should exercise utmost caution to assure that the sponsor and other relevant trial staff members remain blinded to the patient's name on the package (box or label) of the investigational drugs. Upon completion of the trial, the investigator / pharmacist / investigational drug storage manager submits to the sponsor a copy of the investigational drug dispensing and return log. When submitting the copy, the investigator / pharmacist / investigational drug storage manager should exercise caution to assure that the sponsor and other relevant trial staff members remain blinded to the patient's name. 4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT The investigator must record all medication used by the patient in the three months prior to Visit 1 and throughout the trial on the Concomitant Therapy electronic case report form (eCRF). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 51 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 49 of 149 4.2.1 Rescue medication, emergency procedures, and additional treatment(s) 4.2.1.1 Rescue medication Administration of rescue medication is allowed at any point during the trial. Open-label salbutamol (albuterol) HFA MDI (100 µg per puff) will be provided as rescue medication (non-investigational medicinal product). During the complete trial period including screening, treatment and follow-up period, only salbutamol (albuterol) MDI provided by BI is allowed for PRN rescue medication use. Formoterol, alone or in fixed combinations with an ICS such as Symbicort® (budesonide and formoterol), is not allowed as rescue medication in this trial. During the screening and treatment period, patients must record the number of inhalations (puffs) of rescue medication used during the daytime and the nighttime in their electronic diary. If rescue medication is administered during a 3 or 24h PFT visit day, the visit will be discontinued and the patient will not complete the remainder of the pulmonary function testing. If rescue medication is administered during a PK visit, pulmonary function tests may be discontinued, but blood and urine collection for PK evaluation should be completed. Discontinued visits due to rescue medication intake will not be rescheduled. The medication used, dosage, route, date and 24-hour clock time of administration will be recorded on the Rescue Medication eCRF page. If rescue medication is administered on a visit day within 8 hours prior to the pre-dose PFT, the visit will be re-scheduled once. Further rescheduling should be discussed with the local clinical monitor. Salbutamol (albuterol) is considered a non-investigational medicinal product. Source data documentation and full drug accountability in regard to dispensed and returned medication to investigational site and to patients are required. 4.2.1.2 Emergency procedures There are no special emergency procedures to be followed. 4.2.1.3 Additional treatments Medications allowed to control acute asthma exacerbations as medically necessary during the screening, treatment and follow-up period: 1. PRN salbutamol (albuterol) HFA inhalation aerosol (MDI) provided by BI and to be recorded in the patient’s electronic diary. 2. Temporary addition of systemic corticosteroids is allowed during the study period. Pulmonary function testing should not occur within four weeks of the last administered dose of the addition (see Section 6.1 for visit schedule). 3. Temporary increases in the dose of inhaled corticosteroids are allowed during the study period. Pulmonary function testing should not occur within three weeks of the last Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 52 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 50 of 149 administered dose of an increase (see Section 6.1 for visit schedule). Patients should, whenever possible, return to the ICS medication and dose used prior to the exacerbation after the recovery from the exacerbation. 4. Temporary addition of theophylline preparations is allowed during the study period. Pulmonary function testing should not occur within seven days of the last administered dose of an increase or addition (see Section 6.1 for visit schedule). 5. The use of antibiotics is not restricted and may be used as medically necessary for asthma exacerbations and/or other infections. Pulmonary function testing should not occur within seven days of the last administered dose of an increase or addition of antibiotics if given for an asthma exacerbation or respiratory tract infection (see Section 6.1 for visit schedule). The treatment of asthma exacerbations including initiation of systemic corticosteroids should be done according to the investigator´s or treating physician´s medical judgement and should be in line with national and international recommendations. In the case of life-threatening exacerbations, any and all therapies deemed medically necessary may be prescribed. Medications allowed prior to and throughout the trial: 1. Maintenance treatment with medium doses inhaled corticosteroids (required for study entry; refer to inclusion criterion no. 6). 2. Leukotriene modifiers (if stabilised for at least 4 weeks prior to the trial and remains stable throughout the trial). 3. Mucolytic agents not containing bronchodilators. 4. Any orally inhaled rapid-acting beta-adrenergic agent is allowed prior to Visit 0. During the screening and randomised treatment periods and during the follow-up period, only salbutamol (albuterol) MDI provided by BI is allowed for PRN rescue medication use. The washout requirements before clinic visits need to be followed. 5. Antihistamines. Oral beta-adrenergics and beta blockers may be re-introduced during the follow-up period. However, it is not allowed to start with oral beta-adrenergics and beta blockers if not already prescribed prior to study entry. Treatment with pulmonary medications should remain stabilised as far as possible throughout the trial period. Please refer to Table 4.2.2.1: 1 for more information on medication permitted during the follow-up period. Refer to Section 4.2.2.1 for washout periods prior to pulmonary function testing during the study (including Visit 1). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 53 Page U12-2466-01 5 Dec 2011 Page 51 of 149 Trial Protocol 4.2.2 Restrictions 4.2.2.1 Restrictions regarding concomitant treatment The following table provides an overview of required, permitted and restricted medication. Table 4.2.2.1: 1 Overview of required, permitted and restricted medication Medications prescribed for asthma may be washed out after Visit 0 (after signing informed consent) and prior to Visit 1 to comply with the criteria in the table below. Study Period Drug Class Sub-class Prior to study Screening Period Treatment Period Follow up Period Corticosteroids Inhaled corticosteroids1 REQUIRED Patients must have been on maintenance treatment with a medium, stable dose for at least 4 weeks prior to Visit 1 Permitted Maintenance treatment with a medium, stable dose REQUIRED Maintenance treatment with a medium, stable dose REQUIRED Maintenance treatment with a medium, stable dose REQUIRED Permitted Permitted Permitted NOT permitted for at least four weeks prior to Visit 1 NOT permitted Temporary addition to treat exacerbations is allowed.1 NOT permitted Temporary addition to treat exacerbations is allowed. 1 Permitted Inhaled shortacting betaadrenergics Permitted Rescue (prior to all visits at least 8-hour washout) Rescue (prior to all visits at least 8-hour washout) Rescue Inhaled longacting betaadrenergics Permitted NOT permitted from 24 hours prior to Visit 1 Study medication Permitted Topical nasal steroids Systemic (including oral) corticosteroids Betaadrenergics / Beta-blockers Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 54 Page U12-2466-01 5 Dec 2011 Page 52 of 149 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class Sub-class Betaadrenergics / Beta-blockers Anticholinergics Miscellaneous Prior to study Screening Period Treatment Period Follow up Period Oral and patch beta-adrenergics NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted Permitted (only reintroduction is allowed. NOT allowed to start if not used prior to trial entry) Beta blockers NOT permitted for at least four weeks prior to Visit 1 Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. NOT permitted Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. NOT permitted Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. Permitted Short-acting anticholinergics: inhalation aerosol and nasal spray Permitted NOT permitted from 8 hours prior to Visit 1 Not permitted Permitted Long-acting inhaled anticholinergics NOT permitted for at least four weeks prior to Visit 1 NOT permitted Study medication NOT permitted All other (longacting) anticholinergics (e.g. for the treatment of overactive bladder) NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted Other investigational drugs NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted (only reintroduction is allowed. NOT allowed to start if not used prior to trial entry) Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 55 Page U12-2466-01 5 Dec 2011 Page 53 of 149 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class Sub-class Prior to study Screening Period Treatment Period Follow up Period Combination ICS/LABA (e.g. Advair®/ Seretide®; Symbicort®; Foster®) Permitted NOT permitted Permitted Combination ICS/SABA (e.g. Butasol®) Permitted NOT permitted Permitted Combination short-acting anticholinergic/ SABA (e.g. Berodual®, Combivent®, Duovent®) Permitted NOT permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 24 hours prior to Visit 1 NOT permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 8 hours prior to visit 1 NOT permitted from 8 hours prior to Visit 1 NOT permitted Permitted NOT permitted for at least two weeks prior to Visit 1 NOT permitted NOT permitted Permitted Permitted Permitted Permitted Permitted NOT permitted for at least two weeks prior to Visit 1 NOT permitted Temporary addition of theophylline to treat exacerbations is allowed1 NOT permitted Temporary addition of theophylline to treat exacerbations is allowed1 Permitted Cromone Antihistamines Methylxanthines /phosphodiesterase 4 inhibitors Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 56 Page U12-2466-01 5 Dec 2011 Page 54 of 149 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class 1 Sub-class Prior to study Screening Period Treatment Period Follow up Period Mucolytics Permitted Permitted Permitted Permitted Leukotriene modifiers Permitted To be stabilised for four weeks prior to Visit 1 and throughout the trial. Permitted Permitted Permitted Anti-IgE treatment (e.g. Omalizumab) NOT permitted for at least 6 months prior to Visit 1 NOT permitted NOT permitted Permitted ´Experimental´, non-approved asthma medications (e.g TNF-alpha blockers) NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted Refer to Section 4.2.1.3 for washout period prior to PFTs in case of treatment of an asthma exacerbation. Medication restrictions for pulmonary function testing (including Visit 1): 1. At least a 24-hour washout of long-acting beta-adrenergic bronchodilators prior to Visit 1 (not allowed between Visit 1 and 6). 2. At least a 24-hour washout of combination products, long-acting beta-adrenergic bronchodilators/corticosteroid prior to Visit 1 (not allowed between Visit 1 and 6). Patients should be switched to the inhaled steroid mono-product without changing the steroid dose at least 24 hours prior to Visit 1. 3. At least an 8-hour washout of short-acting beta-adrenergic bronchodilators prior to PFTs. 4. At least an 8-hour washout of short-acting anticholinergic bronchodilators prior to Visit 1 (not allowed between Visit 1 and 6). 5. At least an 8-hour washout of combination short-acting anticholinergic/SABA prior to Visit 1 (not allowed between Visit 1 and 6) 6. At least an 8-hour washout of combination products ICS/SABA prior to Visit 1 (not allowed between Visit 1 and 6). Patients should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 8 hours prior to Visit 1 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 57 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 55 of 149 7. On a visit day, the evening doses of the patient's regular ICS therapy, LTRA (if applicable) and trial medication should be taken after the visit day pre-dose PFT (i.e. at the clinic and not at home). 4.2.2.2 Restrictions on diet and life style Restrictions prior to PFT visits 1. Medication washout restrictions should be adhered to as described in Section 4.2.2.1. 2. The patient must remain in the building where the pulmonary function testing is performed and must return to the laboratory at least ten minutes prior to the start of each test. 3. On pulmonary function test days (including the Screening Visit), patients must refrain from strenuous activity for at least 12 hours prior to pulmonary function testing and throughout the testing period. Patients should also avoid cold temperatures, environmental smoke, dust or areas with strong odours (e.g. perfumes). 4. Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and icecold beverages are not allowed at least 2 hours prior to and during the pulmonary function testing period at clinic visits. Decaffeinated beverages are acceptable. 5. If a patient (re-)starts smoking during the trial, smoking should be discouraged for the 12 hours prior to pulmonary function testing and throughout the test day and will not be permitted in the 30-minute period prior to spirometry. Additional restrictions for patients participating in PK subset Patients who participate in pharmacokinetic sampling are not allowed to take any fruit juices (e.g. oranges, grapefruits), as well as products containing St. John´s wort (Hypericum perforatum) 72 hours before the pharmacokinetic sampling at Visits 2, 2A, 2B, 2C and 3. 4.3 TREATMENT COMPLIANCE The patient will complete an eDiary confirming that trial medication has been taken and indicating the number of puffs of salbutamol (albuterol) MDI use. The investigator will review these records with the patient at each visit (Visits 2 to 6) to assess treatment compliance. Compliance should be emphasised with a goal of at least 80% compliance rate. However, randomised patients will not be discontinued for lack of compliance without prior discussion with the local clinical monitor. On visit days, compliance will be guaranteed by administration of the trial drug under supervision of the investigating physician or designee. Each patient will be trained in the correct use of the Respimat® inhaler at Visit 1 and Visit 2. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 58 Page U12-2466-01 Trial Protocol 5. VARIABLES AND THEIR ASSESSMENT 5.1 EFFICACY - CLINICAL PHARMACODYNAMICS 5.1.1 Endpoint(s) of efficacy 5 Dec 2011 Page 56 of 149 Combined data of the two twin trials 205.418 and 205.419 will be used to ensure an adequate number of patients for the endpoints ACQ, time to first severe asthma exacerbation and time to first asthma exacerbation. These endpoints will be comprehensively analysed in a metaanalysis, the individual reports will only provide basic descriptive displays regarding these endpoints. 5.1.1.1 Primary Endpoints The co-primary endpoints are 1. Peak forced expiratory volume in one second (FEV1) response (within 3 hours post dosing) determined at the end of the 24-week treatment period. 2. Trough FEV1 response determined at the end of the 24-week treatment period. Peak FEV1 is defined as the highest FEV1 reading observed within 3 hours after administration of the evening dose of each randomised treatment. Peak FEV1 response is defined as the change from baseline in peak FEV1. Trough FEV1 is defined as the FEV1 measured (in the evening) at the -10 minute time point at the end of the dosing interval (24 hours post drug administration). Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline is the pre-treatment FEV1 measured at Visit 2 in the evening 10 minutes prior to the evening dose of patient’s usual inhaled corticosteroid controller medication (if regular posology), leukotriene modifier (LTRA) (if applicable) and first dose of trial medication (inhalation via MDI followed by inhalation via Respimat® inhaler). Meta-Analysis: The primary endpoint is the responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period on combined data from the two twin trials 205.418 and 205.419. The following definition for responder will be used. A patient is said to be a responder if for that patient an improvement of at least 0.5 for the ACQ was observed. The minimum clinical important difference (MCID) for the ACQ is 0.5. 5.1.1.2 Secondary Endpoints In a subgroup of patients FEV1, FVC and PEF readings are also available at 5 and 15 minutes post-dose, these readings will be analysed as mentioned in endpoint no. 11. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 59 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 57 of 149 1. Peak (within 3 hours post dosing) and trough forced vital capacity (FVC) determined at the end of the 24-week treatment period (as defined above for FEV1). 2. FEV1 (AUC0-3h) and FVC (AUC0-3h) at the end of the 24-week treatment period. The AUC0-3h will be calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough values will be assigned to zero time. FEV1 AUC 0−3h = 1 4 1 ∑ ( FEV1 (t i−1 ) + FEV1 (t i )) * (t i − t i −1 ) 3h i =1 2 (Trapezoid rule) where FEV1(ti) = FEV1 reading at planned time ti t0 = pre-dosing (= 0 min), t1 = 0.5h, …t4 = 3h FVC (AUC0-3h) is defined in the same way as FEV1 (AUC0-3h). 3. Individual in-clinic FEV1, FVC and PEF measurements at all time-points including peak, trough and AUC0-3h during the 24-week treatment period. 4. Quality of Life as assessed by standardised Asthma Quality of Life Questionnaire (AQLQ (S)) at all clinic visits during the 24-week treatment period. 5. PEF am/pm: change from baseline in mean weekly pre-dose morning and evening PEF measured by patients at home in the last week of the 24-week treatment period. Baseline is defined as the last week prior to randomization. 6. Use of PRN salbutamol (albuterol) rescue medication during the 24-week treatment period: number of puffs of rescue therapy used per day (i.e. the full 24 hour period, the daytime and the nighttime; weekly means will be compared). 7. Asthma symptoms as assessed by the patient’s electronic diary during the 24-week treatment period. Analysis with regard to daytime and nocturnal symptoms will be done. 8. Asthma symptom free days as assessed by the patient’s electronic diary during the 24week treatment period: asthma symptom free day is defined as a day with no reported symptoms and no use of rescue medication. 9. The responder rate as assessed by the ACQ determined at the end of the 24-week treatment period for each trial separately. Additionally in a subset of patients: 10. FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC1224h), FVC (AUC0-24h) after 24-week treatment FEV1 AUC n − mh = 1 k 1 ( FEV1 (t i −1 ) + FEV1 (t i )) * (t i − t i −1 ) ∑ i= j mh 2 (Trapezoid rule) Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 60 U12-2466-01 Trial Protocol 5 Dec 2011 Page 58 of 149 where FEV1(ti) = FEV1 reading at planned time ti t0 = pre-dosing (= 0 min), t1 = 0.5h, …t16 = 23.5h and tj-1=nh, tk=mh FVC (AUCn-mh) is defined in the same way as FEV1 (AUCn-mh). The FEV1 (AUC0-12h), FEV1 (AUC12-24h), and FEV1 (AUC0-24h) will be calculated as described above for FEV1 (AUC0-3h). The same method applies to the different areas under the curve for FVC. 11. Individual FEV1 and FVC measurements at 5 and 15 minutes post dose including peak and AUC0-3h. Peak and AUC0-3h are defined as described above, including the 5 and 15 minutes recordings. Meta-Analysis: The secondary endpoints on combined data from the two twin trials 205.418 and 205.419 are: 1. Time to first severe asthma exacerbation during the 24-week treatment period. 2. Time to first asthma exacerbation during the 24-week treatment period. 3. The ACQ value at each visit during the 24 week treatment period 5.1.1.3 Other Endpoints Three additional pulmonary function endpoints will be analysed: 1. PEF am/pm: weekly mean pre-dose morning and evening PEF measured by patients at home (weekly means will be compared) from baseline to the last week of the 24-week treatment period. Baseline is defined as the last week prior to randomization. 2. FEV1 am/pm: mean pre-dose morning and evening FEV1 measured by patients at home (weekly means will be compared) from baseline to the last week of treatment. Baseline is defined as the last week prior to randomization. 3. PEF variability: PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values (weekly means will be compared) during the 24-week treatment period. 5.1.2 Assessment of efficacy Pulmonary Function Testing (PFT) on study visits formerly known as MasterScope® CT spirometers ( , Germany) will be provided to sites for the in-clinic spirometry measurements. The spirometers and their use, including daily calibration, must meet ATS/ERS criteria [P05-12782]. Spirometry will be conducted with the patient in a seated position having abstained from medications as specified in Section 4.2.2.1, and it is preferable that the same trained individual performs the PFTs for a given patient. The best of Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 61 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 59 of 149 three efforts will be defined as the highest FEV1, the highest FVC and the highest PEF each obtained on any of three blows meeting the ATS criteria (with preferably a maximum of five manoeuvres: however, a maximum of eight manoeuvres would be acceptable). The highest FEV1, FVC and PEF will be selected regardless of whether they come from different spirometric manoeuvres or from the same manoeuvre. At the 24-hour PFT test-day (Visit 6), patients participating in this subset should be woken 40 minutes (± 10 minutes) prior to the start of the initial morning PFT (11h50’ time point). For each patient, pulmonary function testing will always start at approximately the same time of the day and depending on the time of dosing. At Visit 1 pulmonary function testing will be performed between 06.00 and 08.00 pm. At Visits 2 to Visit 6, visits and PFTs will be scheduled to enable dosing between 6:00 pm and 8:00 pm. At Visits 3 to Visit 6 pulmonary function testing should start with ± 30 minutes maximum difference between the start of the tests on Visit 2 and the tests conducted on subsequent test days . The end of the 2nd inhalation of evening dose of study medication from the Respimat® will be regarded as time point zero for pulmonary function testing. At Visits 2 to 6, the 10 minute pre-dose measurement will be obtained in the period from 25 minutes to 5 minutes prior to the evening dose of ICS and study medication. The 30 and 60 minute measurements will be obtained within ± 5 minutes of the specified time point; and measurements made from 2-24 hours post-dose will be performed within ± 10 minutes of the scheduled time point. If a patient is unable to complete the PFTs during a visit, the local clinical monitor should be notified as soon as possible. The eCRF will be completed indicating the reason for stopping testing. Refer to Section 4.2.1.1 for more details on conduction of trial procedures if rescue medication was administered during a visit day. Patients who are unable to complete the trial visit may leave the clinic only upon instruction from the supervising physician. Refer to Section 4.1.4 (Trial medication at clinic visits) for more information on medication intake times that will be captured with the Masterscope® CT spirometer. Refer to Section 4.2.2.1 for restrictions regarding concomitant therapy prior to PFTs. Refer to Section 4.2.2.2 for restrictions on diet and life style prior to PFTs. Refer to the Flow Chart for the time schedule. Asthma Control Questionnaire (ACQ) The Asthma Control Questionnaire (ACQ) developed by Elizabeth Juniper [R00-1157] has 6 patient self-administered questions for the time period of the last week prior to the visit and one question concerning pre-bronchodilator FEV1 to be completed by a member of the clinic staff. Each question has a 7-point scale. The ACQ will be completed from Visit 1 to Visit 6 and should be the first questionnaire completed during Visit 2 to 6 and should precede any discussion with a health professional (physician, nurse or study co-ordinator). Question 7 will be completed after pulmonary function testing. The questions in the questionnaire are weighted equally, the score is the mean of the responses to all 7 questions. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 62 U12-2466-01 Trial Protocol 5 Dec 2011 Page 60 of 149 The ACQ is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Please refer to Appendix 10.6 for an example of the questionnaire. Electronic peak flow meter with electronic diary (Asthma Monitor® AM3) , formerly known as The patients will receive an Asthma Monitor® AM3 ( , Germany) which combines the features of an electronic peak flow meter (measurement of both PEF and FEV1) and an electronic diary in one device. , Patients will receive the AM3 at Visit 1 and instructions for the use of the device at Visit 1 and Visit 2. They will use the device during the screening and treatment period (Visit 1 to Visit 6). The device will be used twice daily to first record questions related to asthma symptoms and quality of life, use of rescue salbutamol (albuterol), use of trial medication (during the treatment period only), and then to measure PEF and FEV1. The patient will be alerted by the AM3 to contact the investigator in case of one of the following situations: • A decrease of patient's best morning PEF of ≥ 30% from the patient's mean morning PEF for at least two consecutive days During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. • The patient used 12 or more puffs of rescue medication for at least two consecutive days All PEF/FEV1 and eDiary data saved in the AM3 will be downloaded at each visit after Visit 1 (except at Visits 2A, 2B and 2C) and transmitted via the MasterScope® CT to central data management of the vendor. At each trial visit the investigator receives a print-out of all downloaded AM3 data for review. Details and instructions for use are given in the Appendix 10.9 and the ISF. Electronic diary (eDiary) at home The diary part of the AM3 will be used to record the answers to the questions raised in the daily diary. The eDiary includes questions on asthma symptoms, quality of life and number of puffs of rescue medication. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 63 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 61 of 149 Morning and evening recordings should be performed at approximately the same time of the day (± 30 minutes) between 6:00 and 08:00 am and 6:00 and 08.00 pm, respectively. An alarm will sound at 8:00 and 8:30 am and pm to remind the patient to use the AM3. When the patient forgot to use the AM3 between 06:00 and 08:00, the patient should be instructed to use the AM3 if it is still before 11:59 (am or pm). The diary must be answered in the morning immediately upon arising (after the patient has cleared out mucus) and in the evening both prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication (and rescue medication if needed). Trial medication taken during the treatment period (morning and evening) will also be recorded in the AM3. Peak flow measurements at home The patient will record twice-daily PEF and FEV1 during the screening and treatment period (Visit 1 to Visit 6) with the AM3 immediately after answering the eDiary questions. The morning measurement should be performed upon arising after the patient has cleared out mucus and prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication (and rescue medication if needed). The evening measurement will be performed prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication (and rescue medication if needed). The patient should perform three peak expiratory flow manoeuvres in the standing position with the AM3. All acceptable PEF and FEV1 values are stored in the AM3 with date and time of the reading. The highest PEF and the highest FEV1 out of up to three acceptable blows, but not necessarily from the same blow, will be used for evaluation. Peak flow measurements and eDiary at Visit days 2 to 6 The morning recordings at home should be done as usual. In the afternoon/evening, patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic between -1:00 and -0:30h and prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication. The medication should be administered at the clinic after the pre-dose pulmonary function testing with the MasterScope® CT. Peak flow measurements and eDiary at 24 hour visits (Visit 2, 3 and/or 6 at selected sites) The morning recordings at home and on the following morning in the clinic should be done as usual. Also see the Flow Chart. The afternoon/evening recordings should be done in the clinic as described above. On the following afternoon/evening (at the end of the visit), patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic prior to Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 64 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 62 of 149 administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication and prior to leaving the clinic. Peak flow measurements and eDiary at Visits 2A, 2B and 2C at selected sites The morning recordings at home should be done as usual. In the afternoon/evening, patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic between -1:00 and -0:30h and prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication.The medication administration should be performed at the clinic after the pre-dose PK sample has been drawn. Asthma Exacerbations The patient will document any worsening of asthma symptoms during the screening and treatment period in the electronic diary of the AM3 and measure the PEF twice daily (see Appendix 10.9). In addition, the patient will receive a paper patient diary card to document specific asthma symptoms, required medical treatment (e.g. change in asthma medication, need for medical care) or lost working days due to the asthma worsening (see Appendix 10.8). The investigator will review the patient’s entries and enter the relevant information from the paper patient diary card in the eCRF. The paper patient diary card will remain at the site. A new patient diary card should be dispensed at every visit as needed. The investigator should collect all information regarding asthma exacerbations including review of the electronic and paper diary. Specific questions should be raised to capture any asthma worsening, any changes in concomitant asthma medication including the introduction of systemic corticosteroids or any unplanned need for medical care due to asthma or lost working days that have not been documented in the patient’s diaries. It is the investigator’s responsibility to report any deterioration of asthma as an AE regardless if the sponsor’s definition of asthma exacerbations is fulfilled or not. The treatment of asthma exacerbations including initiation of systemic corticosteroids should be done according to the investigator´s or treating physician´s medical judgement and should be in line with national and international recommendations. If systemic corticosteroids are required, the GINA guidelines recommend to initially dose oral glucocorticosteroids between 0.5 to 1 mg of prednisolone or equivalent /kg body weight during 24-hours [P10-03196]. Whenever feasible, the following scheme is recommended for the trial: 30 mg/day prednisolone or prednisolone equivalent for 7 days. The onset of an asthma exacerbation should be defined by the onset of the first worsened symptom respectively PEF deterioration. The end of an asthma exacerbation should be recorded as defined by the investigator. Courses of systemic corticosteroids that are separated by one week or more should be treated as separate exacerbations. Refer to Appendix 10.10 for the BI definition of an asthma exacerbation in general and a severe asthma exacerbation. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 65 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 63 of 149 Asthma Quality of Life Questionnaire (AQLQ (S)) The standardised Asthma Quality of Life Questionnaire (AQLQ (S)) developed by Elizabeth Juniper [R08-0092] is administered on every visit from Visit 2 to 6. The AQLQ (S) is patient self-administered. The AQLQ (S) has 32 questions for the time period of the last two weeks prior to the visit and each question has a 7-point scale. Eleven questions refer to activity limitations, twelve questions refer to symptoms, five questions to emotional function and another four questions to environmental stimuli. The AQLQ (S) should be the second questionnaire completed (ACQ is completed first) and should precede any discussion with a health professional (physician, nurse or trial co-ordinator). The AQLQ (S) is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Challenges to inconsistent responses (pronounced outliers) should only be done very infrequently and with very careful consideration. Please refer to Appendix 10.5 for an example of the questionnaire. 5.2 SAFETY 5.2.1 Endpoint(s) of safety 1. All adverse events. 2. Vital signs: pulse rate and blood pressure (seated) recorded in conjunction with spirometry until 3 hours post-dose. 3. Vital status information of prematurely discontinued patients to be collected for all randomised patients on the originally planned follow up visit date (Visit 7). 5.2.2 Assessment of adverse events 5.2.2.1 Definitions of adverse events Adverse event An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. The event does not necessarily have to have a causal relationship with this treatment. Serious adverse event A serious adverse event (SAE) is defined as any AE which results in death, is immediately life-threatening, results in persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an important medical event when based upon appropriate medical judgement which may jeopardise the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above definitions. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 66 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 64 of 149 Additional information for Japan: An AE which possibly leads to disability will be reported as an SAE. Every new occurrence of cancer will be reported as a SAE regardless of the duration between discontinuation of the drug and the occurrence of the cancer. Significant Adverse Events No events have been classified as "significant" for this trial. Significant events The following are considered as significant events: • Hepatic injury defined by the following alterations of liver parameters: an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the same blood draw sample. Significant events are to be reported in an expedited manner similar to SAEs, even if they do not meet any of the seriousness criteria (for details see Section 5.2.2.2). Intensity of adverse event The intensity of the AE should be judged based on the following: • • • Mild: Moderate: Severe: Awareness of sign(s) or symptom(s) which is/are easily tolerated Enough discomfort to cause interference with usual activity Incapacitating or causing inability to work or to perform usual activities Causal relationship of adverse event Medical judgment should be used to determine the relationship, considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant medication, concomitant diseases and relevant history. Assessment of causal relationship should be recorded in the case report forms. Additional information for Japan: The reason for the decision on causal relationship needs to be provided in the eCRF. • • Yes: There is a reasonable causal relationship between the investigational product administered and the AE. No: There is no reasonable causal relationship between the investigational product administered and the AE. If a SAE is reported from a still blinded trial, the causal relationship must be provided by the investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. any active comparator or placebo according to the trial design). Worsening of underlying disease or other pre-existing conditions Worsening of the underlying disease or of other pre-existing conditions will be recorded as an (S)AE in the (e)CRF. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 67 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 65 of 149 Expected fluctuations or expected deterioration of the underlying disease and other preexisting conditions should not be recorded as an AE unless at least one of the following criteria is met: − the worsening of the disease constitutes an SAE, − the investigational drug is discontinued or the dose is reduced or increased, − additional treatment is required, i.e. concomitant medication is added or changed. − an unexpected deterioration from baseline has occurred in the opinion of the investigator. Changes in vital signs, ECG, physical examination, and laboratory test results Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator. Changes in vital signs including blood pressure, pulse rate, ECG, physical examination, and laboratory tests will be only then recorded as AEs if they are not associated with an already reported AE, symptom or diagnosis, and the investigational drug is either discontinued, reduced or increased, or additional treatment is required, i.e. concomitant medication is added or changed. Listed Adverse Events Please refer to Section 8.4.1 for more information. 5.2.2.2 Adverse event and serious adverse event reporting All adverse events, serious and non-serious, occurring during the course of the clinical trial (i.e., from signing the informed consent onwards through the observational phase and until 21 days after the last dose of trial medication) will be collected, documented and reported to the sponsor by the investigator on the appropriate CRF(s) / eCRFs / SAE reporting forms. Reporting will be done according to the specific definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File. All AEs, including those persisting after trial completion must be followed up until they have resolved or have been sufficiently characterised. For each adverse event, the investigator will provide the onset date, end date, intensity, treatment required, outcome, seriousness, and action taken with the investigational drug. The investigator will determine the relationship of the investigational drug to all AEs as defined in Section 5.2.2.1. If not stipulated differently in the ISF, the investigator must report the following events via telephone/fax using the SAE form immediately (within 24 hours or the next business day whichever is shorter) to the sponsor: SAEs and non-serious AEs occurring at the same time as an SAE and/or which are medically related to the SAE(s). BI has set up a list of AEs which are defined to be always serious. In order to support the investigator with the identification of these “always serious adverse events”, if a non serious AE is identified to be serious per BI definition, a query will be raised. The Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 68 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 66 of 149 investigator must verify the description and seriousness of the event. If the event description is correct, the item “serious” needs to be ticked and an SAE has to be reported in expedited fashion following the same procedure as above. The list of these adverse events can be found via the Remote Data Capture (RDC)system. Additional information for Japan: This information must be also reported immediately to the head of the trial site. With receipt of any further information to these events, a follow-up SAE report has to be provided. SAEs and non-serious AEs must include a causal relationship assessment made by the investigator. The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU (country-specific contact details will be provided in the Investigator Site File). This immediate report is required irrespective of whether the investigational product has been administered or not and irrespective of causal relationship. It also applies if new information to existing SAEs becomes available. Vital status information After any premature withdrawal of patients that took at least one dose of trial medication, the vital status information (dead or alive) will be collected on the originally planned visit date of the follow up visit (Visit 7). Any death during the vital status observation period needs to be reported as SAE by the investigator according to the Boehringer Ingelheim SAE procedures. Pregnancy In rare cases, pregnancy might occur in clinical trials. Once a female subject has been enrolled into the clinical trial, after having taken study medication, the investigator must report immediately any drug exposure during pregnancy to the sponsor. Drug exposure during pregnancy has to be reported immediately (within 24 hours or next business day whichever is shorter) to the defined unique entry point for SAE forms of the respective BI OPU (country-specific contact details will be provided in the Investigator Site File). The outcome of the pregnancy associated with the drug exposure during pregnancy must be followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B). 5.2.3 Assessment of safety laboratory parameters Clinical laboratory testing Clinical laboratory testing will be conducted on all patients at Visit 1 (to determine patient's eligibility) and Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. Lab parameters will be analysed by the local laboratory of each participating site. Please refer to Appendix 10.11 for methodological details. At Visit 1, the white blood cell count, eosinophil count (absolute and relative), total serum IgE and creatinine levels will be recorded on the eCRF. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 69 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 67 of 149 Pregnancy testing A pregnancy test will be conducted at Visit 1 and Visit 6 (or at the withdrawal visit if the patient does not complete all trial visits) in all women of childbearing potential. It will be sufficient to use a urine test kit (provided by BI or by the investigator/hospital). 5.2.4 Electrocardiogram A standard 12-lead electrocardiogram (ECG) will be performed on all patients at Visit 1 (to obtain information about the patient's baseline condition and to determine patient's eligibility) and at Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. All clinically significant findings at screening (Visit 1) will be recorded on the Medical History/Baseline Condition page in the eCRF. New clinically significant findings or worsening of screening conditions detected at Visit 6 (or at a withdrawal visit) will be recorded as adverse events on the appropriate eCRF page. An explanation of the aetiology of clinically significant abnormal findings must be made on the eCRF. All relevant abnormal findings have to be followed up until they have normalised or have been sufficiently characterised. 5.2.5 Assessment of other safety parameters Vital signs Pulse rate, systolic and diastolic blood pressure will be measured and recorded in conjunction with pulmonary function testing at Visit 2 to Visit 6 and prior to inhalation of medication and until 3 hours post-dose. Measurements will always be obtained immediately before pulmonary function testing with the patient seated and rested for a minimum of five minutes. The same person using the same blood pressure instrument on the same arm should perform all recordings. Physical examination A complete, head-to-toe physical examination will be completed on all patients at the screening visit (Visit 1) and at Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. The physical examination will also include measurements of systolic and diastolic blood pressure and pulse rate, which will be measured with the patient seated after having rested for at least 5 minutes. All clinically significant findings at screening (Visit 1) will be recorded on the Medical History/Baseline Condition page in the eCRF. New clinically significant findings or worsening of screening conditions detected at Visit 6 (or at a withdrawal visit) will be recorded as adverse events on the appropriate eCRF page. An explanation of the aetiology of clinically significant abnormal physical findings must be made on the eCRF. All relevant abnormal physical findings have to be followed up until they have normalised or have been sufficiently characterised. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 70 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 68 of 149 Vital status Vital status information (dead or alive) will be collected at the originally planned visit date of the follow up visit (Visit 7) for discontinued patients following randomisation. The vital status eCRF will be completed. Collection of vital status information does not require a patient visit. If no information can be collected despite at least 3 (documented) phone calls and at least one registered letter have remained unanswered, the patient will be regarded as lost to follow-up. 5.3 OTHER 5.3.1 Other endpoints Health economic analysis For the purpose of a separate health economic analysis (for example cost-effectiveness analysis including the clinical endpoint as effectiveness parameter), health care resource utilisation (HCRU) data will be collected and Quality of Life will be assessed at all time points during the 24-week treatment period. The economic evaluation of the HCRU and EQ-5D data will not be part of the clinical trial report. PASAPQ In a subset of patients the satisfaction and acceptance of the device will be investigated using the PASAPQ. The following PASAPQ-endpoints will be analyzed: • • • • • • • 5.3.2 The performance domain score (Q1-Q5, Q10-Q11) The convenience domain score (Q6-Q9, Q12-Q13) The total score (Q1-Q13) The overall satisfaction question score (Q14) The score for device preference question (Q15) The score for willingness to continue question (Q16) The score for 13 individual items (Q1-Q13) Other assessments HCRU data Resource use related to asthma will be captured within the trial in order to estimate and compare cost of treatment across treatment arms. HCRU data will be collected from Visit 2 to 6. Resource use data collected for calculating direct costs will include, e.g. number of days in hospital, number of unscheduled health care provider visits, number of visits in emergency room, number of days in intensive care unit, concomitant medications, and lost working days due to asthma. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 71 U12-2466-01 Trial Protocol 5 Dec 2011 Page 69 of 149 EQ-5D The EQ-5D self-report questionnaire was developed by the ( ) and is a standardised instrument for use as a measure of health outcome [R96-2382]. The EQ-5D is patient self-administered and will be completed from Visit 2 to 6. The questionnaire essentially consists of 2 pages. The first page is the descriptive system with 5 questions to the patient’s health state today. Each question captures one dimension of health (e.g. mobility, self-care) and has three levels to answer. The second page records the patient’s self-rated health status of today on a vertical graduated (0-100) visual analogue scale. The EQ-5D should be the third questionnaire completed and should precede any discussion with a health professional (physician, nurse or study co-ordinator). The EQ-5D is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. In instances where a patient cannot give or decide upon a response, no response should be recorded. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Please refer to Appendix 10.7 for an example of the questionnaire. PASAPQ The PASAPQ will be self-administered at Visit 6 in selected countries. The Patient Satisfaction and Preference Questionnaire (PASAPQ) is a multi item measure of respiratory inhalation device satisfaction and preference designed to be easy to understand and administer to asthma patients [P05-02607]. The PASAPQ is a two part questionnaire. Part I consists of 14 questions, the first 13 generating the Performance, Convenience and Total Score domains. The 14th question is a stand alone question for Overall Satisfaction. Part II consists of stand alone questions concerning a subject’s device preference and willingness to continue use. The PASAPQ should be the fourth questionnaire completed and should precede any discussion with a health professional (physician, nurse or study coordinator). Scoring will be according the methods used in the validation of the questionnaire (refer to PASAPQ User Manual) and will be described in detail in the TSAP. The PASAPQ is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. Patients should be requested to complete the Patient Satisfaction questionnaire as completely and as accurately as possible. If the patient requests help or clarification, the investigator will instruct the patient to re-read the instructions and to give the best answer possible to each question. The investigator will not provide the patient with an answer to any question or review their responses for accuracy. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Please refer to Appendix 10.13 for an example of the questionnaire. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 5.3.3 Page 72 U12-2466-01 Trial Protocol 5 Dec 2011 Page 70 of 149 Pharmacogenetic evaluation Exploratory genetic investigations in respiratory diseases might be done after complete anonymisation of the patient’s blood sample. 5.3.3.1 Methods of sample collection To allow pharmacogenetic analyses, all patients (who signed a separate informed consent) will be asked for one blood sample after successful randomisation at Visit 2 (or at any other subsequent Visit after randomisation). The samples will be taken and stored in accordance with local ethical and regulatory requirements. Participation in the pharmacogenetics part is voluntary and not a prerequisite for participation in the trial. The blood sample will be completely anonymised. The anonymisation procedure will guarantee a very high level of data protection for the donor. Once the anonymisation has been carried out, there will be no legal way to trace back to the identity of the donor. The anonymised DNA may be analysed at a later time to identify whether there are genetic factors that could contribute to a better therapeutic outcome or a higher risk of developing treatment related adverse drug reactions. Genetic investigations will be limited to the investigation of the effects of genetic variations on respiratory diseases, and on efficacy, safety and pharmacokinetics of the trial drug. After anonymisation, the blood sample (or the DNA derived thereof) will be stored at Boehringer Ingelheim for 15 years after the end of the clinical trial or until there is no more material available for tests. 5.3.3.2 Analytical determinations Genomic DNA will be extracted from blood samples according to standard molecular genetics methods. 5.4 APPROPRIATENESS OF MEASUREMENTS Pulmonary function tests are a validated and well established measurement tool for lung function testing. Pulmonary function tests will be conducted at clinic visits using the MasterScope® CT Spirometer ( formerly known as , Germany). FEV1 is a standard measurement for the assessment of lung function. The AM3 device ( formerly known as , Germany) will be used for measurement of PEF and FEV1 and to record the data of the eDiary. The AM3 complies with the regulations of European Medical Device Directive and the FDA guidelines in the United States. The EQ-5D, AQLQ(S) and ACQ are well established and validated questionnaires. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 5.5 73 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 71 of 149 DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS A subset of at least 80 patients will participate in the PK part of the trial. Plasma and urine concentration monitoring of tiotropium will be performed in order to assess drug exposure and to characterise the pharmacokinetics of tiotropium bromide in this patient population. A separate informed consent will be signed by the patients in accordance with local ethical and regulatory requirements. 5.5.1 Pharmacokinetic endpoint(s) The following pharmacokinetic parameters will be determined at Visit 2 (day 1) in relation to the administration of the first dose of tiotropium, when feasible: 1. Cmax (maximum concentration of tiotropium in plasma) 2. tmax (time from dosing to maximum tiotropium plasma concentration) 3. AUC0-tz (area under the concentration-time curve of tiotropium in plasma over the time interval from 0 to the last quantifiable data point within the first dosing interval) 4. Aet1-t2 (amount of tiotropium that is eliminated unchanged in urine from the time point t1 to time point t2) 5. fet1-t2 (fraction of tiotropium dose excreted in urine from time point t1 to t2) 6. AUCt1-t2 (area under the concentration-time curve of tiotropium in plasma over the time interval t1 to t2) 7. AUC0-∞ (area under the concentration-time curve of tiotropium in plasma over the time interval from 0 extrapolated to infinity) 8. %AUCtz-∞ (the percentage of the AUC0-∞ that is obtained by extrapolation) 9. λz (terminal rate constant of tiotropium in plasma) 10. t½ (terminal half-life of tiotropium in plasma) 11. MRTih (mean residence time of tiotropium in the body after inhalation) 12. CL/F (apparent clearance of tiotropium in the plasma after extravascular administration) 13. Vz/F (apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose) 14. CLR,t1-t1 (renal clearance of tiotropium in plasma from the time point t1 to time point t2) A pre-dose blood sample will be obtained at Visits 2A, 2B and 2C and will be reported as Cpre,N (pre-dose concentration of tiotropium in plasma). Similarly, a blood sample will be Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 74 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 72 of 149 obtained 5 minutes post-dosing at Visits 2A, 2B and 2C and will be reported as C0.083,N (tiotropium plasma concentration 5 minutes post-dosing). At Visit 3 (week 4) tiotropium steady state will be assumed and the following parameters will be determined, when feasible: 1. AUCt1-t2,ss (area under the concentration time curve of tiotropium in plasma over the time interval t1 to t2 at steady state) 2. AUCτ,ss (area under the plasma concentration-time curve at steady state over a uniform dosing interval τ at steady state) 3. Cmax,ss (maximum measured concentration of tiotropium in plasma at steady state) 4. tmax,ss (time from dosing to the maximum concentration of tiotropium in plasma at steady state) 5. λz,ss (terminal rate constant in plasma at steady state) 6. t½,ss (terminal half-life of tiotropium in plasma at steady state) 7. MRTih,ss (mean residence time of tiotropium in the body after inhalational administration to steady state) 8. CL/F,ss (apparent clearance of tiotropium from plasma after extravascular administration to steady state) 9. Vz/F,ss (apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose) 10. Aet1-t2,ss (amount of tiotropium that is eliminated in urine from the time point t1 to time point t2 (Ae0-2, Ae2-6 at steady state) 11. fet1-t2, ss (fraction of tiotropium eliminated in urine from time point t1 to time point t2 (fe02, fe2-6 at steady state) 12. CLR,t1-t2,ss (renal clearance of tiotropium from the time point t1 until the time point t2) (CLR,0-2, CLR, 2-6 at steady state) 13. Cpre,ss (predose concentration of tiotropium in plasma at steady state) 14. Cmin,ss (minimum concentration of tiotropium in plasma at steady state) In addition, the linearity index (LI) and the following accumulation ratios of the analyte in plasma following 28 doses over a uniform dosing interval τ will be calculated: 15. RA,Cmax,28 based on Cmax 16. RA,AUC based on AUC Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 75 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 73 of 149 Further pharmacokinetic parameters may be calculated as appropriate. Details on the pharmacokinetic methods can be found in Appendix 10.12. The pharmacokinetic parameters will be included in the clinical trial report. 5.5.2 Methods of sample collection Date and exact clock time of pharmacokinetic sampling have to be recorded and documented in the eCRFs by the site personnel. Clocktime of the MasterScope® CT should be used at Visit 2 and Visit 3. The time point zero for pharmacokinetic sampling is defined as end of last inhalation from the Respimat®. For handling of medication administration at clinic visits and collection of medication administration time points, please refer to Section 4.1.4. The pre-dose PK blood sample will be obtained 15 minutes before trial drug administration. A planned time of -0:15 will be used for data base set-up. The pre-dose urine sample collection interval will be the hour prior to trial drug administration. A planned start time of -1:00 and a stop time of 0:00 will be used for data base set-up. At Visit 2 and 3, the patient may leave the clinic after the morning inhalation of trial medication (or, if preferred by the patient, after the 6 hour post-dose sample has been drawn) and should return 30 minutes prior to the planned time for the last PK sample. Patients should continue urine collection at home and take the container with them from and to the clinic. All urine fractions must be kept cold at all times, i.e., during collection and transport. This includes the 6-24 hour urine fraction which will be taken home by the patient. A cold box will be provided to the patients for this purpose. Blood sampling For quantification of tiotropium plasma concentrations, at each sampling time point about 6 mL (Vacutainer®) or 4.9 mL (Monovette®) blood will be taken from a forearm vein using a Monovette or Vacutainer collection tube containing EDTA (ethylenediaminetetraacetic acid) as anticoagulant. Blood samples shall be drawn as close to the planned time as possible. Two aliquots of plasma will be prepared from each blood sample. The sampling/collection tubes will be labeled with at least patient number, visit number and planned sampling time. A total amount of approximately 150-180 mL blood will be taken per patient during the trial for pharmacokinetic purposes. Refer to the Flow Chart for the time schedule. Detailed instructions for pharmacokinetic sampling, handling and shipment of plasma samples are provided in the ISF/labmanual. Urine sampling All urine voided during the collection intervals will be collected in containers. The urine bladder will be voided within 5 minutes before the beginning of each collection interval. In order to enable a sufficient urine flow patients might be asked to drink at least 150-200 mL of a non-caffeinated beverage 15 minutes prior to the end of each urine fraction in order to support a miction in time. The collection containers and tubes will be labeled with at least patient number, visit number and planned sampling time. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 76 U12-2466-01 Trial Protocol 5 Dec 2011 Page 74 of 149 Urine container weights (i.e. tare and gross) and times of collection will be documented in the eCRFs (weight will be set equal to volume without correction for specific gravity of urine when calculating the urine weight for analysis). Refer to the Flow Chart for the time schedule. Detailed instructions for pharmacokinetic sampling, handling and shipment of urine samples are provided in the ISF/labmanual. Prevention of contamination Tiotropium is known to be a very adhesive substance. In order to avoid contamination of plasma and urine samples PK blood sampling, urine collection and plasma and urine preparation procedures must NOT take place in the same room where priming of the Respimat® inhaler or drug inhalation takes place. Also, the priming and drug inhalation must be carried out in different rooms. More than one patient must not be present in a room at the time of drug inhalation on the pharmacokinetic days. Patients and study personnel should handle the Respimat® inhaler with gloves on, and these gloves should be changed and discarded immediately after a patient has completed inhalation and before any container for PK samples is handled. The urine containers, plasma vials and transfer pipettes should not be touched with the same gloves already used for blood sampling. Plasma and urine vials/containers should be stored closed and should only be opened if necessary for the procedure. The patients must be advised to handle the urine containers with gloves on or to wash hands thoroughly before and after urine collection. The site of cannulation should remain covered (e.g. use of overalls) during the time the patient remains in the room where drug inhalation is planned. The covering should only be removed once the patient is moved to the room where blood sampling etc is planned. 5.5.3 Analytical determinations Plasma and urine concentrations of tiotropium will be determined by validated HPLC/MS/MS assays (high performance liquid chromatography) [U10-1855-01]. The analysis will be performed by (formlery known as )( , Germany) and will be described in an Appendix in the clinical trial report. Plasma concentration measurement of samples from the salmeterol and placebo treatment will be restricted to the blood samples taken before treatment and taken at Cmax (i.e. plasma sample taken at 5 minutes after inhalation). Similarly, urinary concentrations of samples from salmeterol and placebo treatment will be restricted to pre-dose and 0-2 hour intervals (Visits 2 and 3). Only if one of these samples reveals tiotropium, the remaining samples of that particular patient will be analysed as well. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 5.6 77 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 75 of 149 BIOMARKER(S) Not applicable to this trial. 5.7 PHARMACODYNAMICS Not applicable to this trial. 5.8 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP Not applicable to this trial. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 78 Page U12-2466-01 Trial Protocol 6. INVESTIGATIONAL PLAN 6.1 VISIT SCHEDULE 5 Dec 2011 Page 76 of 149 This trial consists of a screening period, a treatment period and a follow-up period. Following the screening visit (Visit 1) and the four-week screening period, patients will be randomised into the double-blind portion of the study (Visit 2). Additional visits will be scheduled after 4, 8, 16 and 24 weeks of therapy (Visits 3, 4, 5 and 6) and once 21 days post-treatment (Visit 7). For patients participating in the pharmacokinetic evaluations, additional visits will be scheduled after 1, 2 and 3 weeks of therapy (Visit 2A, 2B, and 2C). Patients should make every attempt to complete the study as specified. Investigators should encourage patient treatment compliance and adherence to other protocol specific activities. All deviations from the planned visit schedule will be documented. Rescheduling in general • A patient may be rescheduled twice (within two weeks of the scheduled visit date) due to lack of medication washout compliance. Rescheduling prior to randomization • The screening period (between Visit 1 and Visit 2) may be extended by an additional 4 weeks for administrative reasons. • If a patient experiences an asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1, the visit will be postponed until 4 weeks following recovery from the infection or exacerbation. • If a patient experiences an asthma exacerbation or respiratory tract infection during the screening period (between Visit 1 and 2), randomisation will be postponed until 4 weeks following recovery from the infection or exacerbation. • If the screening period is extended by more than an additional 4 weeks, but not more than an additional 8 weeks (calculated from the initial Visit 1 if the reversibility test and ACQ are repeated as described below), the screening examination has to be repeated prior to randomisation. The repeat screening examination will include a physical examination, vital signs (blood pressure and pulse rate), 12-lead ECG and clinical laboratory evaluation (haematology, serum chemistry, and pregnancy test). The patient should return for these evaluations 2 weeks prior to the re-scheduled randomisation visit (Visit 2). All adverse events and concomitant therapies will be recorded. If the screening period is to be extended more than an additional 8 weeks, the clinical monitor should be contacted. • If at Visit 1 the reversibility criterion (inclusion criterion 5) is not met, the reversibility test may be repeated once within two weeks. The ACQ should in this Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 79 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 77 of 149 case also be repeated (prior to any discussion with a health professional and prior to pulmonary function testing) and this ACQ score should be used to assess patient eligibility. Visit 2 must be scheduled 4 weeks after the repeated reversibility test of Visit 1. • If on Visit 2, the eDiary completion compliance is below 80%, rescheduling of Visit 2 is required. Patients may continue the trial if they show an eDiary completion compliance of at least 80% at the randomisation visit (Visit 2). Rescheduling of Visit 2 (for two weeks) is allowed twice. eDiary Completion Compliance is derived from the number of acceptable sessions. A session is either a set of morning data entries, or evening data entries. An acceptable session during the screening period is one in which at least two acceptable PEFs at the morning and evening session were stored and all diary data were entered. The calculation of the compliance during the screening period will be based on the last 10 days prior to Visit 2. • If on Visit 2, the inclusion criteria of an ACQ mean score of ≥ 1.5 or of the FEV1 variation within ± 30% between the pre-bronchodilator value of Visit 1 as compared to the pre-dose FEV1 of Visit 2 (absolute values of FEV1) are NOT met, Visit 2 can be repeated once within two weeks. If a respiratory tract infection or asthma exacerbation in the screening period was the reason for the FEV1 deterioration resulting in a FEV1 variation from Visit 1 of below 30%, Visit 2 may be repeated four weeks following recovery from the infection or exacerbation. At the repeated Visit 2, both criteria must be met; otherwise the patient is considered as non-eligible. Refer to Section 4.2.1.3 for details on medications allowed to control acute asthma exacerbations and restrictions for these medications prior to PFTs. Rescheduling after randomization • If rescheduling of visits after randomisation is necessary, the total daily doses of the Respimat® inhaler and MDI (i.e. 30 days) need to be obeyed and the need to take reserve medication should be avoided. If possible an additional intermediate visit to dispense the new drug supply should be planned in order to avoid use of the reserve trial medication. Refer to the Flow Chart for the rescheduling time windows. • If rescue medication is administered during a visit day within 8 hours prior to the pre-dose PFT, the visit will be rescheduled once. Further rescheduling should be discussed with the local clinical monitor. • Subsequent visits should always be planned to take place at the originally scheduled dates to assure a 24 week treatment period. Refer to Section 4.2.1.3 for details on medications allowed to control acute asthma exacerbations and restrictions for these medications prior to PFTs. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 80 Page U12-2466-01 Trial Protocol 6.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS 6.2.1 Screening and run-in period(s) 5 Dec 2011 Page 78 of 149 Informed Consent Visit (Visit 0) • • • • • • Informed Consent will be obtained prior to patient participation in the trial, which includes any medication washout procedures or restrictions. Upon obtaining Informed Consent, the patient will be instructed on the medication washout and other restrictions needed for the screening pulmonary function test at Visit 1. At sites capable of performing 24h PFT: patients will be asked to give Informed Consent for the 24-h PFT at visit 6. At selected sites: patients will be asked to give Informed Consent for the PK analyses. Patients will be asked to give Informed Consent to the pharmacogenomic analyses. The patient will receive directions on the as needed use of the salbutamol (albuterol) MDI (as rescue medication) that will be dispensed at this visit. A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid unnecessary washout procedures in non-eligible patients. Observations and procedures at Visit 1 • • • • • • • • • • Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms prior to any discussion with a health professional and prior to pulmonary function testing. Medication washout compliance will be verified. Demographic data (sex, race, date of birth, height, weight, duration of asthma, asthma background characteristics, pack years, smoking and employment status) will be recorded. Medical history regarding cardiovascular disorders, CVAs, urinary/renal disorders/diseases, cancer and narrow-angle glaucoma will be recorded. Current conditions and conditions for which therapy is given in the last 3 months prior to Visit 1 as well as any chronic disease (excluding asthma) will be recorded (baseline conditions). Physical examination including vital signs (blood pressure and pulse rate) will be conducted and a 12-lead ECG will be recorded. The vital signs (seated) and ECG should be conducted following five minutes of rest and prior to the PFT measurements. All adverse events experienced since signed Informed Consent will be reviewed and recorded. Concomitant therapy for the previous three months will be recorded. Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. Blood samples need to be taken prior to the salbutamol (albuterol) dosing. A urine pregnancy test will be conducted (if applicable). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • • • • • • 81 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 79 of 149 Pulmonary function testing with the MasterScope® CT spirometer will be conducted in the evening between 06.00 and 08.00 pm immediately prior to (-10 min) and 15 to 30 minutes after the inhalation of 4 puffs of salbutamol (albuterol). Question 7 of the ACQ questionaire (regarding pre-bronchodilator FEV1 predicted) will be completed by qualified site staff. Inclusion and exclusion criteria will be reviewed. Patients will be trained in the use of the Respimat® inhaler. The patient's ability to perform technically acceptable pulmonary function tests and their ability to use the Respimat® inhaler will be assessed. Patients qualified to enter the 4-week screening period of the trial will be issued - an electronic peak flow meter with integrated electronic diary (AM3) - a paper patient diary card (and a PK Visit Card, if applicable) - additional rescue medication if needed Patients will receive training and instructions on - the use of the AM3 (including performance of PEFs and completing the eDiary) - the use of rescue medication - medication restrictions and washout requirements for the screening period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Screening Period Patients who qualify on Visit 1 will measure twice-daily PEF and record their asthma symptoms and the number of puffs of rescue medication (daytime and nighttime) in the eDiary during the 4-week screening period. If there is any indication during the screening period that the patient is not stable enough to complete the trial or that the patient is non-compliant with the trial medication or restrictions, the patient should not be randomised. This evaluation should take place by the investigator after PEF and eDiary data saved in the AM3 have been downloaded and reviewed. Details of any patient who is screened for the trial but is found to be ineligble must be entered in the Enrolment log and documented in the eCRF. 6.2.2 Treatment period(s) Observations and procedures at Visit 2 • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic. AM3 data will be downloaded and reviewed by the investigator. eDiary compliance should be reviewed (see inclusion criterion 12 and Section 6.1). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • • • • • • • • • • • 82 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 80 of 149 Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional. Medication washout compliance will be verified. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. Patients will be trained in the use of the Respimat® inhaler. Note: the patient should NOT inhale from a placebo inhaler at this visit. Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. The variation from the pre-bronchodilator FEV1 at Visit 1 will be determined (must not exceed ± 30%). Question 7 of the ACQ questionnaire (regarding pre-bronchodilator FEV1 predicted) will be completed by qualified site staff. Vital signs will be conducted in conjunction with the pre-dose PFT measurement. Inclusion and exclusion criteria will be reviewed to determine eligibility. Patients who meet all inclusion criteria and violate none of the exclusion criteria will be assigned to treatment according to the following procedure: 1. Randomise patient using IVRS. 2. Allocate the appropriate medication kits using IVRS. • • • • • • Blood samples will be drawn from patients who consented to participate in the genotyping investigation. If blood sampling is not possible at this visit, it is also allowed at any subsequent visit. For a subset of patients at selected sites: blood and urine samples will be collected for evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). Refer to the Flow Chart for the time schedule. Patients will be issued - study medication including reserve medication - additional rescue medication if needed - a new paper patient diary card if needed (and a PK Visit Card, if applicable) Patients will receive training and instructions on - the use of the AM3 (including performance of PEFs and completing the eDiary) Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 83 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 81 of 149 - the use of rescue medication - medication restrictions and washout requirements for the treatment period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Observations and procedures at Visits 2A, 2B and 2C. • • • For a subset of patients at selected sites: blood samples will be collected for the evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic prior to inhalation of medication. eDiary data will NOT be downloaded. Observations and Procedures at Visits 3, 4 and 5 • • • • • • • • • • • • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic. AM3 data will be downloaded and reviewed by the investigator. Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered questionnaire. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional. Medication washout compliance will be verified. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. Study medication from the previous visit will be collected prior to study medication administration and new study medication will be dispensed. Allocate the appropriate medication kits (including new reserve medication if needed) using IVRS. Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. Question 7 of the ACQ questionnaire (regarding prebronchodilator FEV1 predicted) will be completed by qualified site staff. For a subset of patients at selected sites at Visit 3: blood and urine samples will be collected for evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • • • 84 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 82 of 149 Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). Refer to the Flow Chart for the time schedule. Patients will be issued - new study medication (including reserve medication if needed). - additional rescue medication if needed - a new paper patient diary card if needed Patients will receive instructions on - medication restrictions and washout requirements for the treatment period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Observations and Procedures at Visit 6 • • • • • • • • • • • • • • • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic. AM3 data will be downloaded and reviewed by the investigator. Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional (physician, nurse or study coordinator). PASAPQ will be patient self-administered in selected countries. The PASAPQ should be the fourth questionnaire completed during a clinic visit and should precede any discussion with a health professional (physician, nurse or study coordinator). Medication washout compliance will be verified. The AM3 will be collected. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. The patient's smoking status will be assessed. A 12-lead ECG will be recorded Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. A urine pregnancy test will be conducted (if applicable). Study medication from the previous visit will be collected after study medication administration and no new study medication will be dispensed. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • • • • • • 6.2.3 85 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 83 of 149 Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. Question 7 of the ACQ questionnaire (regarding prebronchodilator FEV1 predicted) will be completed by qualified site staff. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). PFTs will be performed until 24 hours post-dosing in patients who consented to this. Refer to the Flow Chart for the time schedule. Physical examination including vital signs (blood pressure and pulse rate) will be conducted. Patients will be issued additional rescue medication if needed. Patients will receive instructions for the follow-up period. End of trial and follow-up period Observations and Procedures at Visit 7 The patient will visit the clinic 21 days after the last dose of trial medication. Any adverse events or changes in concomitant therapies that have occurred will be recorded in addition to the trial completion information. Any ongoing (serious) adverse events should be followed until the event is resolved or there is a mutual agreement between the investigator and CML that follow-up is sufficient. Rescue medication will be collected. Observations and Procedures in case of premature withdrawal The following procedures should be performed after any premature withdrawal of patients that took at least one dose of trial medication • • • • • • • • • • Physical examination including vital signs (blood pressure and pulse rate) will be conducted A 12-lead ECG will be recorded Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. A urine pregnancy test will be conducted (if applicable). Adverse events (including exacerbations and HCRU data) and changes in concomitant therapies will be recorded. Any ongoing (serious) adverse events should be followed until the event is resolved or there is a mutual agreement between the investigator and CML that follow-up is sufficient. All SAEs that occur within 21 days after a patient terminates trial medication must be reported according to Boehringer Ingelheim SAE procedures. Smoking status will be assessed. Study medication (used and unused) will be collected. AM3 data will be downloaded and reviewed by the investigator. The AM3 will be collected. Patient's paper diary card will be collected and reviewed. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 86 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 84 of 149 The investigator should make every effort to perform the follow-up visit 21 days after the last dose of study medication on patients that withdrew prematurely. Vital status information After any premature withdrawal of patients that took at least one dose of trial medication, the vital status information (dead or alive) will be collected on the originally planned visit date of the follow up visit (Visit 7). The vital status eCRFs will be completed. Collection of vital status information does not require a patient visit. Patients will be asked to consent to telephone follow-up at their normal exit date from the trial. If death occurs, the investigator will review the circumstances, including the relevant medical records to ascertain the most likely primary and secondary causes. Any death during the vital status observation period needs to be reported as SAE by the investigator according to the Boehringer Ingelheim SAE procedures. Collection of vital status information will be performed in accordance with national ethical and regulatory guidelines. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 7. 87 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 85 of 149 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE This trial is one of two twin trials with identical protocols (BI trial numbers 205.418 and 205.419). The analysis described below will be performed for this trial and detailed in the Clinical Trial Report. In addition, a meta-analysis will comprise the analyses on combined data from the twin studies. This comprehensive meta-analysis, specifically indicated below, will be performed on the combined data in order to take advantage of the larger sample size. Separate documentation will be produced for each of the above. 7.1 STATISTICAL DESIGN - MODEL Design This is a randomised double-blind, placebo- and active-controlled, multinational, parallelgroup trial to evaluate the efficacy and safety of 2.5 and 5 µg of tiotropium inhalation solution delivered by the Respimat® inhaler (once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in moderate persistent asthma patients treated with at least medium doses of inhaled corticosteroids. The comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. Primary objective The primary objective of the trial is to demonstrate superiority of tiotropium (2.5 µg and 5 µg) with regard to primary pulmonary function endpoints after 24 weeks of treatment as compared to placebo. Meta-analysis: the primary objective of the meta-analysis is to demonstrate superiority in terms of asthma control (primary ACQ endpoint) of tiotropium (2.5 µg and 5 µg) over placebo after 24 weeks of treatment, on pooled data from the twin trials 205.418 and 205.419. Any comparison of tiotropium versus salmeterol and placebo versus salmeterol will only provide basic descriptive displays and will be used for descriptive purposes only. Primary Endpoints There are two co-primary variables in this trial (Peak FEV1 and trough FEV1) as lung function endpoints measured in relation to the evening dose. The first co-primary efficacy endpoint is the peak FEV1 response (within 3 hours post dosing) determined at the end of the 24-weeks treatment period. Peak FEV1 is defined as the maximum value of the FEV1 measurements within 3 hours post evening dosing. Peak FEV1 response is defined as the change from baseline in peak FEV1. Baseline is the pre-treatment FEV1 measured at Visit 2 in the evening just prior to the evening dose of patient’s usual asthma medication and first dose of trial medication. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 88 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 86 of 149 The second co-primary endpoint is the trough FEV1 response determined at the end of the 24week treatment period. Trough FEV1 is defined as the pre-evening-dose FEV1 measured in the clinic just prior to the inhalation of the evening doses. Trough FEV1 response is defined as the change from baseline in trough FEV1. Meta-analysis The primary endpoint is the responder as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period on combined data from the two twin trials 205.418 and 205.419. The two trials will be combined to get an adequate number of patients for this endpoint. The two trials will run concurrently. Responder is defined as an improvement with at least the minimum clinically important difference (MCID) in the ACQ which is defined as 0.5. Please refer to Section 5 for the list of secondary and safety endpoints. Baseline For all clinical spirometry endpoints, the pulmonary function test in the evening of the randomisation visit (Visit 2), measured just prior to the evening dose of patient’s usual ICS medication and first administration of the randomised treatment, is defined as baseline. For AQLQ (S) and ACQ, baseline is defined as the value obtained at the randomisation visit (Visit 2). For all endpoints measured with the AM3, the average of the data obtained in the week immediately preceding Visit 2 will be used as baseline. Response Response is defined as the change from baseline. Centre Centres might be pooled for analysis if necessary. The detailed strategy for pooling will be specified in the statistical analysis plan prior to database lock and unblinding. 7.2 NULL AND ALTERNATIVE HYPOTHESES The hypothesis will be tested in a stepwise manner to control the probability of Type I error: firstly, to establish the efficacy of tiotropium 5 µg over placebo, and secondly, to establish the efficacy of tiotropium 2.5 µg over placebo. The following hypotheses (α = 0.025 onesided) will be tested for the first co-primary endpoint: H01: H11: Peak FEV1(response) (tiotropium 5 µg) ≤ Peak FEV1(response) (placebo) versus Peak FEV1 (response) (tiotropium 5 µg) > Peak FEV1 (response) (placebo) If the null hypothesis H01 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 H02: H12: 89 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 87 of 149 Trough FEV1 (response) (tiotropium 5 µg) ≤ Trough FEV1 (response) (placebo) versus Trough FEV1 (response) (tiotropium 5 µg) > Trough FEV1 (response) (placebo) If the null hypothesis H02 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: H03: H13: Peak FEV1(response) (tiotropium 2.5 µg) ≤ Peak FEV1(response) (placebo) versus Peak FEV1 (response) (tiotropium 2.5 µg) > Peak FEV1 (response) (placebo) If the null hypothesis H03 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: H04: H14: Trough FEV1 (response) (tiotropium 2.5 µg) ≤ Trough FEV1 (response) (placebo) versus Trough FEV1 (response) (tiotropium 2.5 µg) > Trough FEV1 (response) (placebo) Each step will only be considered confirmatory providing all the previous steps were successful. If any of the previous steps were not successful the analysis of the current step will be considered descriptive. Comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. Meta-analysis The primary endpoint (ACQ) will be tested on pooled data from the two twin-trials 205.418 and 205.419 only. The hypothesis will be tested in a stepwise manner to control the probability of Type I error: firstly, to establish the efficacy of tiotropium 5 µg over placebo, and secondly, to establish the efficacy of tiotropium 2.5 µg over placebo. It will not be used in the sequential testing for US registration. The following hypotheses (α = 0.025 one-sided) will be tested for this endpoint: H0M1: H1M1: Number of ACQ responders (tiotropium 5 µg) ≤ Number of ACQ responders (placebo) versus Number of ACQ responders (tiotropium 5 µg) > Number of ACQ responders (placebo) If the null hypothesis H0M1 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested on pooled data from both twin trials: H0M2: H1M2: Number of ACQ responders (tiotropium 2.5 µg) ≤ Number of ACQ responders (placebo) versus Number of ACQ responders (tiotropium 2.5 µg) > Number of ACQ responders (placebo) Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 90 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 88 of 149 Comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. 7.3 PLANNED ANALYSES The efficacy analyses and the summary of safety data will be based on all randomised patients that received at least one dose of trial medication; this set of patients will be the Treated Set. The efficacy analyses and the summary of safety data will be based on all randomised patients that received at least one dose of trial medication; this set of patients will be the Treated Set (TS), the Full Analysis Set (FAS) includes all patients of the TS for which at least one post-baseline efficacy measurement is available.Full and clear definitions of each analysis set will be provided in the Trial Statistical Analysis Plan (TSAP). All individual data will be listed. Adherence to the protocol (e.g., inclusion/exclusion criteria, times of measurement, completeness and consistency of data, etc.) will be checked using the data recorded. Standard statistical parameters (number of non-missing values, mean, standard deviation (SD), median, quartiles, minimum, and maximum) or frequency tables will be calculated where appropriate. In general, these parameters or frequencies will be calculated separately for each treatment. Data from subjects who are screened but not treated will be listed, but not included in summary statistics. 7.3.1 Primary analyses The primary analysis will be performed on the FAS. The primary FEV1 endpoints (change from baseline) will be analyzed using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Analyses will include the fixed, categorical effects of treatment, centre, visit, and treatmentby-visit interaction, as well as the continuous, fixed covariates of baseline value and baseline value-by-visit-interaction. An unstructured (co)variance structure will be used to model the within-patient errors. If this analysis fails to converge, the following structures will be tested Compound Symmetry, Autoregressive Model (AR (1)) or Spatial Covariance. The (co)variance structure converging to the best fit, as determined by Akaike’s information criterion, will be used as the primary analysis. The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. Significance tests will be based on leastsquares means using a two-sided alpha=0.05 (two-sided 95/% confidence intervals). The primary comparison will be the contrast between treatments at week 24. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. For sensitivity analysis of the primary endpoint an Analysis of Covariance Model (ANCOVA) of the 24-week response data will be performed with baseline, centre and Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 91 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 89 of 149 treatment as main effects. Centre will be included as random main effect. Missing data wil be imputed according the rules in Section 7.4. Meta-analysis The analysis on the primary ACQ endpoint will be conducted after combining the data from the two twin trials 205.418 and 205.419. The number of responders (responder as defined in section 5.1.1.1) wil be analysed using Fisher’s Exact test. The odds ratio and corresponding 95% confidence interval will be presented along with the p-value. 7.3.2 Secondary analyses PFT Parameters The PFT parameters Peak FVC, trough FVC and AUC0-3h FEV1/FVC (change from baseline) and PEF variability will be analysed as detailed above for the co-primary FEV1 endpoint (24 weeks after treatment). In addition individual FEV1, FVC and PEF measurements at all time-points (4, 8, 16 and 24 weeks after treatment) including peak, trough and AUC0-3h will be analysed as mentioned above. The mean pre-dose morning and evening PEF and FEV1 measured with the AM3 device by the patients at home (weekly mean and overall mean) will be compared using the same method as mentioned above. For a subset of patients the endpoints FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h) will be analysed as detailed above for the co-primary FEV1 endpoint (after 24-week treatment). For a subset of patients the 5 and 15 minutes post dose endpoints FEV1 peak response, FEV1 (AUC0-3h), FVC peak response and FVC (AUC0-3h) will be analysed using an Analysis of Covariance Model (ANCOVA) with centre and treatment as main effects. Centre will be included as random main effect. No imputation of missing data will take place. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. AQLQ These parameters (change from baseline) will be analysed as detailed above for the coprimary FEV1 endpoint at all clinic visits during the 24 week treatment period. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 92 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 90 of 149 Use of PRN salbutamol The number of puffs rescue therapy used per day (i.e. daytime, night-time and the full 24 hour period) will be analysed using Poisson regression with log exposure as offset and adjusting for overdispersion. In case Poisson regression gives a bad fit due to large amount of zeros, negative binomial regression will be used for the analysis. Asthma symptoms Nocturnal and daytime asthma symptoms as well as the number of asthma free days will be analysed in the same way as detailed above for the co-primary FEV1 endpoint. Meta-analysis Time to first (severe) asthma exacerbation The analysis of (severe) asthma exacerbations will be conducted after combining the data from the two twin trials 205.418 and 205.419. Treatment groups will be compared with respect to the time to first (severe) asthma exacerbation during the 24 week randomised treatment period. Only (severe) asthma exacerbations with an onset during randomised treatment will be included in the analysis. The analysis will be performed using Cox's proportional hazards regression model with only treatment fitted as an effect. The hazard ration and corresponding 95% confidence interval will be presented along with the p-value. Kaplan-Meier estimates of the probability of not experiencing a (severe) asthma exacerbation over the treatment period will be plotted by treatment group. ACQ These parameters (change from baseline) will be analysed as detailed above for the coprimary FEV1 endpoint at all clinic visits during the 24 week treatment period, for each trial separately and on pooled data from the two twin trials 205.418 and 205.419. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. 7.3.3 Safety analyses All treated patients will be included in the safety analysis. In general, safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis testing is planned prospectively. Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary. Standard BI summary tables and listings will be produced to compare the incidence of adverse events across the treatment groups. All events with an onset after the first dose of trial medication up to a period of 30 days after the last dose of trial Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 93 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 91 of 149 medication will be assigned to the treatment period for evaluation. Other adverse events will be assigned either to the screening or post study period as appropriate. Changes from baseline in vital signs will be summarized by treatment group and compared descriptively. 7.3.4 Interim analyses No interim analysis is planned. 7.3.5 Pharmacokinetic analyses Tiotropium will be analysed in blood and urine samples collected from a subset of patients in this trial with the objective of determining the pharmacokinetics of tiotropium in patients with moderate persistent asthma. Pharmacokinetics of tiotropium will be determined following the administration of a single dose and multiple doses of 2.5 and 5 µg tiotropium via Spiriva® Respimat®. Also, pre- and 5 minutes post-dose blood samples will be obtained at visits 2A, 2B and 2C to determine time needed to reach steady-state. It is not planned to test any statistical hypothesis with respect to the pharmacokinetic parameters. Instead, they will be presented in their entirety and evaluated by descriptive statistical methods 7.3.6 Pharmacodynamic analyses Not applicable. 7.3.7 Pharmacogenetic analyses Not applicable. 7.3.8 Health economic analyses The details of HCRU and EQ-5D analysis will be determined in a separate analysis plan. This HCRU and EQ-5D analysis will not be part of the clinical trial report. 7.3.9 PASAPQ analysis An Analysis of Covariance Model (ANCOVA) will be performed with centre and treatment as main effects. Centre will be included as random main effect. Missing data will be imputed according the rules in Section 7.4. 7.4 HANDLING OF MISSING DATA Every effort will be made to collect FEV1 data at the specified time points, except if the patient has used rescue medication. Post-baseline missing FEV1 values will be replaced with the least favourable FEV1 value if a patient withdraws due to worsening of asthma. Randomly missing data after inhalation of study medication for which there are data from that visit both before and after inhalation will be linearly interpolated. Randomly missing data Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 94 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 92 of 149 with no subsequent non-missing values for that visit will be imputed using the last observation carried forward (LOCF) technique to calculate peak and AUC. Data missing due to worsening of asthma or need of rescue medication will be replaced with the least favourable data for that visit (including pre-dose values). Completely missing data at a post-baseline visit, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used. Completely missing data at the baseline visit, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used. No post baseline data available at all, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used from previous visit. For Patient Daily Record data, when the number of salbutamol (albuterol) doses is missing but other data are filled out on any given day then these data will be imputed by zero (because the presence of other data is interpreted as meaning that the patient was not having a problem). Before calculating the baseline and treatment means, the following data will be excluded: • • • • • data with a missing Patient Daily Record date, PEF data which is less than 50 L/min, duplicate data for the same date Daily Record data for days after drug was discontinued, Patient Daily Record data for the period during which oral steroids or theophylline doses were increased because of an exacerbation of asthma. Missing AQLQ (S), ACQ and PASAPQ data will be imputed according the methods used in the validation of the respective questionnaire and will be described in detail in the TSAP. Methods to handle any other exceptional cases will be considered only before unblinding the data and will be applied in a manner consistent with other trials of this type. Full details on the handling of missing data will be provided in the TSAP. 7.5 RANDOMISATION Patients will be randomized 1:1:1:1 to 2.5 µg tiotropium inhalation solution, or 5 µg tiotropium inhalation solution, or salmeterol HFA-MDI, or placebo over the 24-week treatment period. The sponsor will arrange for the randomisation as well as packaging and labelling of trial medication. Each patient will have a single randomisation number indicating the allocated treatment. Medication numbers will be assigned at a visit level. The randomisation list will be generated using a validated system involving a pseudo-random number generator and a supplied seed number, thereby ensuring that the resulting allocation Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 95 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 93 of 149 to a treatment is both reproducible and nonpredictable. The seed numbers will be documented in the report. An Interactive Voice Response System (IVRS) and/or an Interactive Web Response System (IWRS) will be used. BI will provide the randomisation and medication number lists to the IVRS/IWRS provider and the sites will contact the IVRS/IWRS to obtain the next medication numbers to be dispensed to the patient. 7.6 DETERMINATION OF SAMPLE SIZE For the first two co-primary variables sample size estimation is performed under the following assumptions. For the first co-primary variable peak FEV1 a SD between 310mL and 370mL was observed as worst case SD in period 1 of trial 205.341 for change from baseline. For the second coprimary variable trough FEV1 a SD between 290mL and 350mL was observed in trial 205.342 and between 266mL and 277mL in period 1 of trial 205.341 for change from baseline. Sample size is calculated using a two-group t-test with a power of 90% and a type I error probability of 2.5% (one-sided). The following Table 7.6.: 1 provides several sample size considerations based on a two group t-test with a power of 95% and a type I error of 2.5% (one-sided), to get on overall power for the first co-primary endpoints of about 90% (0.95 x 0.95 = 0.9025) considerations depending on number of patients per group using different scenarios. Table 7.6: 1 Number of patients necessary for the first two co-primary endpoints (Nquery, version 6.01) Endpoint peak FEV1 Delta 150 135 120 SD 310 340 370 310 340 370 310 340 370 N per group 112 135 160 139 166 197 175 210 249 trough FEV1 Delta SD 270 140 310 350 270 120 310 350 270 100 310 350 N per group 98 129 164 133 175 223 191 251 320 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 96 Page U12-2466-01 5 Dec 2011 Page 94 of 149 Trial Protocol With a sample size of 250 patients per group one is able to detect a delta of 120mL and 100mL for peak FEV1 and trough FEV1, respectively under the expectation to have a SD for change from baseline of 370mL in peak FEV1 and 310mL in trough FEV1. Sample size consideration for the third co-primary variable ACQ is based on the endpoint of the relative frequency of patients who reached the minimum clinically important difference (MCID) in the ACQ which is defined as 0.5 (i.e. ACQ score difference to baseline ≥ 0.5 then responder) [R09-1589]. Assuming a delta of 10% in responder rate in comparison to placebo, the following number of patients per group based on a pooling the data of the two trials would be necessary depending on the expected placebo rate. Table 7.6: 2 Number of patients necessary for the third co-primary endpoint ACQ (Nquery, version 6.01) under the assumption of a power of 90% Expected placebo response rate Sample Size per group 20% 392 30% 477 40% 519 With 500 patients per treatment group, the power is 91.34% for the pooled analysis assuming a placebo response rate of 30%. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 8. 97 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 95 of 149 INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS The trial will be carried out in compliance with the protocol, the principles laid down in the Declaration of Helsinki, version as of October 1996 (as long as local laws do not require to follow other versions), in accordance with the ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the treating physician of the patient. The investigator should inform the sponsor immediately of any urgent safety measures taken to protect the study subjects against any immediate hazard, and also of any serious breaches of the protocol/ICH GCP and, for Japan, the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997). The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract. As a general rule, no trial results should be published prior to finalisation of the Clinical Trial Report. Insurance Cover: The terms and conditions of the insurance cover are made available to the investigator and the patients via documentation in the ISF (Investigator Site File). 8.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT This trial will be initiated only after all required legal documentation has been reviewed and approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and competent authority (CA) according to national and international regulations. The same applies for the implementation of changes introduced by amendments. Prior to patient participation in the trial, written informed consent must be obtained from each patient (or the patient’s legally accepted representative) according to ICH GCP and to the regulatory and legal requirements of the participating country. Each signature must be personally dated by each signatory and the informed consent and any additional patientinformation form retained by the investigator as part of the trial records. A signed copy of the informed consent and any additional patient information must be given to each patient or the patient’s legally accepted representative. The patient must be informed that his/her personal trial-related data will be used by Boehringer Ingelheim in accordance with the local data protection law. The level of disclosure must also be explained to the patient. The patient must be informed that his / her medical records may be examined by authorised monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities. ADDITIONAL INFORMATION FOR JAPAN The investigator must give a full explanation to trial patients including the items listed below in association with the use of the patient information form, which is prepared avoiding the Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 98 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 96 of 149 use of technical terms and expressions. The patient is given sufficient time to consider participation in the trial. The investigator obtains written consent of the patient's own free will with the informed consent form after confirming that the patient understands the contents. The investigator must sign (or place a seal on) and date the informed consent form. If a trial collaborator has given supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the informed consent. The following items need to be included: 1. That the clinical trial involves research, i.e. testing of drugs. 2. The objectives of the clinical trial. 3. The clinical trial procedures (including those aspects of the clinical trial that are experimental, patient inclusion criteria, specific fasting requirements for laboratory, and the probability for random assignment to each treatment. 4. Anticipated benefits of the investigational product and anticipated risks to the patient. 5. The expected duration of the patient's participation in the clinical trial. 6. The approximate number of patients involved in the clinical trial. 7. The reasonably foreseeable risks or inconveniences to the patient. If there is no intended clinical benefit to the patient, the patient should be made aware of this. 8. The alternative procedure(s) or course(s) of treatment that may be available to the patient, and their important potential benefits and risks. 9. The patient's primary physician will be informed by the investigator about participation in the trial. 10. The compensation and/or treatment available to the patient in the event of trial-related injury. 11. That the patient's participation in the clinical trial is voluntary and that the patient may refuse to participate in or withdraw from the clinical trial at any time, without penalty or loss of benefits to which the patient is otherwise entitled. 12. That the patient or the patient's proxy consenter will be informed in a timely manner if information becomes available that may be relevant to the patient's willingness to continue participation in the clinical trial. 13. The foreseesable circumstances and/or reasons under which the patient's participation in the clinical trial may be terminated. 14. That the monitor(s), the auditor(s), the IRB, and the regulatory authority(ies) may be provided direct access to the patient's original medical records. In such cases, the confidentiality of the patient should be protected, and by signing and sealing an informed consent form, the patient or the patient's proxy consenter is authorising such access. 15. The type of the IRB which is used for the reviews and deliberations in regard to the appropriate conduct of the clinical trial. The information to be reviewed by each IRB and any other topics concerning the IRBs involved in the clinical trial. 16. If the results of the clinical trial are published, the patient's identity will remain confidential. 17. The anticipated expenses, if any, to the patient for participating in the clinical trial. 18. The anticipated prorated payment, if any, to the patient for participating in the clinical trial. 19. The name, title, and address of the investigator or the sub-investigator to contact. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 99 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 97 of 149 20. The person(s) to contact for further information regarding the clinical trial and the rights of patient, and whom to contact in the event of a trial-related injury. 21. That necessary treatment is available to the patient in the event of trial-related injury and all other issues in regards to compensation in the event of any trial-related injury. 22. The patient's responsibilities. 8.2 DATA QUALITY ASSURANCE A quality assurance audit/inspection of this trial may be conducted by the sponsor or sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance auditor will have access to all medical records, the investigator’s trial-related files and correspondence, and the informed consent documentation of this clinical trial. The data management procedures to ensure the quality of the data are described in detail in the trial data management and analysis plan (TDMAP) available in the CTMF. 8.3 RECORDS Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on paper or via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to Section 4.1.8. 8.3.1 Source documents Source documents provide evidence for the existence of the patient and substantiate the integrity of the data collected. Source documents are filed at the investigator’s site and could for example be physician's notes in patient files, ECG results (original or copies of printouts), lung function test results, worksheets or patient diaries. Data entered in the eCRFs must be derived from source documents and must be consistent with the source documents or the discrepancies must be explained. The investigator may need to request previous medical records or transfer records, depending on the trial; also current medical records must be available. 8.3.2 Direct access to source data and documents The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review and regulatory inspection, providing direct access to all related source data / documents. CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and medical test results must be available at all times for review by the sponsor’s clinical trial monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by reviewing the documents described in Section 8.3.1. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 8.3.3 100 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 98 of 149 Storage of records ADDITIONAL INFORMATION FOR JAPAN ONLY Storage period of records Trial site(s): The trial site(s) must retain the source documents and essential documents for a period defined by the Japanese GCP regulation and the sponsor's SOP. Sponsor: The sponsor must retain the essential documents according to the sponsor's SOPs. When it is no longer necessary for the trial site to retain the source documents and essential documents, the sponsor must notify the head of trial site. 8.4 LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS 8.4.1 Listedness To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. Therefore a unique reference document for the evaluation of listedness needs to be provided. For the 2.5 and 5 µg tiotropium bromide inhalation solution this is the current version of the Investigator’s Brochure (U92-0551). For the salmeterol xinafoate metered dose inhaler this is the EU SP (Serevent Evohaler). For the non-investigational medicinal product salbutamol/albuterol, the reference document is the US-PI (Proair HFA). The current versions of these reference documents are to be provided in the ISF. No AEs are classified as listed for matching placebo, study design, or invasive procedures. 8.4.2 Expedited reporting to health authorities and IECs/IRBs Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local regulatory requirements. Further details regarding this reporting procedure are provided in the Investigator Site File. 8.5 STATEMENT OF CONFIDENTIALITY Individual patient medical information obtained as a result of this trial is considered confidential and disclosure to third parties is prohibited with the exceptions noted below. Patient confidentiality will be ensured by using patient identification code numbers. Treatment data may be given to the patient’s personal physician or to other appropriate medical personnel responsible for the patient’s welfare. Data generated as a result of the trial need to be available for inspection on request by the participating physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities, i.e. the CA. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 8.6 101 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 99 of 149 COMPLETION OF TRIAL ADDITIONAL INFORMATION FOR JAPAN ONLY When the trial is completed, the investigator should inform the head of the trial site of the completion in writing, and the head of the trial site should promptly inform the IRB and sponsor of the completion in writing. ADDITIONAL INFORMATION FOR EU MEMBER STATES The EC/competent authority in each participating EU member state needs to be notified about the end of the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the CTP) or early termination of the trial. 8.7 PROTOCOL VIOLATIONS ADDITIONAL INFORMATION FOR JAPAN ONLY The investigator or sub-investigator should record all CTP violations. The investigator should provide and submit the sponsor and the head of the trial site the records of violations infringing the Japanese GCP or violations to eliminate an immediate hazard to trial subjects and for other medically inevitable reasons. 8.8 COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL RELATED INJURY ADDITIONAL INFORMATION FOR JAPAN ONLY In the event of health injury associated with this trial, the sponsor is responsible for compensation based on the contract signed by the trial site. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 102 Page U12-2466-01 Trial Protocol 9. REFERENCES 9.1 PUBLISHED REFERENCES 5 Dec 2011 Page 100 of 149 P86-0614 Beck R, Robertson C, Galdes-Sebaldt M, Levison H Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma. J Pediatr 107, 605 - 608 (1985) P97-9482 Beakes DE The use of anticholinergics in asthma. J Asthma 34 (5) 1997: 357368 P98-7763 Lanes SF, Garrett JE, Wentworth CE, Fitzgerald JM, Karpel JP. The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma: a pooled analysis of three trials. Chest 114 (2) 1998: 365-372 P98-9345 Plotnick LH, Ducharme FM. Should inhaled anticholinergics be added to beta2 agonists for treating acute childhood and adolescent asthma? A systematic review. Br Med J 317 (7164) 1998: 971-977 P99-02952 Rodrigo G, Rodrigo C, Burschtin O. A meta-analysis of the effect of ipratropium bromide in adults with acute asthma. Am J Med 107 (4) 1999: 363-370 P04-11193 Israel E, et al. Use of regulary scheduled albuterol treatment in asthma: genotype statified, randomised, placebo-controlled cross-over trial. Lancet 364 (9444) 2004: 1505-1512 P05-01207 Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev (3) 2004 [P05-02607] Kozma CM, Slaton TL, Monz BU, Hodder R, Reese PR. Development and validation of a patient satisfaction and preference questionnaire for inhalation devices. Treat Respir Med 4(1) (2005): 41-52 P05-05129 Gosens R, Bos IS, Zaagsma J, Meurs H: Protective effects of tiotropium bromide in the progression of airway smooth muscle remodelling, Am J Respir Crit Care Med 2005; 71:1096-1102 P05-08960 Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systemic review with metaanalysis. Thorax 2005; 60 (9): 740-746 P05-11064 Profita M,Di Giorgi R, Sala A, Bonanno A, Riccobono L, Mirabella F, Gjomarkaj M, Bonsignore G, Bousquet J, Vignola: Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients; Allergy 2005; 60:1361-1369 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 103 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 101 of 149 P05-12782 Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J Standardisation of spirometry. Eur Respir J 26 (2) , 319-338 (2005) P06-03400 Wechsler ME, Lehman E, Lazarus SC, Lemanske RF, Boushey HA, Deykin A, et al. Beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173 (5):519-526. P07-10315 Bos IST, Gosens R, Zuidhof AB, Schaafsma D, Halayko AJ, Meurs H, Zaagsma . Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison. Eur Respir J 2007, 30 (4), 653-661 P07-12448 Buehling F, Lieder N, Kuehlmann UC, Waldburg N, Welte T. Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro. Respir Med 2007, 101 (11), 2386-2397 P08-00177 Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 370 (9605), 2118 - 2125 (2007) P09-07838 Asthma Clinical Research Network (ACRN) Long Acting beta agonist Response by GEnotype (LARGE). See website: acrn.org/large.html (access date: 15.06.2009) (2009) P10-03196 Global strategy for asthma management and prevention, Global Initiative For Asthma (GINA) 2009. Available from website: ginasthma.org. R94-1408 Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows.Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J 1993 ;6 (Suppl 16) :5 -40. R96-2382 EuroQol - a new facility for the measurement of health-related quality of life. Health Policy 1990; 16: 199-208 R00-1157 Juniper EF, O´Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999; 14: 902-907 R05-0813 Sato E, Koyama S, Okubo Y, Kubo K, Sekiguchi M Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am J Physiol (Lung Cell Mol Physiol 18) 1998; 274: L970-L979 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 104 U12-2466-01 Trial Protocol 5 Dec 2011 Page 102 of 149 R05-2327 Koyama S, Sato E, Nomura H, Kubo K, Nagai S, Izumi T: Acetylcholine and substance P stimulate bronchial epithelial cells to release eosinophil chemotactic activity. J Appl Physiol. 1998; 84(5):1528-34 R06-0573 Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, et al. Systematic review and meta-analysis of the association between beta2adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol 2005 ;162 (3) :201 -211. R06-0585 Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JPA. Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol 2005 ;115 (5) :963 -972. R08-0092 Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999, 115: 1265-1270. R08-5197 Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P Relationship of the type of tobacco and inhalation pattern to pulmonary and total mortality. Eur Respir J 5, 1111 - 1117 (1992) R09-1589 Juniper E. Asthma Control Questionnaire: background, administration and analysis. See website: qoltech.co.uk; Bosham: QOL Technologies 2005 9.2 UNPUBLISHED REFERENCES U92-0551 Investigator´s Brochure - Tiotropium Bromide, Ba 679 BR (tiotropium bromide inhalation powder and tiotropium bromide inhalation solution). BPO5601. Version 01 March 2008 U96-0240 A double-blind, placebo-controlled, crossover study to determine the effect of inhaled Ba 679 BR (tiotropium) on methacholine responsiveness in patients with mild asthma. 205.121. 03 June 1996. U97-2651 Ba 679 BR: in vitro inhibition studies on cytochrome P450 dependent metabolic reactions. B820. 09 October 1997 U98-3174 The effect of twenty-one day dosing of tiotropium on bronchomotor tone in patients with moderate to severe asthma (a randomized, double-blind, placebo-controlled, parallel study). 205.201. 17 August 1998 U98-3274 The effect of tiotropium in patients with nocturnal asthma (a randomized, double-blind, double- Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 105 U12-2466-01 Trial Protocol 5 Dec 2011 Page 103 of 149 dummy, placebo and active-controlled, parallel study). 205.202. 09 November 1998 U99-1004 New mathematical model for the determination of the slow dissociation kinetics of the long antimuscarinic Tiotropium bromide and BEA 2108 BR in comparison to ipratropium bromide from human muscarinic receptors. BC5.A06. 15 October 1998 U99-1019 The protective effect and safety of 36 µg inhaled tiotropium (Ba 679) against exercise-induced bronchoconstriction in patients with bronchial asthma (double-blind, randomised, placebo-controlled, parallel study). 205.203. 20 October 1998 U02-1222 Evaluation of local tolerability of an acidic (pH=2.7) ® solution for inhalation administered via the RESPIMAT device in 32 asthmatic adults. A single-dose (4 puffs), cross-over randomized study. 205.248. 22 Jan 2002 U07-1752 Ba 679 BR (Tiotropium bromide): Partial validation of an existing LC-MS/MS method for the determination in acidified human urine. PA614. 23 July 2007. U08-2081 M. A Randomised, DoubleBlind, Placebo-Controlled, Crossover Efficacy and Safety Evaluation of 8Week Treatment Periods of Two Doses [5 µg (2 actuations of 2.5 µg) and 10 µg (2 actuations of 5 µg)] of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler as Add-on Therapy in Patients with severe persistent Asthma. 205.341. 22 Oct 2008. U09-1701 A 16-week randomised, placebo-controlled, double-blind, double-dummy, parallel-group study comparing the efficacy and safety of tiotropium inhalation solution delivered by the Respimat inhaler (2 puffs of 2.5 mcg once daily) with that of salmeterol from… 205.342. 14 Aug 2009. U10-1855-01 Revalidation of an existing LCMS/MS method for the determination of tiotropium in human EDTA plasma with lowered LLOQ. TA409B. 22 March 2010. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10. APPENDICES Page 106 U12-2466-01 Trial Protocol - 5 Dec 2011 Page 104 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.1 107 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 105 of 149 INSTRUCTIONS FOR THE USE OF THE RESPIMAT INHALER Instructions for Use Respimat® inhaler How to use your Respimat® inhaler This leaflet explains how to use and care for your Respimat® inhaler. Please read and carefully follow these instructions. The Respimat® inhaler releases medication slowly and gently, making it easy to inhale it into your lungs. The Respimat® inhaler enables you to inhale the medicine contained in a cartridge. You will need to use this inhaler only ONCE A DAY. Each time you use it take two PUFFS. In the box you will find the Respimat® inhaler and the Respimat® cartridge. Before the Respimat ® inhaler is used for the first time, the cartridge provided must be inserted. Respimat® inhaler and the Respimat® cartridge Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 108 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 106 of 149 Inserting the cartridge and preparation for use The following steps 1-6 are necessary before first use: 1) With the grey cap closed, press the safety catch (E) and pull off the clear base (G). 2) Take the cartridge (H) out of the box. Push the narrow end of the cartridge into the inhaler until it clicks into place (2a). The cartridge should be pushed gently against a firm surface to ensure that it has gone all the way in (2b). Do not remove the cartridge once it has been inserted into the inhaler. 3) Replace the clear base (G). Do not remove the clear base again. Safety catch 1 2a 2b 3 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 109 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 107 of 149 To prepare the Respimat® inhaler for first-time use 4) Hold Respimat® inhaler upright, with the grey cap (A) closed. Turn the clear base (G) in the direction of the red arrows on the label until it clicks (half a turn). 5) Open the grey cap (A) until it snaps fully open. 6) Point the Respimat® inhaler towards the ground. Press the dose release button (D). Close the grey cap (A). 4 5 Repeat steps 4, 5 and 6 until a cloud is visible. Then repeat steps 4, 5 and 6 three more times to ensure the inhaler is prepared for use. 6 Your Respimat® inhaler is now ready to use. These steps will not affect the number of doses available. After preparation your Respimat® inhaler will be able to deliver 60 puffs. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 110 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 108 of 149 Using the Respimat® inhaler You will need to use this inhaler only ONCE A DAY. Each time you use it take two PUFFS. I) Hold Respimat® inhaler upright, with the grey cap (A) closed, to avoid accidental release of dose. Turn the clear base (G) in the direction of the red arrows on the label until it clicks (half a turn). I II) II III) Open the grey cap (A) until it snaps fully open. Breathe out slowly and fully, and then close your lips around the end of the mouthpiece without covering the air vents (C). Point your Respimat® inhaler to the back of your throat. While taking in a slow, deep breath through your mouth, press the dose release button (D) and continue to breathe in slowly for as long as you can. Hold your breath for 10 seconds or for as long as comfortable. Repeat steps I and II one more time so that you get the full dose. You will need to use this inhaler only ONCE A DAY. Close the grey cap until you use your Respimat® inhaler again. If the Respimat® inhaler has not been used for more than 3 days release one puff towards the ground. If the Respimat® inhaler has not been used for more than 21 days repeat steps 4 to 6 until a cloud is visible. Then repeat steps 4 to 6 three more times. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 111 Page U12-2466-01 5 Dec 2011 Page 109 of 149 Trial Protocol When to get a new Respimat® inhaler The Respimat® inhaler contains 60 puffs (30 doses). The dose indicator shows approximately how many doses are left. When the pointer enters the red area of the scale, there is, approximately, medication for 15 puffs (7 days) left. Once the dose indicator has reached the end of the red scale (i.e., all 60 doses have been used), the Respimat® inhaler is empty and locks automatically. At this point, the base cannot be turned any further. What if... What if... Reason What to do I can’t turn the base easily. a) The Respimat® inhaler is already prepared and ready to use. a) The Respimat® inhaler can be used as it is. b) The Respimat® inhaler is locked after 60 puffs (30 doses). b) Prepare and use your new Respimat® inhaler. I can’t press the dose release button. The clear base has not been turned. Turn the clear base until it clicks. (half a turn) The clear base springs back after I have turned it. The clear base was not turned far enough. Prepare the Respimat® inhaler for use by turning the clear base until it clicks. (half a turn) I can turn the clear base past the point where it clicks. Either the dose release button With the grey cap closed, has been pressed, or the clear turn the base until it clicks. base has been turned too far. (half a turn) How to care for your inhaler Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at least once a week. Any minor discoloration in the mouthpiece does not affect the performance of your Respimat® inhaler. If necessary, wipe the outside of your Respimat® inhaler with a damp cloth. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 112 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 110 of 149 Further information The Respimat® inhaler must not be disassembled after inserting the cartridge and replacing the clear base. Do not touch the piercing element inside the base. Keep out of the reach and sight of children. Do not freeze. Boehringer Ingelheim Pharma GmbH & Co. KG D - 55216 Ingelheim Germany 0123 HI-Master-Version-Respimat-20080831 PLEASE ALWAYS ENTER THE DATE OF FIRST PRIMING ON THE MEDICATION LABEL! Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.2 113 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 111 of 149 INSTRUCTIONS FOR THE USE OF THE MDI Instructions for Use Please read and carefully follow these instructions. You will need to use this inhaler only TWICE A DAY (morning and evening). Each time you use it take two PUFFS. There is enough trial medication for 30 days when the MDI is used according to the directions for use. Testing the inhaler 1. When using the inhaler for the first time or when you have not used the inhaler for a week or more, test that it is working properly. Remove the mouthpiece cover (gently squeeze the sides with your thumb and forefinger and pull apart). Hold MDI as illustrated in the figure below and shake well. Point mouthpiece away from you and release four puffs into the air by pressing the MDI. Using the MDI inhaler 1. Remove the mouthpiece cover. 2. Hold MDI as illustrated in the figure below and shake the inhaler 4 or 5 times to ensure the contents of the inhaler are evenly mixed. 3. Hold the MDI upright between fingers and thumb with your thumb on the base, below the mouthpiece. Breathe out as far as is comfortable and then place the mouthpiece in your mouth between your teeth and close your lips around it. Do not bite. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 114 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 112 of 149 4. Breath in through your mouth. Just after starting to breathe in, press down on the top of the MDI to release a puff while still breathing in steadily and deeply. 5. While holding your breath, take the MDI from your mouth and take your finger from the top of the MDI. Continue holding your breath as long as is comfortable. 6. Keep the MDI upright and wait about half a minute before repeating steps 1-5 to inhale the second puff from the MDI. 7. After use always replace the mouthpiece cover (by firmly pushing until it snaps into place) to keep out dust and fluff. How to care for your inhaler It is important to clean the MDI at least once a week to prevent the inhaler from blocking up. To clean the MDI: 1. Remove the mouthpiece cover. 2. The metal canister should NOT be removed from the plastic casing at any time. 3. Wipe the outside and inside of the mouthpiece and the plastic casing with a dry cloth or tissue. 4. Replace the mouthpiece cover. NEVER put the metal canister in water. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.3 Page 115 U12-2466-01 Trial Protocol 5 Dec 2011 Page 113 of 149 INSTRUCTIONS FOR RETURN OF MALFUNCTIONING RESPIMAT INHALERS Respimat® inhalers, with the used cartridge in situ, that appeared to malfunction, will be returned to the Boehringer Ingelheim OPU responsible for packaging and labeling as soon as possible. The name, address and contact person are listed below: Boehringer Ingelheim Pharma GmbH & Co. KG Business Unit Development Dpt. Quality & Records Management 55216 Ingelheim am Rhein Germany The following information should be included when the inhaler is returned: a) Medication number b) Visit number c) Date of malfunction d) Description of malfunction and cause of malfunction (if known) e) Person identifying malfunction f) Malfunctioned after amount of days or weeks of treatment g) BI personnel contacted and date contacted h) Date shipped to Boehringer Ingelheim i) Trial number / country j) Investigator’s name/ center number l) Date of return to the investigator The original of the Product/Device Complaint Form should be included with the returned inhaler. In parallel, a scanned copy of the form should be send to the responsible CTSU coordinator of the trial via email. A copy of the form should be filed with the Drug Dispensing Log. All inhalers and cartridges should be wrapped in bubble wrap or a similar packing material, placed in a secure shipping box (not a packing envelope) and shipped by overnight express. Any questions regarding shipping and handling should be directed to the local Clinical Monitor. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.4 116 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 114 of 149 ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA Classification of medium ICS doses Table 10.4: 1 Definition of medium daily doses of ICS adapted from GINA 2009 [P10-03196] Drug Medium daily Dose (µg) Beclomethasone dipropionate Budesonide Ciclesonide Flunisolide Fluticasone Mometasone furoate Triamcinolone acetonide ≥500 and ≤1000 ≥400 and ≤800 ≥160 and ≤320 ≥1000 and ≤2000 ≥250 and ≤500 ≥400 and ≤800 ≥1000 and ≤2000 As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the investigator for the equivalent correct dosage. There are specific requirements per country. Please refer to the ISF for a detailed list. Reversibility testing [P05-12782] At the screening visit (Visit 1), following the completion of three acceptable prebronchodilator forced expiratory manoeuvres, salbutamol (albuterol) will be administered to each patient in order to document the degree of reversibility. Immediately after (within 10 min) pre-bronchodilator forced expiratory manoeuvres and after a gentle and incomplete expiration, a dose of 100 µg of salbutamol (albuterol) is inhaled in one breath to total lung capacity (TLC). The breath is then held for 5–10 s before the subject exhales. Four separate doses (total dose 400 µg) are delivered at approximately 30-s intervals (this dose ensures that the response is high on the salbutamol dose–response curve). Three additional, acceptable post-bronchodilator forced expiratory manoeuvre tests are recorded ≥15 min and up to 30 min later after the last dose of salbutamol (albuterol) is inhaled. Calculation of predicted normal values according to ECSC [R94-1408] For height measured in inches Males: FEV1 predicted (L) = 4.30 x [height (inches)/39.37] - 0.029 x [age (yrs)] - 2.49 Females: FEV1 predicted (L) = 3.95 x [height (inches)/39.37] - 0.025 x [age (yrs)] - 2.60 For height measured in meters Males: FEV1 predicted (L) = 4.30 x [height (m)] - 0.029 x [age (yrs)] - 2.49 Females: FEV1 predicted (L) = 3.95 x [height (m)] - 0.025 x [age (yrs)] - 2.60 Patients with ages 18-25 will have predicted FEV1 calculated with age 25. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 117 Page U12-2466-01 5 Dec 2011 Page 115 of 149 Trial Protocol The race correction factors in table 10.4: 2 will apply. Table 10.4: 2 Race correction factors Correction factor FEV1 Races / Ethnicities Caucasian Orientals Hong Kong Chinese Orientals Japanese Americans Polynesians North Indians & Pakistanis South Indians African Descent Other Correction factor FVC 1.0 1.0 0.89 0.9 0.9 0.87 0.87 1.0 1.0 1.0 1.0 0.9 0.9 0.87 0.87 1.0 Calculation of variation of absolute FEV1 values The value of Visit 1 is regarded as 100% and the following formula applies: FEV1 variation (%) = FEV1 pre-dose at Visit 2 (L) FEV1 pre-bronchodilator at Visit 1 (L) x 100 - 100 Calculation of number of pack years Pack years = Number of cigarettes/day 20 x years of smoking The following equivalents for the tobacco content should be used for smokers other than cigarettes smokers [R08-5197]: • • • • One plain or filter cigarette = 1 gram of tobacco One cigar = 5 grams of tobacco One cheroot or cigarillo = 3 grams of tobacco One gram of pipe tobacco = 1 gram of tobacco Calculation of pack years based on tobacco contents: Pack years = Number of gram/day 20 x years of smoking Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.5 Page 118 U12-2466-01 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S)) 5 Dec 2011 Page 116 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 119 U12-2466-01 5 Dec 2011 Page 117 of 149 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID - - - - - - - DATE _ _ _ _ _ _ _ _ __ SELF-ADMINISTERED Page 1 oi5 Please complete all q ue stions by circling the number that best des cribes how you have been d uring the last 2 w eeks as a re-sult of you r asth ma . HOW LIM ITED HAVE YOU BEEN DURING THE LAST 2 WEEKS IN THES E ACTIVITIES AS A RESU LT OF YOUR ASTHMA? 1. 2. 3. O:xtremety v~ Modet~t~ Limite d Lirritt'd li.rnitation Some Umito1tion limit~~ioto A Li~tte No~ ~t 'J limited STRENUOUS A CTIVITIES (suc h as hurrying, exercising, running up stairs, sports} 2 3 4 5 6 7 MODERA TE ACTIVITIES (such as w alking, houseworl<. gardening, shopping, c limbing stairs) 2 3 4 5 6 7 pets/children, visiting f riends/relativ es) 2 3 4 5 6 7 WORK-RELATED ACTIVITIES !tasks y ou have to do at work~) 2 3 4 5 6 7 6 7 SOCIAL ACTIVITIES I such a s t a lking. pla ying with 4. '"If 5. you are not employed or $E!tf-employed, these should be tasks y ou have to do most days. SLEEPING 2 4 3 5 HOW M UCH DISCOMFORT OR DISTRESS HAVE YOU FELT DURING THE LAST 2 WEEKS? A Very Gre;t Oe;~~l 6. How m uch d iscomfort or distress hav e y ou felt over the last 2 weeks as a result of CHEST TIGHTNESS? AGru t De'! A Good M o<ler;t'=' Oul Amou nt 2 3 4 Som• Very None Li~1f..e 5 6 7 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 120 U12-2466-01 - 5 Dec 2011 Page 118 of 149 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATIENT ID SELF-ADMINISTERED DATE Page 2oi5 IN GENERAL. HOW MUCH OF THE TIME DURING THE LAST 2 WEEKS DID YOU: All of the Time 7. 8. 9. Mo$t of the A Good Si~ oi the Some of the Time A L~de ~he of Time H~rdly Any o f the TJmc ..... None Ti~ Time Feel CONCERNED ABOUT HAVING ASTHMA? 2 3 4 5 6 7 Feel SHORT OF BREATH as a result of y our asthma? 2 3 4 5 6 7 Experience asthm a symptom s as a RESULT OF BEING EXPOSED TO CIGARETTE SMOKE? 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 10 . Experience a WHEEZE in y our chest? T ime 11 . Feel you had to AV OID A SITUATION OR ENVIRONMENT BECAUSE OF CIGARETTE SMOKE? HOW M UCH DISCOMFORT OR DISTRESS HAVE YOU FELT DURING THE LAST 2 WEEKS? A Ve-ry G.rut Oc ~1 1 2 . How much d iscomfort or distress have y ou felt over the last 2 weeks as a result of COUGHING? A Grcrt A Good Moc!ero1~c ""' Ou l Amouf'lt 2 3 4 Som• v •.., Not~c Li~tk 5 6 7 IN GENERAL, HOW M UCH OF THE TIM E DURING THE LAST 2 WEEKS DID YOU: ... A!l of Mon of the Tim~~: T<me 13. Feel FRUSTRATED as a result of y our ast hma? 14 . Experience a feeling of CHEST HEA VINESS? 2 A Good Sit ~he r~. of Som• o f the A Little Hardly of the Any o f Time Ti~ the TJme ..... None T ime 2 3 4 5 6 7 2 3 4 5 6 7 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 121 U12-2466-01 - 5 Dec 2011 Page 119 of 149 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID SELF-ADMINISTERED DATE Page 3of 5 IN GENERAL, HOW M UCH Of THE TIM E DURING THE LAST 2 WEEI<S DID YOU: A!l of th< Mo~ of :be Time Time H~rdly A Good Sit Som< A Lrtt!e of :he o f tl'lc of the Any o f r~• Time Time the rune ...... Nol'\e T ime 1 5 . Feel CONCERNED ABOUT THE NEED TO USE M EDICATION for your asthma? 2 3 4 5 6 7 1 6 . Feel t he need to CLEAR Y OUR THROAT? 2 3 4 5 6 7 1 7. Experience asthma symptom s as a RESULT Of BEING EXPOSED TO DUST? 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 20. WAKE UP IN THE MORNING WITH ASTHMA SYMPTOMS? 2 3 4 5 6 7 21 . Feel A FRAID Of NOT HAVING YOUR ASTHMA MEDICATION AVAILABLE? 2 3 4 5 6 7 22 . Feel bothered by HEA VY BREATHING? 2 3 4 5 6 7 23. Experience asthma symptom s as a RESULT Of THE WEATHER OR AIR POLLUTION OUTSIDE? 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 18 . Experience DIFFICULTY BREATHING OUT as a result of y our asthma? 19. Feel y ou nac to A V OI D A SITUATION OR ENVIRONMENT BECAUSE Of DUST? 24. Were y ou WOKEN AT NIGHT by your asthma? 2b. A V U IU UH LIM I I (jO JN(j U U I ~I Ut BECAUSE Of THE WEATHER OR AIR POLLUTION? 3 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 122 U12-2466-01 - 5 Dec 2011 Page 120 of 149 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID SELF-ADMINISTERED DATE Page 4 oi 5 IN GENERAL, HOW M UCH OF THE TIM E DURING THE LAST 2 WEEKS DID YOU: ... Atl of Mo~ ~he of Tin t Time A G ood Sit Some A Litfte of the Time o f the Time oh h< T irM H::~.rdl•t Any o f tfle r~me ...... Nolle Time 26 . Experience asthm a symptom s as a RESULT OF BEING EXPOSED TO STRONG SM ELLS OR PERFUME? 2 3 4 5 6 7 Feel AFR.AID OF GETTING OUT OF BREATH? 2 3 4 5 6 7 28. Feel y ou had t o AV OID A SITUATION OR ENVIRONMENT BECAUSE OF STRONG SMELLS OR PERFUME ? 2 3 4 5 6 7 29. Has y our asthma INTERFERED W ITH GETTING A GOOD NIGHT'S SLEEP? 2 3 4 5 6 7 30. Have a feeling of FIGHTING FOR AIR? 2 3 4 5 6 7 27. HOW LIM ITED HAVE YOU BEEN DURING THE LAST 2 WEEKS? Sever ~ Very Few NotOOl'\e Not Gone No Umit .ltlon 3 1. Think of the OVERALL RANGE Of ACTIVITIES t hat you would have liked to have done during the last 2 weeks. How much has your range of actN ities been lim ited by your asthma? 2 4 3 4 5 6 7 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 123 U12-2466-01 - 5 Dec 2011 Page 121 of 149 Trial Protocol ASTHMA QUALITY OF LI FE QUESTIONNAIRE (S) PATI ENT ID - - - - - - - DATE _ _ _ _ _ _ _ _ _ ___ SELF-ADMINISTERED Page5oi 5 HOW LIMITED HAVE YOU BEEN DURING THE LAST 2 WEEKS? Extreme~ lirA ted 32. Overall, among ALL THE ACTIVITIES that you have done during the last 2 weeks, how limited have you IJeen by your asthma? 2 3 Moderate Some A U We Net at al lirnitat:oo Limita:on Limita:ion limito:d 4 5 6 7 DOMAIN CODE: Symptoms: 6, 8, 10, 121 14: 16! 18, 20, 22, 24, 29, 30 Activity Limitation: 1! 2! 3, 4, 5, 11, 19 , 25, 28, 31., 32 Emotional Function: 7, 13:, 151 21,27 Environmental Stillluli : 9 1 171 231 26 5 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.6 Page 124 U12-2466-01 Trial Protocol ASTHMA CONTROL QUESTIONNAIRE (ACQ) 5 Dec 2011 Page 122 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 125 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 123 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 126 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 124 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.7 Page 127 U12-2466-01 Trial Protocol EQ-5D HEALTH QUESTIONNAIRE ~Q-50 He.nlth Questionnnit·e (Euglish vcnio11 for the US) - 5 Dec 2011 Page 125 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 128 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 126 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 129 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 127 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.8 130 Page U12-2466-01 Trial Protocol PAPER PATIENT DIARY CARD 5 Dec 2011 Page 128 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.9 AM3 PATIENT INSTRUCTION CARD 131 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 129 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 132 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 130 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 133 U12-2466-01 Trial Protocol - 5 Dec 2011 Page 131 of 149 Vacation Card AM3 Tnlsvacation cara aescrlt:>es now to use tne AM3 aurlng your vacation. The AM3 has been programmed with a new time zone by your study doctor. The clock on the AM3 will be adjusted accordingly once the •vacation mode" is activated. If you have any problems using the AM3, please call your study doctor as soon as possible for help. Using t he AM3 at Home When using the AM3 while you are still at home, the following screen will appear when the AM3 is turned on. I I Are you at home? Yes No ESC 0 I = = Selecting"Yes• starts the scheduled session. Selecting "No" turns off the AM3. I:J OK Please note that t11e clock on the AM3 is still set to your home time zone. V-782034_USEN Final Version 02.00 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 134 U12-2466-01 Trial Protocol - 5 Dec 2011 Page 132 of 149 Using the AM3 During Your Vacation As soon as you arrive at your travel desti nation, please activate t he "vacation mode": 1. Press and h ol d t he • /:::t button. 2. While holdin g th e button, press and hold t he "ESC" button. 3 . Hold both buttons for approximately 2 seconds. ESC ·C::t The following screen wi ll appear: Do you want to I change to - i 1--------.,-,-------t= vacation mode? Yes I No Selecting "Yes" sets the clock t o t he local time zone of your t ravel destination. • If you select"No",the clock w ill not be changed. : OK Durin g your vacation t h e followin g screen w ill app ear every time you t urn on the AM3: I Are you on vacation? ; Yes : • Selecting "Yes" starts w ith the scheduled session. • Selecting "No" t urns off the AM3. I No I• I ' - - - - - - - - - . , -"""! _,I O! ESC Using t he AM3 When You Ret urn Home ESC As soon as you return h om e, please activat e the" hom e mode": 1. Press and h ol d t he • £::,.· button. 2. While holdin g th e •/:::t button, press and hold t he "ESC" button. 3. Hold bot h buttons for approximately 2 seconds. The following screen will appear: Do you want to change to home mode? ;;; • 1-----:-: Ye- s- - - - - j I ! No ESC Page 2 • Selectin g "Yes" sets the clock to your home time zone. • If you select "No",the clock will not be changed. !! 0( V·782034_USEN Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.10 135 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 133 of 149 DEFINITION ASTHMA EXACERBATION Asthma exacerbation For the purposes of this trial, an asthma exacerbation in general is defined by the sponsor as • an episode of progressive increase in one or more asthma symptoms, like shortness of breath, cough, wheezing, or chest tightness, or some combination of these symptoms. Respiratory distress is common. The symptoms should be outside the patient´s usual range of day-to-day asthma and should last for at least two consecutive days and/or • a decrease of patient´s best morning PEF of ≥ 30% from the patient´s mean morning PEF for at least two consecutive days. Relevant PEF deteriorations are marked on the AM3 data reports downloaded at each visit. During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. Severe asthma exacerbation Severe asthma exacerbations are defined by the sponsor as a subgroup from all asthma exacerbations according to sponsor´s definition given above that require an initiation of treatment with systemic (including oral) corticosteroids for at least 3 days. PEF decreases marked on AM3 report A asymptomatic PEF-decrease as described above is considered an asthma exacerbation per protocol, regardless of being accompanied by asthma symptoms, need for additional asthma medication or if considered medically relevant or not. At every AM3 download, the report includes an alert section summarizing all relevant PEF-decreases (PD alerts) that occurred since the last visit. The investigator needs to discuss the report with the patient and decide which PD-alerts are valid (explained by decreased lung function) and which are not valid (e.g. explained by non-compliance as for instance device was used by other person than patient or PEF measurement done incorrectly). For each valid PD alert, the investigator needs to document this finding as adverse event in the eCRF. If symptomatic, examples of AE verbatims would be asthma aggravation, asthma Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 136 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 134 of 149 exacerbation or bronchitis. If asymptomatic, the AE verbatim would be ´asymptomatic peak expiratory flow decrease´ if no symptoms were reported. In addition, the Asthma exacerbation verification page in the eCRF needs to be entered. Note: if a respiratory tract infection without asthma worsening was the reason of PEF decrease (e.g. bronchitis), then this would only be documented as AE, not as asthma exacerbation per protocol. For each non-valid PD alert, the investigator needs to document the rationale on the AM3report. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.11 137 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 135 of 149 CLINICAL LAB PARAMETERS Laboratory specimens will be collected in the evening. Blood samples need to be taken prior to the salbutamol (albuterol) dosing. Lab parameters will be analysed by the local laboratory of each participating site. Lab samples may be stored overnight. The local lab should be contacted to discuss the required overnight storage conditions (fridge or room temperature). The haematological parameters will include the following: • • • • • • Haemoglobin Haematocrit Absolute and relative eosinophil count (to be recorded on eCRF) Red blood cell count White blood cell count (to be recorded on eCRF) including differential test (neutrophils, lymphocytes, monocytes, eosinophils, basophils) Platelet count The blood chemistry parameters will include the following: • • • • • • • • • • • Total serum IgE (at Visit 1 only; to be recorded on eCRF) LDH γ-GT SGOT (AST) SGPT (ALT) Calcium Inorganic phosphorus Creatinine (to be recorded on eCRF) Potassium Sodium Chloride Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.12 Page 138 U12-2466-01 Trial Protocol 5 Dec 2011 Page 136 of 149 PHARMACOKINETIC METHODS 10.12.1 Planned analyses for pharmacokinetic evaluations Concentrations will be used for calculations in the format that is reported in the bioanalytical report. The data format for descriptive statistics of concentrations will be identical with the data format of the respective concentrations. For the calculation of pharmacokinetic parameters, only concentrations within the validated concentration range will be used. The actual sampling times will be used for the evaluation of plasma concentrations. If the actual sampling time was not recorded or is missing for a certain time point, the planned time should generally be used for this time point instead. For pre-dose samples, the actual sampling time will be set to zero. Noncompartmental pharmacokinetic parameters will be determined using the WinNonlinΤΜ software program (Professional version 4.1 or higher, , or another validated program. The following descriptive statistics will be calculated for analyte concentrations as well as for all primary and secondary pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. The descriptive statistics of pharmacokinetic parameters will be calculated using the individual values with the number of decimal places as provided by the evaluation program. Then the individual values as well as the descriptive statistics will be reported with three significant digits in the clinical trial report. Plasma concentrations will be plotted graphically versus time for all patients as listed in the drug plasma concentration-time tables. For the presentation of the mean profiles, the arithmetic mean and the planned blood sampling times will be used. 10.12.2 Handling of missing data Drug concentration-time profiles: Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not analyzed), BLQ (below the limit of quantification) and NOP (no peak detectable) will be ignored and not replaced by zero at any time point (including the lag phase). Descriptive statistics of concentrations at specific time points will be calculated only when at least 2/3 of the individuals have concentrations within the validated concentration range. The overall sample size to decide whether the '2/3' rule is fulfilled will be based on the total number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, NOA, NOP will be included). Pharmacokinetic parameters: During the noncompartmental analysis, concentration data identified with NOS, NOR, and NOA will not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag phase is defined as the period between time zero and the first time point with a concentration above the quantification limit. All other BLQ and/or NOP values of the profile will be ignored. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 139 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 137 of 149 If the predose concentration before the first dose is less than or equal to 5% of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements and calculations (i.e. the predose value will not be changed to zero). If the predose value before the first dose is greater than 5% of Cmax, the subject will be dropped from all statistical evaluations. The individual pharmacokinetic parameters will be calculated and listed separately. Every effort will be made to include all concentration data in an analysis. If that were not to be possible, a case to case decision iwill be taken as to whether the value should only be excluded from half-life estimation or the complete analysis. ∗ If a concentration is only excluded from half-life determination, it will be used for all other calculations (e.g. descriptive statistics) and for graphical presentation. ∗ If a concentration value is excluded from all calculations, it will not be presented graphically or used for the calculation of descriptive statistics and parameter determination. However the excluded concentration itself will be listed in the clinical trial report associated with an appropriate flag. Descriptive statistics of parameters are calculated only when at least 2/3 of the individual parameter estimates of a certain parameter are available. If the actual sampling time will not be recorded or will be missing for a certain time point, the planned time will generally be used for this time point instead. Pharmacokinetic parameters which cannot be determined will be identified by "not calculated" (NC). 10.12.3 Derivation of PK parameters Individual Cmax(,ss), tmax(,ss), Cmin(,ss), and Cpre,N values will be directly determined from the plasma concentration time profiles of each patient. If the same Cmax(,ss) concentration occurs at different time points, tmax(,ss) is assigned to the first occurrence of Cmax(,ss). Estimation of λz(,ss): The apparent terminal rate constant λz(,ss) will be estimated from a regression of ln(C) versus time over the terminal log-linear disposition portion of the concentration-time profiles. At least three data points should be used in the calculation of λz(,ss). In addition, the lower (tλz,start(ss)) and upper (tλz,end(ss)) limit on time for values to be included in the calculation of λz,ss will be listed. t1/2(ss): The terminal half-life will be calculated from the terminal rate constant using the equation t1/2(ss) = ln2 λ z(ss) AUC: The area under the curve will be calculated using the linear up/log down algorithm. If an analyte concentration is equal to or higher than the preceding concentration, the linear trapezoidal method will be used. If the analyte concentration is smaller than the preceding concentration, the logarithmic method will be used. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 140 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 138 of 149 Linear trapezoidal rule (t2 > t1 and Ct2 ≥ Ct1): The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by: AUCt1- t2 = 0.5 × (t 2 − t1 )× (C t1 + C t2 ) Logarithmic trapezoid rule (t2 > t1 and Ct2 < Ct1): The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by: AUC t1− t2 = (t 2 − t 1 ) × (C t2 − C t1 ) ln (C t2 /C t1 ) AUCτ,ss: The area under the plasma concentration-time curve at steady state over a uniform dosing interval τ will be calculated using the extra- or interpolated concentration at time tτ (time at the end of the dosing interval). The actual sampling time of the trough value Cpre,N will be set to 0. MRTih(,ss): MRTih(,ss) calculation in the steady state will be performed according to the following equation: MRTih,ss = AUMCss AUC τ,ss AUMCss is the area under the first moment curve at steady state. CL/F,ss: The apparent clearance at steady state following extravascular multiple dose administration will be calculated as follows: CL/F,ss = Dose AUCτ ,ss Vz/F,ss: The apparent volume of distribution during the terminal phase after (multiple) extravascular administration (at steady state) will be determined according to the following equation: Vz F(,ss ) = CL F(,ss) λ z(,ss) fet1-t2,ss: The fraction excreted is calculated according to fe t1- t2(,ss) = Ae t1- t2(,ss) Dose ×100 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 141 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 139 of 149 where Aet1-t2,ss is the total quantity of the analyte that is excreted in urine over the time interval t1 to t2 (at steady state). This may represent the product of urine volume and urine analyte concentration for one time interval, as well as the cumulative amounts excreted calculated as the sum of the excreted amounts of subsequent time intervals. CLR,t1-t2,ss: The renal clearance (CLR) will be calculated as the quotient of the quantity of the analyte that is excreted in urine from the time point t1 until the time point t2 (Aet1-t2(,ss)) and the area under the concentration-time curve within the same time interval (AUCt1-t2(,ss)). CL R, t1− t2(,ss) = Ae t1− t2(,ss) AUCt1− t2(,ss) RA: The accumulation ratio RA will be calculated as follows: RA,Cmax = C max,ss C max RA,AUC = AUC τ ,ss AUC τ LI: The linearity index (LI) will be calculated as follows: LI = AUC τ ,ss AUC 0−∞ gMean, gCV: The geometric mean (gMean) and coefficient of variation, gCV (given in %), will be calculated by the formulae: [ ⎡ n ⎤ gMean = exp ⎢ 1n ∑ ln(x i )⎥ = exp ln(x i ) ⎣ i =1 ⎦ gCV(%) = 100 ⋅ exp [Var(ln(x i ))] − 1 where Var(ln(x i )) = [ 1 n ∑ ln(x i ) − ln(x i ) n − 1 i =1 ] 2 ] Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.13 142 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 140 of 149 PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 143 U12-2466-01 ·- 5 Dec 2011 Page 141 of 149 Trial Protocol PART 1: RATING OF SATISFACTION WITH Il'I"HALER ATTRIBUTES Instru ctions : For the following questions, please check the response that. best describes how satisfied you are with each of the following items. Please take as much ti:me as you need to answer each question. ~ Q) -g~ o;: .~ IJJ .... ~ Q) ;;::: IJJ IJJ ~ (:-VI Q) ~ Q) ;.;:: .!!l >O ... ~ Q) IJJ ... IJJ .r; n! :::$ Q) n! E IJJ .r;O 0 1/)0 0 .!!l ... 1/) 1/) n! IJJ IJJ IJJ :; :;:: .~ nl'"' n! ·.r; .... :;::; :;: Q) · - ~ 'Q) z 0 c: n! ::: Q) E 0 1/) ~ Q) ;;::: ..., IJJ n! 1/) ~ Q) ~~ Q) n! >II) H ow satisfied are you ... 1. With the overall feeling of inhaling your medicine? ~espima~®l 2. With the feeling that the inhaled dose goes to your hutg.~? ~espimar~l 3. That you can tell the amo\utt of medication left in your inhaler? ~e;pima~l ~ ~ ~ 4. That the inhaler works reliably? ~e~pima~l ~ 5. With the ease of inhaling a dose from the inhaler? ~espimar~l ~ 6. With the iustn1ction~ for use? ~esyima~l ~ 7. With the size of your inhaler? Respimat~l 8. That the inhaler is durable (hard wea ring)? ~e;pima~l ~ ~ T D 0 D 0 D D D 0 D 0 D D D 0 D 0 D 0 D 0 D 0 D D D D D 0 D 0 D 0 Please go to the next page @Boehringer Ingelheim F:"IINSnTUT\CUlTAOA?\Fi\OJE-....'""T\!S36'.S11J~·4536'J'fn31_vers:br.$IPASAFO:ng-tfSO~.cJoc· 18.'Q4.12Ql)8 0 0 D 0 0 D 0 0 0 0 0 D D 0 0 0 0 0 D 0 0 D 0 0 0 0 0 D D 0 0 0 D 0 0 D 0 0 D D D 0 D 0 D D D 0 D 0 D 0 D 0 D 0 D D D D D 0 D 0 D 0 D 0 0 D 0 0 0 0 0 D D 0 0 0 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 144 U12-2466-01 - 5 Dec 2011 Page 142 of 149 Trial Protocol ~"0 ~ .~ VI'>- "0 "0 "' "' :;:; ~ ;;:: VI <0 i:':'VI iii VI VI "' .!!! Ci >O 9. With the ease of cleaning your inhaler? Rewimat®! 10. With using the inhaler? Re;pimat®! 11 With the speed at which medicine comes out of the inhaler? IRe;pimat®! 12. With the ease of holding the inhaler during \Lse? Re•pimar~! 13. With the overall convenience of carrying the inhaler with you? IRespimar~! ~ ~ ~ ~ ~ 14. Overall, how satisfied are you with your inhaler? Respimat®! ~ T D D D D D D "0 ~"' <0 ·- j~ Q) <0 VI E 0 .!!! eno :;:; .~ co~ en co VI ,_ VI Q) · - ~0 .~ Q) z ...0 r::: "0 ;;= "'VI ~ en ~ <0 ~ ~ "C "0 E "' ~~"' :;:; en "' <0 en >en Q) 0 ~ VI <0 D D D 0 D D D 0 D D 0 0 D D D D D D D D D D D D D D D D 0 0 D D 0 D D D D D D D 0 0 D D D D D D D D D D D 0 0 D 0 0 D 0 0 D D D D 0 0 D 0 0 Please go to the next page ©Boehringer Inge.lheim f jjNSTITUT\CUlTADA~M.O...~CT'.f.538'l$lUCiy.:!SJe'.Rnli_Wt'$iOr.£~?ASAFQer.g.tJSO(lq.OOc.- ta<NJ20t!8 D D 0 0 D D 0 0 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 145 U12-2466-01 ·- 5 Dec 2011 Page 143 of 149 Trial Protocol PART II: R<\.TING OF PREFERENCE Al'il> WILLINGNESS TO CO!\'TINUE WITH Il'HIALER 15. Comparing the two inhalers that you have used during the study, overall, would you prefer io use Respimat® or MDI? Please che.c.k one box D D D I prefer Respimat® I prefer MDI No preference 16. Comparing the two inhalers that you have used during the study, overall, how would you feel about continuing to use Respimat® or MDI? Plea~e indicate your willingness to continue using each of the inhalers that you used during the study by providing a value between 0 and I 00. 0 indicates that you would not be willing to continue using this inhaler and 100 indicates that you would definitely be willing to continue . Please write Ul a number in each box thai is between 0 and 100. Respimat® ~mi Both boxes should c.ontain a number between 0 amllOO. 'f Please go to the next page ©Boehru1ger Ingelheim F::'tiNSllTUT\CUllAD,A,?'\P.''\O!ECNSJ6\$1Udy~S36\Rnai_Vef'6:.0r!$.\PASAF~n.g-OSOrlq.Cioc-1MI4J2008 D D Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 146 U12-2466-01 Trial Protocol THANK YOU VERY MUCH FOR COMPLETING THIS SURVEY. PLEASE RETURN THIS SURVEY TO THE STUDY COORDINATOR. ©Boe.h ringer Ingelheim F:.INSlllUT\CUlTA.C,4.;r,F.RO.:~~ S3e'.s11Jely453e\Frnll_versi0r.&\PASAPC-er:g-t!SO~.cJce-18JD4i201l8 - 5 Dec 2011 Page 144 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 11. 147 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 145 of 149 SUMMARY OF CLINICAL TRIAL PROTOCOL MODIFICATIONS Summary of Clinical Trial Protocol Modifications Sheet (SOMS) Number of CTP modification Date of CTP modification EudraCT number BI Trial number BI Investigational Product(s) Title of protocol To be implemented only after approval of the IRB/IEC/Competent Authorities To be implemented immediately in order to eliminate hazard – IRB / IEC / Competent Authority to be notified of change with request for approval Can be implemented without IRB/IEC/ Competent Authority approval as changes involve logistical or administrative aspects only 1 19 January 2011 2009-018004-18 205.418 - 2.5 µg tiotropium bromide - 5 µg tiotropium bromide - 50 µg salmeterol xinafoate - Placebo inhalation solution (Respimat®) - Placebo metered dose inhaler A Phase III randomised, double-blind, placebocontrolled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Section to be changed Description of change 148 Page U12-2466-01 Trial Protocol I) 5 Dec 2011 Page 146 of 149 Synopsis, flow chart (including footnotes), abbreviations, section 1.2.1, section 3.2, section 3.3.3, section 4.1.4 (Trial medication administration at clinic visits), section 4.2, section 4.2.1.3, table 4.2.2.1: 1, section 5.1.1.1, section 5.1.1.2, section 5.1.2, section 5.3.2, section 5.4, section 5.5.2, section 5.5.3, section 6.2.2, section 7.1 (Design), section 7.3.1, section 7.6 II) Synopsis, flow chart (including footnotes), timing of trial procedures 3 hour PFT, timing of trial procedures 24 hour PFT, section 3.1, section 3.3, section 5.3.1, section 5.3.2, section 6.2.2 (Observations and procedures Visit 6), section 7.3.9, section 9.1, appendix 10.13 III) Timing of trial procedures 3 hour PFT, section 2.2, section 3.3, section 3.3.2, section 5.1.1.2, section 7.3.2 IV) Section 4.1.4 (Instructing the patient) V) Section 5.1.2 (Electronic peak flow meter with electronic diary) VI) Section 5.1.2 VII) Section 3.3.2, section 6.2.1 (Observations and procedures Visit 1), Appendix 10.4 VIII) Section 3.3.2, section 6.1 VIIII) Section 4.1.4 (Testing of the MDI), Appendix 10.2 IV) Section 5.5.2, section 5.5.3, section 9.2. I) Administrative changes, corrections and added clarifications. II) Implementation of PASAPQ III) Implementation of PFT subset at Visit 5 IV) Change of time windows for medication administration at home in the evenings and mornings in case a patient missed a dose. V) Change in time windows for eDiary use at home in the evenings and mornings in case a patient forgot to use the eDiary. VI) Change in the maximum number of attempts for Pulmonary Function Testing. VII) Extension of time window for reversibility testing. VIII) Addition of option to repeat reversibility test (Visit 1). VIIII) Change in the number of priming puffs. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 149 Page U12-2466-01 Trial Protocol IV) Rationale for change I) II) III) IV) V) VI) VII) VIII) 5 Dec 2011 Page 147 of 149 Change in blood volume PK samples. More detailed instructions to prevent possible contamination of PK samples. Administrative changes/corrections/clarifications. To measure patient satisfaction and preference for the devices used in this study. To explore the onset of action of the study medication. To increase patient treatment compliance. To add instructions in case a patient forgot to use the Asthma Monitor®AM3 within the specified time window. To be consistent with the ATS/ERS criteria and with other studies within the same project (Tiotropium in Asthma). To allow patients who reverse after 30 minutes to participate in the study. To allow patients who do not reverse during the first test, but do during the repeat test to participate in the study. VIIII) To make sure the device is working properly. IV) To increase the quality of the PK analysis. Bioanalytical method has been revalidated. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 150 Page U12-2466-01 Trial Protocol 2 5 December 2011 2009-018004-18 205.418 - 2.5 µg tiotropium bromide - 5 µg tiotropium bromide - 50 µg salmeterol xinafoate - Placebo inhalation solution (Respimat®) - Placebo metered dose inhaler A Phase III randomised, double-blind, placebocontrolled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Number of CTP modification Date of CTP modification EudraCT number BI Trial number BI Investigational Product(s) Title of protocol To be implemented only after approval of the IRB/IEC/Competent Authorities To be implemented immediately in order to eliminate hazard – IRB / IEC / Competent Authority to be notified of change with request for approval Can be implemented without IRB/IEC/ Competent Authority approval as changes involve logistical or administrative aspects only Section to be changed 5 Dec 2011 Page 148 of 149 I) II) III) IV) V) VI) VII) VIII) Abbreviations Section 5.2.2.1 Section 5.2.2.2 Section 5.3.1 Section 6.1 Section 6.1 Flowchart and Section 6.2.3 Appendix 10.11 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Description of change Rationale for change 151 Page U12-2466-01 Trial Protocol I) II) III) IV) V) VI) VII) VIII) I) II) III) IV) V) VI) VII) VIII) 5 Dec 2011 Page 149 of 149 Administrative correction/additions. Administrative change and clarification. Administrative change. Administrative correction. Clarification. Clarification. Administrative change. Clarification. Administrative correction/additions. Administrative change regarding reporting of significant events. Clarification of (S)AE reporting. Administrative change regarding reporting of always serious AEs. Deletion of invalid endpoint. Clarification start of screening period. Clarification scheduling Visit 2 after repeated reversibility test. Administrative change regarding collection of HCRU data. Clarification. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 152 U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 15 Apr 2010 Page 2 of137 Trial Protocol CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 flg once daily) compared with placebo and salmeterol HFA MDI (50 flg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.418 I herewith certify that I agree to adhere to the trial and to all documents referenced in the trial nrfltm·~ Name: ,MD Signed signature page is located in the el Affiliation: Date: The Netherlands Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 153 U12-2466-01 Page 16.1.1.2 Protocol amendments ........................................................................................ 153 0205-0418--protocol-revision-02 ............................................................................... 154 ctp-revision-02-signature-ci........................................................................ 303 ctp-revision-01-signature-ci........................................................................ 304 ctp-am-1-china-english ............................................................................................... 305 protocol-local-signature-china .................................................................................... 310 protocol-am-1-japan ................................................................................................... 311 ctp-am-1-signature-japan ............................................................................................ 323 ctp-am-1-signature-usa ............................................................................................... 324 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 154 U12-2466-01 Clinical Trial Protocol Doc. No.: U10-1634-03 EudraCT No.: 2009-018004-18 BI Trial No.: 205.418 BI Investigational Product(s): Tiotropium bromide Inhalation Solution Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Clinical Phase: III Trial Clinical Monitor: Boehringer Ingelheim bv, Medical department Comeniusstraat 6, 1817 MS Alkmaar, The Netherlands Phone: Fax: , MD Co-ordinating Investigator: The Netherlands Phone: Fax: Status, Version, and Date of Protocol: Final Protocol, Version 1.0, 15 April 2010 Status, Version, and Date of Revised Protocol: Revised Protocol (based on modification 2) Version 3.0, 5 December 2011 Page 1 of 147 149 Proprietary confidential information. © 2011 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. TITLE PAGE Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 155 U12-2466-01 5 Dec 2011 Page 2 of 149 Trial Protocol CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.418 I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Name: , MD Signature:__________________________ Signed signature page is located in the electronic Clinical Trial Master File Affiliation: The Netherlands Date: ___________________________ Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 156 Page U12-2466-01 5 Dec 2011 Page 3 of 149 Trial Protocol LOCAL SIGNATURES (PRINCIPAL INVESTIGATOR OF SITE AND LOCAL CLINICAL MONITOR (CML)) Local Clinical Monitor <optional, delete if not applicable>: Date Name Full name Organisation/Department <Add other signatories if applicable.> I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Principal Investigator (site): Date Name Full name Organisation/Department Signed signature page is located in the electronic Clinical Trial Master File Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 157 U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 Trial Protocol 5 Dec 2011 Page 4 of 149 CLINICAL TRIAL PROTOCOL SYNOPSIS Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 15 April 2010 Title of trial: Trial number: 205.418 Revision date: 5 December 2011 A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma , MD, Co-ordinating Investigator : , The Netherlands Trial site(s) : Multi-centre, Multi-national Clinical phase: III Objective(s): Evaluate the long term efficacy and safety of tiotropium (2.5 and 5 µg once daily administered in the evening) inhalation solution delivered by the Respimat® inhaler compared to placebo and salmeterol (administered twice daily) in patients with moderate persistent asthma Methodology: Randomised, double-blind, placebo- and active-controlled, parallel-group design comparing tiotropium versus placebo and salmeterol over 24 weeks on top of maintenance therapy with an inhaled corticosteroid controller medication No. of patients: total entered: 1000 each treatment: 250 Diagnosis : Asthma Main criteria for inclusion: Outpatients of either sex, age 18 - 75 years, never-smokers or ex-smokers with < 10 pack years and smoking cessation at least one year prior to enrolment. Patients must have at least a 3-month history of asthma that was diagnosed before the age of 40, and a current diagnosis of moderate persistent asthma (according to GINA guideline). Patients need to be still symptomatic, i.e. not fully controlled with their current maintenance treatment (assessed by ACQ mean score and pulmonary lung function tests). Maintenance treatment with medium dose of inhaled corticosteroids (Appendix 10.4) is required. Test products : Tiotropium inhalation solution 2.5µg (2 actuations of 1.25 µg) and 5 µg (2 actuations of 2.5 µg) once daily in the evening mode of admin. : Oral inhalation via Respimat® inhaler dose: Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 158 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 5 of 149 Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 15 April 2010 Trial number: 205.418 Revision date: 5 December 2011 Comparator product 1: Salmeterol hydrofluoroalkane (HFA 134a) metered dose inhaler (MDI) dose: 50 µg (2 actuations of 25 µg per actuations) twice daily (morning and evening) mode of admin. : Oral inhalation from HFA MDI Comparator product 2: Placebo inhalation solution dose: Not applicable mode of admin. : Oral inhalation via Respimat® inhaler Comparator product 3: Placebo MDI dose: Not applicable mode of admin. : Oral inhalation via HFA MDI Duration of treatment: 24 weeks Criteria for efficacy: Co-primary endpoints: peak FEV1 response (within 3 hours post evening dosing) and trough FEV1 response after 24 weeks treatment Secondary endpoints: Peak FVC; trough FVC; FEV1 (AUC0-3h); FVC (AUC0-3h); individual in-clinic FEV1/FVC/PEF measurements; Asthma Quality of Life Questionnaire (AQLQ (S)); Home assessment: PEF am/pm (last weekly mean of treatment period), use of PRN rescue medication; daytime and nocturnal symptoms; asthma symptom free days, control of asthma (Asthma Control Questionnaire; ACQ) after 24 weeks treatment. In a subset of patients: FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h) Other endpoints: Home assessments during treatment period PEF am/pm; FEV1 am/pm; PEF variability Meta-analysis on combined data from the two twin trials 205.418 and 205.419. Primary endpoint: Control of asthma (Asthma Control Questionnaire) after 24 weeks treatment. Secondary endpoints: time to first exacerbation; time to first severe asthma exacerbation. ACQ at each visit. Criteria for pharmacokinetics: Plasma and urine samples for the quantification of tiotropium will be obtained in a subset of patients following the administration of the first dose and following administration of tiotropium for 4 weeks (i.e., at steady state). Additionally, a predose and 5 minute post-dose blood sample will be obtained on study days 7, 14 and 21 to confirm the achievement of steady-state. Enough patients will be included in this subset to ensure at least 80 patients will complete the PK sampling visits. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 159 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 6 of 149 Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 15 April 2010 Trial number: 205.418 Revision date: 5 December 2011 Criteria for health economics: Health care resource utilisation (HCRU) and Quality of Life assessed by EQ-5D Criteria for pharmacogenomics: Unspecified pharmacogenetic testing Criteria for safety: Adverse events, vital signs, vital status information Other criteria: In a subset of patients: patient satisfaction and preference questionnaire (PASAPQ) Statistical methods: For the two co-primary FEV1 endpoints: restricted maximum likelihood (REML)based mixed effects model with repeated measures (MMRM) with terms for treatment, investigative site, visit, and treatment by visit interaction as fixed categorical effects, and baseline and fixed covariates baseline by visit interaction. The comparisons with salmeterol are not part of the inferential analysis. Standard statistical parameters (number of non-missing values, mean, standard deviation (SD), median, quartiles, minimum, and maximum) or frequency tables will be calculated where appropriate for all parameters. Meta analysis: primary endpoint (ACQ): pooled analysis of the twin trials with trial numbers 205.418 and 205.419. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 160 Page U12-2466-01 5 Dec 2011 Page 7 of 149 Trial Protocol FLOW CHART Trial periods Treatment* Screening Visit 0 1 2 Week Day Time window** -1 -4 -28 ±4 0 1 Informed consent1 Instruct patient on washout/restrictions1 Demographics Medical History/Baseline conditions2 Physical examination (incl. vital signs) Review smoking status ECG, laboratory and pregnancy test4 Inclusion/exclusion criteria Dispense rescue medication Respimat® and MDI training Randomisation Dispense trial medication Administration of trial medication in clinic5 Collect trial medication Drug accountability Blood sample for pharmacogenetics6 Pharmacokinetic sampling7 Training eDiary with PEF-meter Issue eDiary with PEF-meter Download eDiary with PEF-meter Collect eDiary with PEF-meter Issue paper diary card Review/collect paper diary card ACQ9 AQLQ (S)9 EQ-5D9 PASAPQ9 Review exacerbation and HCRU Medication washout check11 Pulmonary function test12 Vital signs (seated) Adverse events Concomitant therapy Termination of trial medication Vital status collection18 Completion of trial X X X X X X X X X X X X X1 X X X X X X10 X X13 X X 2A7 2B7 2C7 3 4 5 6 7 7 ±1 14 ±1 21 ±1 4 28 ±2 8 56 ±2 16 112 ±4 24 168 ±4 27 189 +7 X X X X X X X X3 X3 X3 X X X X X X 16 Follow up X X X X X X 16 X X X X X X X X X X X X X X X X X X X X X X X X3 X3 X3, 8 X3 X8 X8 X8 X X X10 X X X X X X X X X X X X X X X X X X X X14 X15 X X X X X14 X15 X X X X X14 X15 X X X X X14 X15 X X X X X X X X X X X16 X X8 X X X3 X X X X17 X3 X X14 X15 X3 X3 X3 X X X18 X Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 161 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 8 of 149 * ** Visit 0 and 7 may be conducted during business hours. Visits 1 to 6 will always start in the evening. Each Respimat® inhaler and MDI contains drug supply for 30 days which must be obeyed regarding visit flexibility after randomisation. 1 All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions (see Section 4.2.2). A separate consent for pharmacokinetic sampling should be signed if patients are participating in the pharmacokinetic substudy. A separate consent for pharmacogenetic sampling should be signed if patients are participating in the pharmacogenetic substudy. The interval between Visit 0 and Visit 1 may be between 1 and 28 days depending on medication washout requirements and restrictions. A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid unnecessary washout procedures in non-eligible patients. Including asthma background characteristics. To be completed by all patients who took at least one dose of trial medication including those who discontinue early. Vital status information has to be collected on the originally planned follow up visit date (Visit 7). Haematology and blood chemistry (local laboratory). White bloodcell count, eosinophil count (absolute and relative), total serum IgE and creatinine levels will be documented in eCRF at Visit 1. Urine pregnancy test required for all women of child-bearing potential. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (LTRA) (if applicable), 2. trial medication from assigned MDI, 3. trial medication from assigned Respimat®. Patient’s ICS should be administered without change in posology (bid/qd; am/pm), i.e. as prescribed by patient’s treating physician prior to trial entry. Blood sample for pharmacogenetics will be drawn from all randomised patients that received at least one dose of trial medication and that gave a separate informed consent. Participation in the pharmacogenetic subset is not a pre-requisite for participation in the trial. The blood sample will be drawn at preferably Visit 2 or at any other subsequent visit after randomisation. PK in a subset of patients at selected sites (separate informed consent should be obtained first). e-Diary compliance check (see Section 4.3 and Section 6.1). First ACQ, then AQLQ (S), then EQ-5D and then PASAPQ will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. ACQ at screening will be used for assessment of degree of asthma control. If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). Refer to Section 4.2.2.1. Pre-bronchodilator FEV1 at Visit 1 and pre-dose FEV1 at Visit 2 must be within ± 30% variation prior to randomisation based on absolute FEV1 values. If the variation of FEV1 in the screening period exceeds ± 30%, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). 10 minutes pre- and 15 to 30 minutes post-bronchodilator PFT after inhalation of 4 puffs (100 µg/puff) salbutamol/albuterol. 10 minutes prior to trial drug administration (pre-dose) and until 3 hours post-dose. In a subgroup of patients at selected sites at Visit 6: 10 minutes prior to trial drug administration and until 24 hours post-dose. In conjunction with pulmonary function testing until 3 hours post-dose (measured immediately before PFT). Rescue medication only. Only in selected countries. After any premature withdrawal of patients who took at least one dose of trial medication, vital status information should be collected (see Section 6.2.3). 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 162 Page U12-2466-01 5 Dec 2011 Page 9 of 149 Trial Protocol TIMING OF TRIAL PROCEDURES DURING THE TREATMENT PERIOD 3 hour pulmonary function test without pharmacokinetic sampling1 Timing related to evening inhalation of study drug -1h -30’ -15’ -10’ Administer patient’s usual ICS medication followed by trial medication2 5' 15' 4 4 30’ 1h 2h 3h X X X X X X X X X AM3 Å ------ Æ Patient self-administration of questionnaires3 Å -------------- Æ Vital signs (seated) X Pulmonary function test 1 0 X X X Order of procedures if performed at the same time point: - Vital signs followed by pulmonary function testing - Use of AM3 device followed by filling out questionnaires Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat®). ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. At Visit 6, the PASAPQ will be patient self-administered as fourth questionnaire in selected countries. Only at Visit 5 and only in a subset of patients at selected sites. 2 3 4 Pharmacokinetic plasma sampling at Visits 2A (day 7), 2B (day 14), and 2C (day 21)1 Timing related to evening inhalation of study drug -1h -30’ -15’ 0 5’ Administer patient’s usual ICS medication followed by trial medication2 Å --------------------- Æ AM3 PK plasma sampling 1 2 X X X At selected sites only. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat®). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments 163 Page U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 5 Dec 2011 Page 10 of 149 Trial Protocol 3 hour pulmonary function test with 24 hour pharmacokinetic sampling at Visit 2 and Visit 31, 2 Timing related to evening inhalation of study drug -1h Administer patient’s usual evening ICS medication followed by trial medication3 Administer patient’s usual morning ICS medication followed by trial medication4 AM3 Patient self-administration of questionnaires6 PK plasma sampling PK urine collection 1 2 3 4 5 6 7 8 9 7 -30' -15' -10' 0 2' 5' 7' 10' 15' 30' 1h 2h 3h 6h 12h 24h8,9 X X X5 Å ----- Æ Å -------------- Æ X X Å ----------------------- Æ X X X X X X Å ---------------------------------------------------- Æ X X Å --- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X X X Å --------------- Æ Order of procedures if performed at the same time point: - PK plasma sampling (as close to planned time point as possible!), vital signs and pulmonary function testing - Use of AM3 device followed by filling out questionnaires At selected sites only. Patients may stay overnight. Refer to Section 5.5.2 for more information. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat ®). Morning trial drug administration will occur between 06.00 and 08.00 am and 12 hours (± 5 minutes) after the time of the pm administration. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI. Patient should use AM3 device immediately upon arising and prior to inhalation of medication. ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. Patients must empty bladder at the end of each urine collection interval. All urine voided during the sampling intervals -1 to 0 pre-dose and 0 to 2, 2 to 6 and 6 to 24 hours post-dose will be collected in containers. Patients should continue urine collection at home. Urine fraction must be kept cold at all times. Patient should return 30 minutes prior to last PK sample. Refer to Section 5.5.2 and Investigator Site File (ISF) chapter 10 for instructions. PK blood sample should be collected 15 minutes prior to the administration of next dose ICS and trial medication, i.e., at time point 23:45. Patients must void urinary bladder into the 6-24 container up to 5 minutes prior to the inhalation of the next day ICS and tiotropium doses (i.e., up to 23:55 hours after last dosing). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments 164 Page U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 5 Dec 2011 Page 11 of 149 Trial Protocol 24 hour pulmonary function test after 24 weeks (Visit 6)1, 2 Timing related to evening inhalation of study drug -1h -30' -15' -10' 0 30' 1h 2h 3h 4h 11h10' 11h50' 12h 12h30' 13h 14h 15h 16h 18h 20h 22h 23h 23h50' Administer patient’s usual evening ICS medication followed by trial medication3 Administer patient’s usual morning ICS medication followed by trial medication4 AM3 Patient self-administration of questionnaires6 1 2 3 4 5 6 X X X5 Å -Æ Å -------- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X X X X X X X X X X X X X Order of procedures if performed at the same time point: - Vital signs followed by pulmonary function testing - Use of AM3 device followed by filling out questionnaires At selected sites only. Requires overnight stay. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat ®). Morning trial drug administration will occur between 06.00 and 08.00 am and 12 hours (± 5 minutes) after the time of the pm administration. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI. Patient should be woken 40 minutes (± 10 minutes) prior to the start of the initial morning PFT (11h50’ time point). Patient should use AM3 device immediately upon arising and prior to inhalation of medication. ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. The PASAPQ will be patient self-administered as fourth questionnaire in selected countries. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 165 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 12 of 149 TABLE OF CONTENTS TITLE PAGE ...................................................................................................... 1 CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................ 4 FLOW CHART ................................................................................................... 7 TABLE OF CONTENTS ................................................................................. 12 ABBREVIATIONS ........................................................................................... 16 1. INTRODUCTION................................................................................ 20 1.1 MEDICAL BACKGROUND ............................................................................ 20 1.2 DRUG PROFILE ............................................................................................... 21 1.2.1 Inhalation solution and Respimat® Inhaler ................................................ 25 2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT ..................................................................................... 26 2.1 2.2 2.3 3. RATIONALE FOR PERFORMING THE TRIAL ........................................ 26 TRIAL OBJECTIVES ....................................................................................... 27 BENEFIT - RISK ASSESSMENT.................................................................... 28 DESCRIPTION OF DESIGN AND TRIAL POPULATION.......... 29 3.1 OVERALL TRIAL DESIGN AND PLAN ...................................................... 29 3.1.1 Administrative structure of the trial ........................................................... 30 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S) ..................................................................................... 31 3.3 SELECTION OF TRIAL POPULATION ...................................................... 31 3.3.1 Main diagnosis for study entry .................................................................... 32 3.3.2 Inclusion criteria............................................................................................ 32 3.3.3 Exclusion criteria ........................................................................................... 34 3.3.4 Removal of patients from therapy or assessments ..................................... 36 3.3.4.1 Removal of individual patients ................................................................... 36 3.3.4.2 Discontinuation of the trial by the sponsor ................................................. 37 4. TREATMENTS .................................................................................... 39 4.1 TREATMENTS TO BE ADMINISTERED .................................................... 39 4.1.1 Identity of BI investigational product and comparator product(s) .......... 39 4.1.2 Method of assigning patients to treatment groups ..................................... 40 4.1.3 Selection of doses in the trial ........................................................................ 41 4.1.4 Drug assignment and administration of doses for each patient ................ 41 4.1.5 Blinding and procedures for unblinding ..................................................... 44 4.1.5.1 Blinding ...................................................................................................... 44 4.1.5.2 Procedures for emergency unblinding ........................................................ 45 4.1.6 Packaging, labelling, and re-supply ............................................................. 45 4.1.7 Storage conditions ......................................................................................... 47 4.1.8 Drug accountability ....................................................................................... 47 4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT .................................................................................................... 48 4.2.1 Rescue medication, emergency procedures, and additional treatment(s) 49 4.2.1.1 Rescue medication ...................................................................................... 49 4.2.1.2 Emergency procedures ............................................................................... 49 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 166 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 13 of 149 4.2.1.3 Additional treatments ................................................................................. 49 4.2.2 Restrictions..................................................................................................... 51 4.2.2.1 Restrictions regarding concomitant treatment ............................................ 51 4.2.2.2 Restrictions on diet and life style ............................................................... 55 4.3 TREATMENT COMPLIANCE ....................................................................... 55 5. VARIABLES AND THEIR ASSESSMENT ..................................... 56 5.1 EFFICACY - CLINICAL PHARMACODYNAMICS ................................... 56 5.1.1 Endpoint(s) of efficacy .................................................................................. 56 5.1.1.1 Primary Endpoints ...................................................................................... 56 5.1.1.2 Secondary Endpoints .................................................................................. 56 5.1.1.3 Other Endpoints .......................................................................................... 58 5.1.2 Assessment of efficacy ................................................................................... 58 5.2 SAFETY .............................................................................................................. 63 5.2.1 Endpoint(s) of safety ..................................................................................... 63 5.2.2 Assessment of adverse events ....................................................................... 63 5.2.2.1 Definitions of adverse events ..................................................................... 63 5.2.2.2 Adverse event and serious adverse event reporting.................................... 65 5.2.3 Assessment of safety laboratory parameters .............................................. 66 5.2.4 Electrocardiogram......................................................................................... 67 5.2.5 Assessment of other safety parameters ....................................................... 67 5.3 OTHER ............................................................................................................... 68 5.3.1 Other endpoints ............................................................................................. 68 5.3.2 Other assessments.......................................................................................... 68 5.3.3 Pharmacogenetic evaluation......................................................................... 70 5.3.3.1 Methods of sample collection ..................................................................... 70 5.3.3.2 Analytical determinations ........................................................................... 70 5.4 APPROPRIATENESS OF MEASUREMENTS ............................................. 70 5.5 DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS .................................................................................. 71 5.5.1 Pharmacokinetic endpoint(s)........................................................................ 71 5.5.2 Methods of sample collection........................................................................ 73 5.5.3 Analytical determinations............................................................................. 74 5.6 BIOMARKER(S) ............................................................................................... 75 5.7 PHARMACODYNAMICS ................................................................................ 75 5.8 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP...... 75 6. INVESTIGATIONAL PLAN ............................................................. 76 6.1 VISIT SCHEDULE ............................................................................................ 76 6.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................ 78 6.2.1 Screening and run-in period(s) .................................................................... 78 6.2.2 Treatment period(s) ...................................................................................... 79 6.2.3 End of trial and follow-up period ................................................................ 83 7. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................................................................................... 85 7.1 7.2 7.3 STATISTICAL DESIGN - MODEL ................................................................ 85 NULL AND ALTERNATIVE HYPOTHESES .............................................. 86 PLANNED ANALYSES .................................................................................... 88 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 167 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 14 of 149 7.3.1 Primary analyses ........................................................................................... 88 7.3.2 Secondary analyses ........................................................................................ 89 7.3.3 Safety analyses ............................................................................................... 90 7.3.4 Interim analyses............................................................................................. 91 7.3.5 Pharmacokinetic analyses ............................................................................. 91 7.3.6 Pharmacodynamic analyses.......................................................................... 91 7.3.7 Pharmacogenetic analyses ............................................................................ 91 7.3.8 Health economic analyses ............................................................................. 91 7.3.9 PASAPQ analysis .......................................................................................... 91 7.4 HANDLING OF MISSING DATA .................................................................. 91 7.5 RANDOMISATION .......................................................................................... 92 7.6 DETERMINATION OF SAMPLE SIZE ........................................................ 93 8. INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS ............................................................................................ 95 8.1 8.2 8.3 8.3.1 8.3.2 8.3.3 8.4 8.4.1 8.4.2 8.5 8.6 8.7 8.8 9. STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT .......................................................................................................... 95 DATA QUALITY ASSURANCE ..................................................................... 97 RECORDS .......................................................................................................... 97 Source documents .......................................................................................... 97 Direct access to source data and documents ............................................... 97 Storage of records .......................................................................................... 98 LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS .............................................................................................................................. 98 Listedness ....................................................................................................... 98 Expedited reporting to health authorities and IECs/IRBs ........................ 98 STATEMENT OF CONFIDENTIALITY ....................................................... 98 COMPLETION OF TRIAL .............................................................................. 99 PROTOCOL VIOLATIONS ............................................................................ 99 COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL RELATED INJURY............................................................................. 99 REFERENCES ................................................................................... 100 9.1 9.2 10. 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 PUBLISHED REFERENCES ......................................................................... 100 UNPUBLISHED REFERENCES ................................................................... 102 APPENDICES .................................................................................... 104 INSTRUCTIONS FOR THE USE OF THE RESPIMAT INHALER ........ 105 INSTRUCTIONS FOR THE USE OF THE MDI ........................................ 111 INSTRUCTIONS FOR RETURN OF MALFUNCTIONING RESPIMAT INHALERS ....................................................................................................... 113 ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA ........ 114 ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S)) ............. 116 ASTHMA CONTROL QUESTIONNAIRE (ACQ) ..................................... 122 EQ-5D HEALTH QUESTIONNAIRE........................................................... 125 PAPER PATIENT DIARY CARD ................................................................. 128 AM3 PATIENT INSTRUCTION CARD ...................................................... 129 DEFINITION ASTHMA EXACERBATION ............................................... 133 CLINICAL LAB PARAMETERS ................................................................. 135 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 168 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 15 of 149 10.12 PHARMACOKINETIC METHODS ............................................................. 136 10.12.1 Planned analyses for pharmacokinetic evaluations ................................. 136 10.12.2 Handling of missing data ............................................................................ 136 10.12.3 Derivation of PK parameters ..................................................................... 137 10.13 PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE .. 140 11. SUMMARY OF CLINICAL TRIAL PROTOCOL MODIFICATIONS ............................................................................ 145 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 169 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 16 of 149 ABBREVIATIONS °C °F µg ACQ ACRN Ae AE Aet1-t2,ss Degree Celsius Ddegree Degree Fahrenheit Microgram Asthma Control Questionnaire Asthma Clinical Research Network Amount of analyte that is eliminated in urine Adverse Event Amount of analyte that is eliminated in urine from the time point t1 to time point t2 (Ae0-2, Ae2-6 at steady state) ALT Alanine aminotransferase am Ante meridiem AM3 Asthma Monitor® 3 ANCOVA Analysis of Variance AQLQ(S) Standardised Asthma Quality of Life Questionnaire AST Aspartate aminotransferase ATS American Thoracic Society AUC Area under the curve Area under the plasma concentration-time curve at steady AUCτ,ss state over a uniform dosing interval τ at steady state AUCt1-t2,ss Area under the concentration time curve of analyte in plasma over the time interval t1 to t2 at steady state AUMCss Area under the first moment curve at steady state b.i.d. Bis in die (twice daily) BAC Benzalkonium chloride BARGE trial Beta-Adrenergic Response by Genotype trial BDI Baseline Dyspnoea Index BI Boehringer Ingelheim BLQ Below the limit of quantification CA Competent Authority CCDS Company Core Data Sheet CFC Chlorofluorocarbon CL/F,ss Apparent clearance of analyte in the plasma after extravascular administration Renal clearance of analyte in plasma from the time point t1 to CLR,t1-t1 time point t2 Cmax [pg/mL] Maximum measured concentration of the analyte in plasma Cmax,ss Maximum measured concentration of analyte in plasma at steady state Cmin,ss Minimum concentration of analyte in plasma at steady state CML Clinical Monitor Local COPD Chronic obstructive pulmonary disease Cpre,ss Predose concentration of analyte in plasma at steady state CRA Clinical Research Assistant/Associate CRO Contract Research Organisation Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 CTMF CTP CTR CVA CZ DNA DPI DSMB ECG eCRF ECSC EDC EDTA EEC EQ-5D ERS ERT EU FAS FDA fet1-t2 FEV1 [L] FVC [L] GCP gCV GINA gMean h HCRU HFA HPLC/MS/MS ICH ICS IEC IgE INN IRB ISF IVRS IWRS kg L LABA LARGE trial 170 Page U12-2466-01 Trial Protocol Clinical Trial Master File Clinical Trial Protocol Clinical Trial Report Cerebrovasculair accident Climate Zone Deoxyribonucleic acid Dry powder inhaler Drug safety monitoring board Electrocardiogram Electronic Case Report Form European Community for Steel and Coal Electronic Data Capture Ethylenediaminetetraacetic acid European Economic Community Quality of life questionnaire developed by EuroQol group European Respiratory Society eResearch Technology European Union Full Analysis Set Food and Drug Administration Fraction of analyte eliminated in urine from time point t1 to time point t2 Forced expiratory volume in one second Forced vital capacity Good Clinical Practice Geometric coefficient of variation Global Initiative for Asthma Geometric mean Hour(s) Health Care Resource Utilization Hydrofluororalkane High Performance Liquid Chromatography/ Mass Spectrometry/Mass Spectrometry International Conference on Harmonisation Inhaled CorticoSteroids Independent Ethics Committee Immunoglobulin E International Non-proprietary Name Institutional review board Investigator Site File Interactive Voice Response System Interactive Web Response System Kilogram Litre(s) Long-acting beta-adrenergic Long-Acting Beta Agonist Response by Genotype trial 5 Dec 2011 Page 17 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 LDH LI LOCF LTRA max MCID MD MDI MedDRA mg min mL MMRM MRTih NA NC nnACh No. NOA NOP NOR NOS OPU PASAPQ PEF(R) [L/sec] PFT pg PK pm pMDI PRN q.d. RA RDC REML ROW SABA SAE SD SGOT SGPT SNP SOMS SOP SPC SUSAR 171 Page U12-2466-01 Trial Protocol Lactate dehydrogenase Lineary Index Last observation carried forward Leukotriene Receptor Antagonist (leukotriene modifier) Maximal Minimum clinically important difference Multiple dose Metered dose inhaler Medical Dictionary for Regulatory Activities Milligram Minimal; minute Millilitre(s) Mixed effect model with repeated measures mean residence time of analyte in the body after inhalation Not applicable Not calculated Non-neuronal acetylcholine Number Not analysed No peak detectable No valid result No sample Operative Unit (of BI) Patient satisfaction and preference questionnaire Peak expiratory flow (rate) Pulmonary function test Picogram Pharmacokinetic(s) Post meridiem Pressurized Metered Dose Inhaler As occasion requires Quaque die (once daily) Accumulation ratio Remote Data Capture (eCRF) Restricted maximum likelihood Rest of World Short-acting beta-adrenergic Serious Adverse Event Standard deviation or single dose Serum glutamic oxaloacetic transaminase Serum glutamic pyruvic transaminase Single nucleotide polymorphisms Summary of Clinical Trial Protocol Modifications Sheet Standard Operating Procedure Summary of product characteristics Suspected Unexpected Serious Adverse Reaction 5 Dec 2011 Page 18 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 T, t [h or min] t.b.d. t½,ss t1/2 TCM TDMAP TinA tmax tmax,ss TNF TSAP ULN USA USPI Vz/F γ-GT 172 Page U12-2466-01 Trial Protocol Time To be determined Terminal half-life of analyte in plasma at steady state Terminal half-life of analyte in plasma Trial Clinical Monitor Trial data management and analysis plan Tiotropium in Asthma Time from dosing to the maximum concentration of the analyte in plasma Time from dosing to the maximum concentration of analyte in plasma at steady state Tumor Necrosis Factor Trial Statistical Analysis Plan Upper Limit of Normal United States of America US prescribing information Apparent volume of distribution of analyte during the terminal phase following an extravascular dose Gamma glutamyltransferase 5 Dec 2011 Page 19 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 173 Page U12-2466-01 Trial Protocol 1. INTRODUCTION 1.1 MEDICAL BACKGROUND 5 Dec 2011 Page 20 of 149 Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular products play a role. The overall worldwide prevalence of asthma is about 5%, affecting 300 million people worldwide with over 60 million affected in the United States and Europe and high variability from country to country. Researchers estimate that an additional 100 to 150 million persons are likely to have asthma by 2025 with the projected increase of world’s urban population from 45% to 59% [P10-03196]. Central to the various phenotypic patterns of asthma is the presence of chronic underlying airway inflammation. The inflammatory cell components involved are variable, but with overlapping patterns that reflect the different phenotypes of the disease, such as intermittent versus persistent or acute versus chronic manifestations.The inflammation causes airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment [P10-03196]. According to the worldwide accepted guidelines of GINA (Global Initiative for Asthma 2009) [P10-03196] asthma is categorised into different severity categories and three levels of asthma control. The severity assessment is based on level of symptoms, airflow limitation, and lung function variability. Asthma severity can be intermittent, or it can be persistently mild, moderate or severe. The classification of asthma by severity is useful for initial assessment of the patient and initial treatment decisions. Due to the variability of asthma severity over time and individual patient’s response to treatment, a periodic assessment of the achieved asthma control is more relevant for ongoing treatment decisions. Asthma control is categorized into three levels based on daytime and nocturnal symptoms, limitations of activities, need for reliever treatment, lung function and exacerbations. Asthma can be controlled, partly controlled or uncontrolled. The aim of any asthma treatment is to achieve and maintain control for prolonged periods, thereby considering the safety of treatment, potential for adverse effects, and the cost of treatment required to achieve this goal. Asthma severity can be classified into so called GINA steps 1 to 5. The severity of asthma determines the treatment to be required. For many patients, medication must be taken everyday to control symptoms, to improve lung function and to prevent exacerbations. Medications are optionally also required to relieve acute symptoms such as wheezing, chest tightness, and cough. The role of long-acting anticholinergics as controller medication remains still to be eludicated in the treatment of asthma but appears to be promising based on preclinical findings and a successful proof-of-concept trial with tiotropium in patients with severe persistent asthma who were not fully controlled despite adequate treatment with at least high-dose ICS and LABAs. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 174 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 21 of 149 In this present study we will investigate if patients with moderate persistent asthma who are not fully controlled despite treatment with medium doses inhaled corticosteroids would benefit from tiotropium. The effects on pulmonary function and patient-reported outcomes of two different doses of tiotropium will be compared to placebo and salmeterol. 1.2 DRUG PROFILE Please refer to the "Investigator’s Brochure" [U92-0551] for the detailed outline of the existing quality, non-clinical and clinical data of tiotropium. Tiotropium is a quaternary ammonium compound developed as a long-acting orally inhaled anticholinergic bronchodilator and approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Two product formulations have been investigated in clinical trials. The first formulation is a single-dose capsule containing 18 µg of tiotropium (equivalent to 22.5 µg of tiotropium bromide monohydrate) formulated in a powder blend with lactose monohydrate. The inhalation powder formulation has been registered in about 100 countries (Spiriva® Handihaler®) and is presently being used in Phase IV clinical studies. The second product is an aqueous solution of tiotropium formulated with the excipients benzalkonium chloride and EDTA (2.5 µg tiotropium per actuation, 2 actuations per dose), which is intended for oral inhalation only via the Respimat® inhaler. The Respimat® inhaler is a novel propellant-free inhaler, which may prove to be an alternative to metered-dose and dry powder inhalers (MDIs and DPIs). The Respimat®inhaler is designed to deliver a single dose of Spiriva® in two actuations. Tiotropium in the Respimat® inhaler has been tested in a set of Phase III clinical studies, has been registered in several countries of the European Union and filed for New Drug Application in the United States of America. The beneficial effect of tiotropium on bronchoconstriction is well established and clinically used for years in the treatment of chronic obstructive pulmonary disease (COPD). The following text describes the pharmacological properties of tiotropium on a molecular level. Investigations on mucus (hyper-) secretion, potential anti-inflammatory effects as well as on anti-remodelling properties of tiotropium are reviewed. Receptor binding In vitro studies with human and animal muscarinic receptor subtypes (M1, M2, and M3) and with human and animal isolated tracheal preparations established tiotropium as a potent, selective and reversible muscarinic receptor antagonist. No other receptor interactions were detected at relevant concentrations. Association and dissociation from muscarinic receptors (M1, M2, and M3) were slow compared to ipratropium. The dissociation half-life of tiotropium-M3-complexes at 23°C was 34.7 hours compared to 0.26 hours for ipratropiumM3-complexes. Tiotropium-M2-complexes and ipratropium-M2-complexes dissociate more rapidly than M3- or M1-receptor-complexes. This pattern suggests a “kinetic receptor subtype selectivity” of occupation and blockade of M3>M1>M2-receptors [U99-1004]. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 175 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 22 of 149 Mucus modifying effects In a model of ovalbumine-induced asthma in guinea pigs [P05-05129] tiotropium prevented goblet cell hyperplasia and reduced the histologically assessed mucus gland area. In particular, the ovalbumine-stimulated increase in mucus gland area was reduced to baseline by inhalative treatment with tiotropium. These effects may positively influence mucus hypersecretion and airway plugging, and may thus improve lung function in asthma patients. Anti-inflammatory properties First in vitro investigations on the inflammatory potential of acetylcholine, the endogenous ligand of muscarinic receptors, were performed by Sato et al. [R05-0813]. Acetylcholine induced the release of neutrophil and monocyte chemotactic activity in bovine airway epithelial cells. Furthermore, acetylcholine stimulated alveolar macrophages to release eosinophil chemotactic mediators [R05-2327]. In a similar trial [P07-12448] acetylcholine stimulated different primary airway cells and cell lines to release inflammatory chemotactic factors. The acetylcholine-induced release of neutrophil chemotactic factors was abolished by tiotropium bromide suggesting an effect mediated by M3 receptors. Anti-inflammatory effects have also been shown for oxitropium bromide, another antimuscarinic, by Profita et al. in sputum cells derived from COPD patients [P05-11064]. In vivo investigations in an asthma model in guinea pigs have shown that eosinophilic inflammation was in part prevented by tiotropium [P07-10315]. Anti-remodeling effects In the above mentioned guinea pig asthma model ovalbumine induced an increase in airway smooth muscle mass measured morphometrically as well as on the alpha smooth muscle myosin heavy chain expression level. This may reflect airway smooth muscle hyperplasia observed in asthma patients. This pathophysiological proliferative effect on airway smooth muscles in guinea pigs was significantly reduced by inhaled tiotropium [P05-05129]. The above mentioned non-bronchodilating effects may contribute to beneficial long-term effects of tiotropium in the treatment of chronic airway diseases, including asthma. Comprehensive information about the development program of tiotropium is provided in the "Investigator´s Brochure" [U92-0551]. Renal impairment Tiotropium is mainly excreted renally. Increased plasma concentrations were described in patients with moderate to severe renal impairment (creatinine clearance ≤ 50mL/min). A dose reduction based on renal dysfunction cannot be recommended. Tiotropium should only be used in patients with moderate to severe renal impairment if the expected benefit outweighs the potential risk. As with all predominantly renally excreted drugs, tiotropium use should be monitored closely in patients with moderate to severe renal impairment. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 176 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 23 of 149 Drug-Drug Interaction Drug interactions of tiotropium with other drugs are unlikely due to the small dose and very low steady state plasma levels of tiotropium and the lack of inhibition of cytochrome P 450 isoenzymes by tiotropium [U97-2651]. The Respimat® Inhaler The Respimat® is a multi-dose inhaler differing from currently marketed dry powder and pressurized metered dose inhalers (pMDIs) by several features, including: (1) relatively slow aerosol delivery (1.5 seconds spray duration) that facilitates a better inhalation coordination for the patient, (2) high fine particle fraction of the spray permitting increased efficiency of drug delivery to the target organ, (3) a delivered dose independent of patient’s inspiratory flow, (4) propellant-free environment-friendly formulation, (5) convenience of a multidose inhaler, and (6) technological advances that enhance the proper use by the patient (e.g. a dose indicator and a locking mechanism that prevent tail-off of dosing after the declared number of doses). Tiotropium inhalation powder/HandiHaler® in Patients with Asthma Four randomized clinical trials have been conducted in patients with asthma using the inhalation powder capsule formulation of tiotropium [U96-0240, U98-3174, U98-3274, U991019]. These trials in the general (and exercise-induced) asthma population have demonstrated that tiotropium provides some degree of bronchodilation in asthmatic patients. Dose-dependency and convincing pharmacodynamic duration of action were not shown. Tiotropium did provide dose-related protection against methacholine induced bronchoconstriction in patients with mild to moderate asthma. The incidence of adverse events was low in all four asthma trials using doses up to 36 µg inhalation powder/HandiHaler® over 21 to 28 days of treatment. The type and rate of events were not different from those seen in the trials with COPD patients, aside from “asthma exacerbation”. The most common events were asthma exacerbation, upper respiratory infection, headache and dry mouth. Tiotropium inhalation solution/Respimat® in Patients with Asthma Three trials have been conducted with Spiriva® Respimat® in patients with asthma: Trial 205.248 [U02-1222]: local tolerability of Spiriva® Respimat® placebo formulation in hypersensitive asthmatic patients Trial 205.248 was a Phase II, single-dose, randomised, double-blind (within-device), fourway crossover trial conducted to evaluate the local tolerability of an acidic solution (pH = 2.7) for inhalation with the Spiriva® Respimat® placebo solution. This trial was conducted in 34 hypersensitive asthmatic patients. No adverse effects were attributed to the acidic solution, which was well tolerated. Neither spirometric parameters nor vital signs were changed by study treatment. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 177 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 24 of 149 Trial 205.341 [U08-2081]: Phase II proof-of-concept, severe persistent asthma This trial was an 8-week randomised, placebo-controlled, double-blind, 3-way crossover comparison of 5 µg and 10 µg Spiriva® Respimat® and placebo Respimat® administered once daily in the morning as add-on therapy in 100 adult asthmatics with maximized controller medication, who were still symptomatic. The primary endpoint of peak FEV1 response showed statistically significant superiority for both doses of Spiriva® Respimat® compared to placebo, with these results supported by the analysis of secondary endpoints. Thus, clinical proof of concept has been demonstrated for the 5 and 10 µg doses of Spiriva® Respimat® as add-on therapy in a population of patients with symptomatic severe persistent asthma. The 5 µg Spiriva® Respimat® administered as once daily in the morning was shown to be well tolerated with a comparable safety profile to placebo. Treatment with 10 µg Spiriva® Respimat® was similarly effective, generally well tolerated with comparable safety profile to placebo too; however, the higher occurrence of dry mouth is interpreted as sensitive indicator of a systemic anticholinergic reaction. Trial 205.342 [U09-1701]: Phase II proof-of-concept, moderate persistent asthma This trial was a 16-week randomised, placebo- and active-controlled, double-blind, doubledummy, parallel-group study comparing the efficacy and safety of Spiriva® Respimat® (5 µg once daily) in the evening with that of salmeterol HFA MDI (2 puffs of 25 µg twice daily) both in addition to maintenance ICS in moderate persistent asthma patients homozygous for arginine at ADRB2. The primary endpoint of this study, the change in mean weekly morning PEF from baseline to the last week of treatment,demonstrated the statistical non-inferiority of 5 µg Spiriva® Respimat® versus salmeterol and its superiority versus placebo. Thus, 5 µg Spiriva® Respimat® was as effective as salmeterol in the treatment of patients homozygous for arginine at the 16th amino acid position of the β2-adrenergic receptor (B16-Arg/Arg) with moderate persistent asthma. Spiriva® Respimat® showed an acceptable safety profile with no marked differences compared to salmeterol or placebo. Relevance of the B16-Arg/Arg genotype for the adrenergic or anticholinergic response The implications of selecting this subgroup of patients by receptor genotype are discussed extensively in the Investigator's Brochure [U92-0551]. Trial 205.342 [U09-1701] investigated the effect of Spiriva® Respimat® in B16-Arg/Arg patients with moderate persistent asthma for whom previously published studies suggested that they might not benefit from a LABA such as salmeterol therapy [P04-11193 and P0907838]. There is currently no evidence or mechanistic rationale to assume that the anticholinergic response is different in asthma patients homozygous for arginine at ADRB2. For this reason, the efficacy profile shown in patients homozygous for B16-arginine is most likely relevant for the general population with moderate persistent asthma. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 178 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 25 of 149 In conclusion: Two BI trials 205.341 [U08-2081] and 205.342 [U09-1701] showed a significant efficacy signal and a favourable safety profile for tiotropium administered via the Respimat® inhaler in moderate or severe persistent asthma in patients adequately treated with ICS according to current treatment guidelines. All trials for tiotropium Respimat® in asthma were and will be conducted only with an appropriate maintenance treatment with an ICS. 1.2.1 Inhalation solution and Respimat® Inhaler Active ingredient solution The tiotropium inhalation solution is aqueous based. The pH value is adjusted to pH 2.9 ± 0.2, near the stability optimum of the active substance. Administration of tiotropium inhalation solution is achieved with the Respimat® inhaler in combination with a drug reservoir/cartridge. The drug is delivered from the Respimat® inhaler as two actuations per dose. As a multi-dose device and solution, the drug formulation contains ethylenediaminetetraacetic acid, disodium salt (EDTA) and the bacteriostatic agent benzalkonium chloride (BAC), which have been reported to induce bronchospasm in some patients inhaling such solutions from a nebulizer. However, the doses of EDTA and BAC administered with two actuations of the Respimat® are well below the amounts for which bronchospasm has been reported with nebulized solutions. Additionally, clinical data for the Respimat® inhaler with a variety of drug substances (including tiotropium) indicates that it is unlikely that patients using the Respimat® inhaler will experience an EDTA or preservativerelated bronchospasm (see Section 6.2.4.4.4 of the tiotropium Investigator's brochure for further information) [U92-0551]. Details of the Respimat® device and the cartridge for active ingredient solution and the instructions for use are found in Appendix 8.2 of the tiotropium Investigator's Brochure [U92-0551] and in this protocol (Section 10.1). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 179 Page U12-2466-01 Trial Protocol 2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT 2.1 RATIONALE FOR PERFORMING THE TRIAL 5 Dec 2011 Page 26 of 149 Airway smooth muscle tone is controlled by sympathetic and parasympathetic influences as well as a range of other mediators. The predominant neural constrictor pathway is cholinergic but its impact depends on the influence of a range of other involved mediators. As consequence, anticholinergics have been explored as anti-obstructive therapies with variable responses in the different obstructive airway diseases. Neuronally released acetylcholine stimulates M3 muscarinic receptors on the airway smooth muscle and mucus glands causing bronchoconstriction and mucus (hyper-) secretion. Classically regarded as a neurotransmitter of the parasympathetic nervous system, acetylcholine is suggested to be also synthesized in many other cell types found in the airways as concluded from the expression of choline acetyl transferase, the enzyme responsible for the acetylcholine synthesis. Acetylcholine produced by these non-neuronal cells is commonly referred to as non-neuronal acetylcholine (nnACh). Additional components of the cholinergic system, in particular muscarinic receptors have been detected in nearly all cell types present in the lungs. Consequently, increasing evidence suggests that non-neuronal acetylcholine may play a role in various pathophysiological processes relevant in the course of chronic airway diseases. Taken together, these effects suggest that tiotropium, an anticholinergic, might have (beside its well characterized bronchodilatory mode of action) additional important characteristics which could be of potential therapeutic benefit for the patient. Preclinical in vivo studies in a guinea pig asthma model revealed that tiotropium attenuates airway inflammation as well as remodelling processes in these models [P05-05129 and P07-10315]. A published Cochrane Database review concluded that “the role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma” [P05-01207]. Anticholinergics are considered as a first-line therapy in COPD and there is a large body of evidence demonstrating its efficacy and safety, whereas, the place of anticholinergics in the treatment of asthma is less well-defined, particularly in patients with not optimally controlled or uncontrolled asthma. Patients with severe persistent asthma who are inadequately controlled despite treatment with a combination of inhaled steroids/long- acting ß2-agonists therapy are a therapeutic challenge with significant unmet medical need. An additional anticholinergic bronchodilator may provide added benefits for these patients. For some patients still symptomatic on maintenance therapy with an ICS alone, treatment with a longacting anticholinergic could be an alternative bronchodilator controller medication instead of a long-acting ß2-agonist. Short-acting anticholinergic agents such as ipratropium bromide, alone or in combination with ß2-agonists, are used in the management of chronic asthma in many countries. They are recognized particularly as alternative bronchodilators for patients who experience adverse effects such as tachycardia, arrhythmia and tremor from rapid-acting ß2-agonists (Global Initiative for Asthma (GINA) (2009) [P10-03196]). A meta-analysis of trials in which nebulized ipratropium bromide was added to a nebulized ß2-agonist [P99-02952] showed that Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 180 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 27 of 149 ipratropium bromide has an additional effect when nebulized together with a rapid-acting ß2agonist for exacerbations of asthma.The anticholinergic not only produced a statistically significant improvement in pulmonary function, but also significantly reduced the risk of hospital admission. According to the results of Beck R, et al. [P86-0614] a beneficial effect of ipratropium inhalation added to the standard care could be shown. Therefore clinical efficacy of inhaled tiotropium as a long acting anticholinergic can be expected. As tiotropium offers a superior time-response profile as a bronchodilator to ipratropium in COPD, tiotropium also likely will be more effective and have sustained antiobstructive effects for 24 hours in asthma. The 24-hour duration of action profile may be of special value in a population suffering from nocturnal events of, e.g., shortness of breath, which is the case in moderate and severe but still not optimally controlled asthma. Two completed phase II proof-of-concept trials (205.341 and 205.342) confirmed clinically relevant effectiveness of the 5 µg dose of tiotropium inhalation solution in patients with severe and moderate persistent asthma. Two identical 1-year phase III trials (205.416 and 205.417) are currently in conduct to confirm the safety and efficacy of 5 µg tiotropium inhalation solution (on top of at least ICS and LABA) in patients with severe persistent asthma. Trials 205.418 and 205.419 will be performed to evaluate the safety and efficacy of 2.5 and 5 µg tiotropium inhalation solution (on top of ICS) in patients with moderate asthma. Comprehensive information about the development program of tiotropium is provided in the "Investigator’s Brochure" [U92-0551]. Refer to Section 4.1.3 for the selection of doses in the trial. Please refer to Section 3.2 for a discussion on the trial design, including the choice of control groups, and to Section 4.1.3 for information on the selection of doses in the trial. 2.2 TRIAL OBJECTIVES This is one of two confirmatory phase III trials with identical protocols (twin trials with BI trial numbers 205.418 and 205.419). The primary objective of each trial is to evaluate the long term (24 weeks) efficacy and safety of two doses (2.5 µg and 5 µg) of tiotropium inhalation solution (administered once daily) compared to placebo and to salmeterol (50 µg; administered twice daily) on top of maintenance therapy with inhaled corticosteroid controller medication in patients with moderate persistent asthma. The comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. A 24 hour PK profile of tiotropium is only available for COPD patients. In this trial PK samples will be collected from 80 patients to confirm this 24 hour profile in asthma patients. A substudy will be done to explore the onset of action of the study medication. The substudy will comprise of 2 additional PFTs (5 and 15 minutes post-dose) at Visit 5 only and will be completed in approximately 480 patients. Refer to Section 5 for the endpoints. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 2.3 181 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 28 of 149 BENEFIT - RISK ASSESSMENT The favourable benefit-risk ratio based on the so far acquired knowledge about inhaled tiotropium is the rationale to conduct further studies with tiotropium in asthma. The incidence of adverse events was low in all four asthma trials using doses up to 36 µg inhalation powder/HandiHaler® over 21 to 28 days of treatment. The type and rate of events were not different from those seen in the trials with COPD patients, aside from “asthma exacerbation”. The most common events were asthma exacerbation, upper respiratory infection, headache and dry mouth. Single doses of placebo inhalation solution/Respimat® were well tolerated, as evaluated in 32 mild asthmatic patients. During a crossover efficacy and safety evaluation trial (205.341) of 8-week treatment periods of two doses (5 and 10 µg ) tiotropium inhalation solution delivered by the Respimat® inhaler as add-on therapy in patients with severe persistent asthma the overall occurrence of adverse events was similar between the placebo and 5 µg tiotropium groups (39.8% and 42.3% of patients, respectively, reported at least one adverse event), but slightly higher in the 10 µg tiotropium group (49.5% of patients reported at least one adverse event). The most common treatment-emergent adverse events were nasopharyngitis and asthma (MedDRA preferred term classification including aggravated asthma and exacerbation of asthma), with both being reported overall by 28 patients (26.2%). The only treatment-emergent adverse event reported in more than one patient was dry mouth, which was considered drug-related in 4 patients (3.9%) only in the 10 µg tiotropium group [U08-2081]. During the double-blind treatment and follow-up period of trial 205.342, mean (standard deviation) duration of double-blind exposure to trial medication was 109.6 (21.3) days (placebo), 110.9 (16.2) days (tiotropium), and 111.8 (16.8) days (salmeterol). During the double-blind treatment and follow-up periods, the overall incidence of AEs was similar in the active treatment and placebo groups: 52 (41.3%) placebo patients; 51 (39.8%) tiotropium patients; 56 (41.8%) salmeterol patients. Few AEs were considered drug-related and the incidences of such AEs were also similar across groups: 4 (3.2%) placebo patients, 6 (4.7%) tiotropium patients, and 3 (2.2%) salmeterol patients. The most common AEs by preferred term were asthma exacerbation (including preferred term asthma) and nasopharyngitis [U091701]. In conclusion, the studies conducted in asthmatic patients provided no evidence of serious adverse effects with suspected causal relationship to tiotropium treatment. The administration of tiotropium can be considered as safe for patients. For detailed information regarding the safety of tiotropium in COPD, please refer to the "Investigator’s Brochure" [U92-0551]. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 182 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 29 of 149 3. DESCRIPTION OF DESIGN AND TRIAL POPULATION 3.1 OVERALL TRIAL DESIGN AND PLAN This is a randomised, double-blind, double-dummy, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of 2.5 and 5 µg of tiotropium inhalation solution delivered by the Respimat® inhaler (once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in moderate persistent asthma patients treated with medium doses of inhaled corticosteroids. After signing informed consent and an initial screening visit, patients will enter a 28-day screening period. Patients who meet all inclusion and none of the exclusion criteria will be randomised into the 24-week treatment period in which they will receive either 2.5 µg tiotropium (2 puffs of 1.25 µg) once daily, 5 µg tiotropium (2 puffs of 2.5 µg) once daily, 50 µg salmeterol (2 puffs of 25 µg) twice daily or placebo in a double-dummy fashion. Patients will be evaluated for an additional 21 days following completion of the randomised treatment period. Visit 0 and Visit 7 may be conducted during business hours. Visit 1 to Visit 6 will always start in the evening. Patients who withdraw prematurely from the randomised treatment period will be followed up regarding their vital status. They will be contacted at their predicted normal exit date from the trial, i.e. completion of the 24 week treatment period plus 21 days follow-up period. Pulmonary function testing will be conducted at the screening visit (Visit 1) and vital signs will be measured in conjunction with pulmonary function tests until three hours post-dosing at all visits (except at Visits 2A, 2B and 2C) during the randomised treatment period. Asthma exacerbations according to protocol-specific definition (see Appendix 10.10) will be documented together with additional observations including utilisation of healthcare resources, adverse events and concomitant therapies. Three paper-based questionnaires (ACQ, AQLQ (S) and EQ-5D) will be patient self-administered during the treatment period. In selected countries a fourth questionaire (PASAPQ) will be patient self-administered at V6. The ACQ will also be self-administered at Visit 1. The ACQ mean score at Visit 1 and Visit 2 will be used to determine the patient's eligibility. The patient will record morning and evening PEF and FEV1 and use an electronic diary throughout the screening and treatment period. Physical examination will be performed together with an evaluation of the patient's smoking status and asthma background characteristics at Visit 1. Blood samples for clinical laboratory testing will be obtained and a 12-lead ECG will be recorded at Visit 1 to evaluate the patient's eligibility. Urine pregnancy testing will be done at Visit 1 in females of childbearing potential. The physical examination, laboratory testing, pregnancy testing, ECG and evaluation of the patient's smoking status will be repeated on completion of patient's participation in the randomised treatment period of the trial. Analysis of clinical laboratory samples will be performed by the local laboratory of each site. Depending on patient's informed consent, a blood sample for pharmacogenetics will be drawn at Visit 2 (or any subsequent visit) from all randomised patients that received at least one dose of trial medication. If a patient signed an informed consent for participation in the PK substudy, blood samples for pharmacokinetic evaluation will be drawn over 24 hours at Visits Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 183 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 30 of 149 2 and 3 and pre- and post-dose at Visit 2A, 2B and 2C (in a subset of patients at selected sites). Pulmonary function testing over 24 hours will be performed at Visit 6 in a subset of patients at sites capable of performing 24 hour measurements. Adverse events will be documented throughout the trial, i.e. starting with informed consent and ending 21 days after last administration of trial medication. All trial relevant documentation will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). Trial relevant documentation for the trial sites will be filed in the Investigator Site File (ISF) at the investigator sites. 3.1.1 Administrative structure of the trial Sponsor: Clinical trial drug supplies including trial, training and rescue medication will be provided by the sponsor. Co-ordinating Investigator: The co-ordinating investigator was selected by the sponsor. He will review the trial protocol, any subsequent amendments to the protocol and the (draft) Clinical Trial Report (CTR). He will provide his signature on the final protocol signature page and amendments and will provide his signature on the (draft) Clinical Trial Report (CTR) indicating that, to the best of Co-ordinator’s knowledge, the final CTR accurately describes the conduct and results of the Trial. Targeted group of Investigators: Pulmonologists/qualified sites with access to the requested patient population. The following local facilities/equipment are required at the investigational site: clinical laboratory, ECG, scale and sphygmomanometer. The sites have to be able to perform the 3 hour PFT measurements in the evening. Selected sites have to be able to perform the (24 hour) PK and/or 24 hour PFT measurements. DSMB: A DSMB will not be implemented on trial level, but might be implemented on project level. If so, safety review meetings will be held as per separate DSMB charter Central laboratory: The sample transport logistics (from site to sponsor) for PK and pharmacogenetic samples will be the responsibility of the central lab. The central lab will provide sampling and shipment materials. IVRS: An interactive voice response system (IVRS) will be used for randomisation to a treatment group in this trial and for appropriate re-supply of medication to patients. The ability to unblind will be available to the investigator via the IVRS. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 184 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 31 of 149 CROs: A CRO will provide MasterScope® CT and AM3® devices for the complete duration of the trial. All contracts and relevant meeting minutes will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S) The trial design has been selected to allow comparison of the effects on pulmonary function and patient-reported outcomes of different doses of tiotropium to placebo and salmeterol in patients with moderate persistent asthma that is not fully controlled although the patients are treated with medium doses inhaled corticosteroids. The selection of evening administration in this patient subgroup was mainly to consider nocturnal control of airway patency. In trials 205.341 [U08-2081] and 205.342 [U09-1701] no untoward events happened to patients treated with placebo and the overall incidence of AEs and the incidence of asthma exacerbations were similar in active treatment and placebo arms. Based on these data, a 'placebo' (i.e. no second controller medication) treatment group in this trial could be considered safe, because all patients are at least on a maintenance treatment with a stable dose of an anti-inflammatory medication (inhaled corticosteroid). Moreover, all patients will be provided with so-called rescue medication (open-label salbutamol (albuterol) HFA MDI). Boehringer Ingelheim intends to conduct a Phase 3 program that will fulfil global registration requirements. According to EU regulations, inclusion of an active comparator treatment arm is required. BI decided to use Serevent® HFA MDI as approved and commercially available in the EU as the active comparator. Washout requirements prior to pulmonary function testing and other medication restrictions (see Section 4.2.2) are given to reduce possible influences on pulmonary function testing and ensure patient's safety during the trial. The permitted concomitant asthma medication (see Section 4.2) should be kept stable during the complete trial period with the exception of acute treatment of asthma exacerbations. The data collected in a controlled, double-blind, randomised and placebo-controlled trial will provide useful information to health care providers and patients regarding the efficacy and safety of 2 doses of tiotropium inhalation solution delivered by the Respimat® inhaler added to inhaled corticosteroids in the treatment of not fully controlled moderate asthma in comparison to placebo and salmeterol. 3.3 SELECTION OF TRIAL POPULATION A sufficient number of patients of either sex with a diagnosis of moderate persistent asthma will be enrolled in the study to ensure approximately 1000 adult patients are entered (randomised) in the trial. Additional sites may be initiated and 'non-productive' sites may be closed to ensure sponsor's timelines. Randomisation will end when the trial clinical monitor has determined that enough patients are evaluable. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 185 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 32 of 149 Participation in the PK part of the trial is optional and not a prerequisite for patients to participate in the trial. Several sites capable of performing 24 hour PK sampling will be selected to participate in the PK part of the trial. All participating patients at these sites will be asked to consent to the PK visits until at least 80 patients have completed the PK substudy. Participation in the 24 hour PFT visit (at Visit 6) is optional and not a prerequisite for patients to participate in the trial. All sites capable of performing 24 hour PFT measurements will be selected to perform the 24 hour PFT visit. All participating patients at these sites will be asked to consent to the 24 hour PFT visit. The number of patients participating in the 24 hour PFT measurements is not limited. Several sites will be selected to perform a PFT at 5 and 15 minutes post-dose at Visit 5. A total of approximately 480 patients will be asked to participate (120 patients in each treatment arm). The Patient satisfaction and preference questionnaire (PASAPQ) will be patient selfadministered in selected countries at Visit 6. Every effort should be made to keep patients in the trial until they complete all trial procedures. Patients who discontinue after randomisation may not be re-enrolled at a later date. A record will be kept of all patients who fail to complete all trial visits and their reason for discontinuation. A log of all patients included into the study (i.e. having given informed consent) will be maintained in the ISF at the investigational site irrespective of whether they have been treated with investigational drug or not. 3.3.1 Main diagnosis for study entry Outpatients with a history of asthma and a current diagnosis of moderate persistent asthma (according to GINA guideline) and who are symptomatic (partly controlled) despite their current maintenance treatment with at least a medium dose of inhaled corticosteroids are eligible for inclusion if they fulfil all the inclusion criteria (Section 3.3.2) and none of the exclusion criteria (Section 3.3.3). 3.3.2 Inclusion criteria 1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1). 2. Male or female patients aged at least 18 years but not more than 75 years. 3. All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5. 4. The initial diagnosis of asthma must have been made before the patient's age of 40. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 186 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 33 of 149 If the patient is > 40 years and the diagnosis has not yet been recorded in the patient's medical files, the investigator should assess whether the patient's medical history (e.g. symptoms and prescribed medications) confirms the patient suffered from asthma since before the age of 40. If so, this patient may be considered for inclusion after consultation with the Clinical Monitor Local (CML). 5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 to 30 minutes after 400 µg salbutamol (albuterol)) resulting in a FEV1 increase of ≥ 12% and ≥ 200mL (see Appendix 10.4). NOTE: If this criterion is not met, the reversibility test may (in combination with the ACQ) be repeated once within two weeks (see Section 6.1). 6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (see Appendix 10.4) (alone or in a fixed combination with a LABA or SABA) for at least for 4 weeks prior to Visit 1. 7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ (see Appendix 10.6) mean score of ≥ 1.5. NOTE: If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). 8. All patients must have a pre-bronchodilator FEV1 ≥ 60% and ≤ 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to ECSC [R94-1408] (see Appendix 10.4). 9. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30% (see Appendix 10.4 for calculation). NOTE: If this criterion is not met, the patient’s Visit 2 may be repeated once within two weeks (see Section 6.1). 10. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years (see Appendix 10.4 for calculation). 11. Patients must be able to use the Respimat® inhaler (Appendix 10.1) and metered dose inhaler (Appendix 10.2) correctly. 12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter (diary compliance of at least 80% is required; refer to Section 6.1 for instructions). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 3.3.3 187 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 34 of 149 Exclusion criteria 1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial. 2. Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion 1. 3. Patients with a recent history (i.e. six months or less) of myocardial infarction. 4. Patients who have been hospitalised for cardiac failure during the past year. 5. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. 6. Patients with lung diseases other than asthma (e.g. COPD). 7. Patients with known active tuberculosis. 8. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed. 9. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1. 10. Patients with significant alcohol or drug abuse within the past two years. 11. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening). 12. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA, salmeterol xinafoate or any other components of the study medication delivery systems. 13. Pregnant or nursing woman. 14. Women of childbearing potential not using a highly effective method of birth control. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner. Barrier methods of contraception are accepted if condom or occlusive cap are used together with spermicides (e.g. foam, gel). Female patients will be considered to be of childbearing potential unless surgically sterilised by Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 188 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 35 of 149 hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years. 15. Patients who have taken an investigational drug within four weeks prior to Visit 1. 16. Patients who have been treated with beta-blocker medication - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed. 17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 18. Patients who have been treated with oral or patch beta-adrenergics - within four weeks prior to Visit 1 and/or - during the Screening period (period between Visit 1 and Visit 2) 19. Patients who have been treated with oral corticosteroids - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 20. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), - within 6 months prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 21. Patients who have been treated with cromone - within two weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors - within two weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 23. Patients who have been treated with other non-approved and according to international guidelines not recommended ’experimental’ drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 24. Patients with any asthma exacerbation or any respiratory tract infection - in the four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 to Visit 2). Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection. Refer to Section 6.1 for information on re-scheduling of visits. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 189 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 36 of 149 25. Patients who have previously been randomised in this trial or in the respective twin trial (205.419) or are currently participating in another trial. Precautionary statement Tiotropium As an anticholinergic drug, tiotropium may potentially worsen symptoms and signs associated with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction and should be used with caution in patients with any of these conditions. As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min) treated with tiotropium should be monitored closely. Salmeterol Salmeterol should be administered with caution in patients predisposed to low levels of serum potassium, patients with thyrotoxicosis or pre-existing cardiovascular disease, or patients with a history of diabetes mellitus. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A4 inhibitors (e.g. ketoconazole, atazanavir, ritonavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir) is not recommended. Both non-selective and selective beta-blockers should be avoided, unless there are compelling reasons for their use. 3.3.4 Removal of patients from therapy or assessments 3.3.4.1 Removal of individual patients An individual patient is to be withdrawn from the trial if any of the following criteria apply: • • • • The patient withdraws consent, without the need to justify the decision. The patient is no longer able to participate for medical reasons (e.g. pregnancy, surgery, adverse events, or other diseases). Administrative reasons (protocol violations, persistent non-compliance). Decision by Boehringer Ingelheim to discontinue a specific patient (e.g. in case of SAEs). No patient should be discontinued from the trial for a protocol violation before discussion with the clinical monitor. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 190 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 37 of 149 Withdrawal from the trial of an individual patient may be considered if any of the following criteria apply: • • • • • Intercurrent illness or an adverse event, which requires discontinuation of treatment per protocol. Investigators should check carefully if this applies for patients who experience any of the following criteria: More than 3 courses of systemic corticosteroids are required to treat asthma exacerbations. Twelve or more puffs of rescue medication (salbutamol/albuterol MDI) per day are used for more than 2 consecutive days (use of 12 or more puffs of rescue medication for at least 2 consecutive days will be alerted by the AM3®) A drop of patient’s pre-bronchodilator FEV1 (clinic assessment) below 40% predicted. A decrease of patient's best morning PEF of ≥ 40% from the patient's mean morning PEF for more than 2 consecutive days (a decrease of ≥30% for at least 2 consecutive days will be alerted by the AM3®). During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. Data of patients who discontinue or withdraw prior to randomisation will be entered in the trial database and will be listed. Data of patients who discontinue or withdraw after randomisation must be documented and the reason for withdrawal must be recorded in the eCRF. The data must be included in the trial database and must be reported. Refer to Section 6.2.3 for procedures to be followed for patients prematurely terminating the trial. Pregnancy If a patient becomes pregnant during the trial the investigational product needs to be stopped and the patient should be followed up until birth or otherwise termination of the pregnancy. The data of the patient will be collected and reported in the clinical trial report until patients last visit and any events thereafter will be reported in the BI drug safety database. Refer to Section 5.2.2.2 for detailed information on event reporting in case of pregnancy. 3.3.4.2 Discontinuation of the trial by the sponsor Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial site at any time for the following reasons: • • Failure to meet expected enrolment goals overall or at a particular trial site. Emergence of any efficacy/safety information that could significantly affect continuation of the trial. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • 191 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 38 of 149 Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the appropriate conduct of the trial. The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of trial termination (except in case of the third reason). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 192 Page U12-2466-01 Trial Protocol 4. TREATMENTS 4.1 TREATMENTS TO BE ADMINISTERED 5 Dec 2011 Page 39 of 149 Patients will be randomized 1:1:1:1 to 2.5 µg tiotropium inhalation solution, or 5 µg tiotropium inhalation solution, or salmeterol HFA-MDI, or placebo over the 24-week treatment period. The double-blind, double-dummy design of the study is realized by the use of matching placebos. During the treatment period the patients inhale two puffs from the MDI (salmeterol or placebo) every morning and every evening. In addition, the patients inhale two puffs from the Respimat® inhaler (tiotropium or placebo) every evening. Patients randomised to 2.5 µg tiotropium (treatment A) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations of tiotropium from the 1.25 µg Respimat® inhaler. Patients randomised to 5 µg tiotropium (treatment B) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations of tiotropium from the 2.5 µg Respimat® inhaler. Patients randomised to salmeterol (treatment C) inhale the following medication In the morning: two actuations of 25 µg salmeterol from the salmeterol MDI, In the evening: two actuations of 25 µg salmeterol from the salmeterol MDI followed by two actuations from the placebo Respimat® inhaler. Patients randomised to placebo (treatment D) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations from the placebo Respimat® inhaler. Boehringer Ingelheim Pharma GmbH & Co. KG will supply the investigational product. 4.1.1 Identity of BI investigational product and comparator product(s) Investigational product - 2.5 µg tiotropium bromide Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Tiotropium bromide Inhalation solution 2.5 µg (1.25 µg per actuation) delivered dose ex mouthpiece Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 193 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 40 of 149 Investigational product - 5 µg tiotropium bromide Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Tiotropium bromide Inhalation solution 5 µg (2.5 µg per actuation) delivered dose ex mouthpiece Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Comparator - 50 µg salmeterol xinafoate Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Salmeterol xinafoate Hydrofluoroalkane (HFA 134a) metered dose inhaler 50 µg (25 µg per actuation) Pressurised metered dose inhaler 2 actuations of 25 µg twice daily (in the morning and the evening) Oral inhalation Placebo - inhalation solution Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Placebo Inhalation solution NA Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Placebo - metered dose inhaler Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Placebo Metered dose inhaler NA Pressurised meter dose inhaler 2 actuations twice daily (in the morning and the evening) Oral inhalation Instructions for use of the Respimat® and metered dose inhaler are provided in Appendix 10.1 and Appendix 10.2 respectively. 4.1.2 Method of assigning patients to treatment groups When a patient is qualified for entry into the randomised treatment period, treatment assignment will be by means of a third-party phone/web-based randomisation on Visit 2. This Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 194 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 41 of 149 will involve the use of an Interactive Voice Response System (IVRS/Interactive Web Response system, IWRS). To facilitate the use of IVRS, the investigator will receive an IVRS/IWRS worksheet for each patient with the complete IVRS/IWRS dialogue and all necessary instructions for using the IVRS/IWRS. Upon signing informed consent, patients will be assigned a unique patient number. At each visit (Visit 2 - 5), the IVRS/IWRS will assign medication numbers to each patient. Refer to Section 4.1.6 for details on packaging and labelling, Details on the IVRS/IWRS system are provided in the ISF. 4.1.3 Selection of doses in the trial Two completed Phase 2 proof-of-concept trials (205.341 and 205.342) provide evidence that the 5 µg dose of Spiriva® Respimat® is effective in severe persistent asthma on top of ICSLABA and provide clinically effective bronchodilation in patients with severe and moderate persistent asthma. Trial 205.341 also evaluated the 10 µg dose and established the therapeutic plateau for the higher dosing level. The lower dose of 2.5 µg has been added to the Phase III trials in moderate persistent asthma (205.418 and 205.419) to assess whether a lower dose may still offer sufficient response. The selection of evening administration in this patient subgroup was mainly to consider nocturnal control of airway patency. 4.1.4 Drug assignment and administration of doses for each patient Dispensing of trial medication Patients will be randomised at Visit 2 to one of the four treatment groups. Trial medication will be dispensed to the patient by the investigator/pharmacist at Visits 2 to 5. The amount of trial medication dispensed will be recorded on the drug accountability forms. Priming of the Respimat® inhaler Each newly assembled Respimat® inhaler has to be primed. The inhaler should be primed by actuating it until an aerosol is visible plus three additional actuations. All priming actuations should be directed to the ground. Priming should NOT take place in the same room where the patient is inhaling trial medication nor where samples for PK analyses are drawn or processed (to avoid undue contamination of the environment). Once assembled, the shelf-life of the Respimat® is 3 months (study medication and training devices). Therefore it is important to ALWAYS enter the date of first priming on the medication label of the Respimat® immediately after first priming. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 195 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 42 of 149 Testing of the MDI Before using for the first time, four actuations should be released into the air to make sure the device is working properly. This testing should NOT take place in the same room where the patient is inhaling trial medication (to avoid undue contamination of the environment). Instructing the patient Detailed instructions and training for the use of the Respimat® inhaler and MDI will be given to the patient at Visits 1 and 2 (see Appendix 10.1 and 10.2). Patients should NOT inhale from a training device on Visit 2. At all subsequent visits (Visit 3, 4, 5 and 6) the investigator or qualified study personnel will observe the inhalation procedure and will reinforce a correct inhalation technique. Patients will be instructed to contact the site should they need to use their reserve inhaler and the site will document this. Patients will be instructed at each visit to retain and return all used and unused medication and devices at the subsequent visit. If the patient forgot to take the evening dose of patient’s own ICS, LTRA (if applicable) and trial medication within the specified time window, the patient is allowed to administer the evening dose until 12:00 am (midnight). After 12:00 am the patient should skip the evening dose and take the next dose at the next scheduled time. The evening dose on the day before the clinic visit should be taken at the specified time window to avoid influence on the data collected on the clinic visit day. If the patient took the evening dose after 08:00 pm on the day before the clinic visit, the clinic visit should be re-scheduled. If the patient forgot to take the morning dose of patient’s own ICS, LTRA (if applicable) and trial medication (MDI only) within the specified time window, the patient is allowed to administer the morning dose until 12:00 pm (noon). After 12:00 pm the patient should skip the morning dose and take the next dose at the next scheduled time. The morning dose on the day of the clinic visit should be taken at the specified time to avoid influence on the data collected on the clinic visit day. If the patient took the morning dose (at home) after 08:00 am on the day of the clinic visit, the clinic visit should be re-scheduled. Trial medication administration at clinic visits Patients will be instructed to withhold their evening dose of study medication and the evening dose of their usual ICS (if regular posology) and their leukotriene modifier (LTRA) (if applicable) on the day of clinic visits. The administration of the evening doses of ICS, LTRA (if applicable) and trial medication should be done in the clinic only after the pre-dose procedures (which include AM3 PEF/FEV1 measurement and eDiary, questionnaires, vital signs and pulmonary function test, and PK if applicable). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 196 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 43 of 149 At each clinic visit during the treatment period medication administration will be conducted in a fixed sequence (1. ICS (if regular posology) and LTRA (if applicable), 2. from MDI, 3. from Respimat®). Patient’s ICS should be administered without change in posology (bid/qd; am/pm), i.e. as previously prescribed by patient’s treating physician. Study medication must be inhaled within 5 minutes after the inhalation of the patient's own ICS medication and the patient should inhale from the Respimat® immediately after inhaling from the MDI. The patient should be in a seated position under the direct supervision of the investigator or his/her delegate. Trial medication will be administered in the evening between 06.00 - 08.00 pm and within ± 30 minutes of time of administration at Visit 2 at all visits during the treatment period: 1. Patient will inhale own ICS (if patient usually administrates in the evening) and take their LTRA (if applicable) 2. Patient will inhale 2 actuations of the trial medication from the assigned MDI 3. Patient will inhale 2 actuations of the trial medication from the assigned Respimat® inhaler On the 24 hour visits (PK and PFT), trial medication (MDI only) will also be adminstered on the following morning between 06.00 - 08.00 am and this should be 12 hours (± 5 minutes) after the time of pm administration the previous evening: 1. Patient will inhale own ICS (if patient usually administrates in the morning) and take their LTRA (if applicable) 2. Patient will inhale 2 actuations of the trial medication from the assigned MDI On all clinic visits the start time of the first inhalation and end time of the second inhalation from the Respimat® will be captured with the MasterScope® CT spirometer provided by Boehringer Ingelheim, except on PK Visits 2A, 2B and 2C where no pulmonary function testing is planned. On Visits 2A, 2B and 2C both, the start and end time of the inhalation from the Respimat® will be recorded on the eCRF. For patients participating in the PK measurements, on Visits 2, 2A, 2B, 2C and 3, the end time of the evening administration from the Respimat® device on the evening preceeding the visit will be recorded on the eCRF. A PK Visit Card will be provided to the patients to record the end time of inhalation at home. On 24 hour PFT visit days the start time of the first inhalation and end time of the second (inclinic) inhalation from the MDI in the morning of the visit will also be captured with the MasterScope® CT spirometer. Trial medication administration at home Patients will self-administer the morning and evening doses of trial medication between clinic visits and will record the administration of each dose of trial medication in the electronic diary. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 197 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 44 of 149 The evening dose of patient's own ICS, LTRA (if applicable) and trial medication should be administered within ± 30 minutes of the time of evening administration at Visit 2 and between 06.00 and 08.00 pm. The morning dose of patient's own ICS, LTRA (if applicable) and trial medication (MDI only) should be administered 12 hours (± 30 minutes) after the time of pm administration and between 06.00 - 08.00 am. Medication must be taken immediately after the eDiary questions have been answered and the PEF measurements have been performed. Respimat® and MDI Inhaler Return Patients should return all dispensed trial medication (including reserve and rescue medication) to the clinic at all visits. Study medication dispensed at Visit 2, will be used for the trial medication administration at Visit 2 and will be returned at Visit 3. Study medication dispensed at Visit 3, will be used for the trial medication administration at Visit 3 and will be returned at Visit 4. Study medication dispensed at Visit 4, will be used for the trial medication administration at Visit 4 and will be returned at Visit 5. Study medication dispensed at Visit 5, will be used for the trial medication administration at Visit 5 and at Visit 6 and will be returned at Visit 6. No study medication will be dispensed at Visit 6. Any Respimat® inhaler that has been reported as malfunctioning by a patient or investigator will be returned to the Department of Drug Delivery, Boehringer Ingelheim Pharma GmbH & Co. KG (Germany), for investigation. A detail of the procedure for the return of used inhalers is provided in Appendix 10.3. See Section 4.1.8 for details regarding drug accountability requirements. 4.1.5 Blinding and procedures for unblinding 4.1.5.1 Blinding Patients, investigators and everyone involved in analysing or with an interest in this doubleblind study will remain blinded with regard to the randomised treatment assignments until after database lock. Boehringer Ingelheim will generate the randomisation schedule, and prepare and code the medication in a blinded fashion. Trial supplies will be assigned to the patients via IVRS. The randomisation codes will be provided to bioanalytics prior to database lock to allow them to exclude PK samples taken from placebo and salmeterol patients from the bioanalytical Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 198 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 45 of 149 analyses. Bioanalytics will not disclose the randomisation code or the results of their measurements until the study is officially unblinded. Refer to Section 4.1.5.2 for rules of breaking the code for an individual or for all patients in emergency situations. 4.1.5.2 Procedures for emergency unblinding The ability to unblind will be available to the investigator via the IVRS. Unblinding must only be used in emergency situations when the identity of the study drug must be known by the investigator to provide appropriate medical treatment. Each site receives a manual from the IVRS provider that contains instructions on how to unblind the treatment of a patient via the IVRS (via 24-hour Emergency helpline). If possible, the Clinical Monitor Local (CML) and Trial Clinical Monitor (TCM) must be contacted prior to the site unblinding a patient's treatment. Patients unblinded to treatment will be withdrawn from the trial. 4.1.6 Packaging, labelling, and re-supply All study medication will be contained in individual patient treatment boxes identified with the trial number and a medication number. The boxes will have a two-part tear-off label. One part of each tear-off label will remain on the box, and the other part will be attached to a special drug dispensing log which will be part of the ISF. Examples of the labels are provided in the ISF. The investigator or designee should fill out the following information on the medication label prior to dispensing the medication to the patient: • • investigator's name (should be entered at time of dispense) date of first priming (Respimat® only; should be entered at time of first priming) For details of packaging and the description of the label, refer to the ISF. Respimat® treatment box The 1-month Respimat® treatment box will contain one Respimat® inhaler plus one drugfilled cartridge. The 1-month treatment box will contain sufficient medication for 30 days of treatment. The 2-month Respimat® treatment box will contain two Respimat® inhalers plus two drugfilled cartridges. The 2-month treatment box will contain sufficient medication for 60 days of treatment. The Respimat® inhaler will lock after 60 actuations have been administered and will no longer actuate any medication. Each Respimat® device and treatment box label will be identified by a moon indicating evening administration. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 199 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 46 of 149 MDI treatment box The 1-month MDI treatment box will contain one MDI. The 1-month treatment box will contain sufficient medication for 30 days of treatment. The 2-month MDI treatment box will contain two MDIs. The 2-month treatment box will contain sufficient medication for 60 days of treatment. Each MDI device and treatment box label will be identified by a sun and a moon indicating morning and evening administration. Medication dispensing The allocation of treatment boxes dispensed at each visit will be handled by an IVRS/IWRS system. At Visit 2, patients will be dispensed a 2-month Respimat® treatment box and a 2-month MDI treatment box. One Respimat® and one MDI (labeled with R1 and M1 respectively) will contain a sufficient amount of study medication to last the patient until Visit 3. The second Respimat® and the second MDI (labeled with R2 and M2 respectively) are reserve medication. This is to allow the patient the flexibility of not having to return to the clinic immediately to replace a lost Respimat® inhaler or MDI. The reserve Respimat® and drugfilled cartridge should NOT be assembled prior to leaving the clinic. The patient must assemble and prime the reserve device at home if needed. At Visits 3, patients will be dispensed a 1-month Respimat® treatment box and a 1-month MDI treatment box which will contain a sufficient amount of study medication to last the patient until the next clinic visit. At Visits 4 and 5, patients will be dispensed a 2-month Respimat® treatment box and a 2month MDI treatment box which will contain a sufficient amount of study medication to last the patient until the next clinic visit. The second Respimat® and drug-filled cartridge in the Respimat® treatment box should NOT be assembled prior to leaving the clinic. The patient must assemble and prime this device at home after the first cartridge is emptied. Additional 1-month Respimat® and additional 1-month MDI treatment boxes are available at the investigational site for issuing on an as needed basis. Patients should always have a reserve Respimat® (plus drug-filled cartridge) and a reserve MDI in their possession. At each visit, site staff should assess whether the reserve medication can be re-dispensed to the patient (considering remaining puffs and shelf-life) or if dispense of a new (replacement) reserve Respimat® inhaler plus drug-filled cartridge and/or MDI is needed. New reserve Respimats® and drug-filled cartridges should NOT be assembled prior to leaving the clinic. The patient must assemble and prime the reserve device at home if needed. Allocation of new reserve medication boxes will be handled by the IVRS/IWRS system. Re-supply One or more re-supplies are currently planned for this trial. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 200 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 47 of 149 Open-label supplies Boehringer Ingelheim will provide the following open-label supplies: • • 4.1.7 Respimat® inhalers, placebo cartridges and disposable mouthpieces for training purposes. A training device may be used for more than one training session. The training Respimat® can be used until 3 months after priming or until the device is empty. The date of first priming should be entered on the medication label of the Respimat®. A new mouthpiece should be used for each patient. Salbutamol (albuterol) HFA MDI inhalation aerosol (100 µg per actuation) for use as rescue medication during screening, treatment and follow-up periods (Visit 0 to V7). It will also be used for reversibility testing at Visit 1. Salbutamol (albuterol) will be dispensed to the patient at clinic visits as needed. Storage conditions All clinical trial supplies must be stored in a locked, secure cabinet and must be kept in their original packaging under the recommended storage conditions and may only be dispensed to trial subjects according to protocol. A temperature log must be maintained at the site. If the storage conditions are found to be outside the specified range, immediately contact the local clinical monitor. Further details are provided in the IB and on the country-specific labels, a sample of which will be part of the ISF. 4.1.8 Drug accountability Drug supplies, which will be provided by the sponsor, must be kept in a secure, limited access storage area under the storage conditions defined by the sponsor. A temperature log must be maintained to make certain that the drug supplies are stored at the correct temperature. The investigator / pharmacist / investigational drug storage manager will receive the investigational drugs delivered by the sponsor when the following requirements are fulfilled: • approval of the study protocol by the IRB / ethics committee, • availability of a signed and dated clinical trial contract between the sponsor and the Head of Trial Centre, • approval/notification of the regulatory authority, e.g. competent authority, • availability of the curriculum vitae of the principal investigator, • availability of a signed and dated clinical trial protocol or immediately imminent signing of the clinical trial protocol, • if applicable, availability of the proof of a medical licence for the principal investigator, • for USA only: availability of the Form 1572. The investigator / pharmacist / investigational drug storage manager must maintain records of the product’s delivery to the trial site, the inventory at the site, the use by each patient, and Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 201 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 48 of 149 the return to the sponsor or alternative disposition of unused product(s). Any discrepancies in drug supplies will be noted and explained. These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and the unique code numbers assigned to the investigational product(s) and trial patients. The investigator / pharmacist / investigational drug storage manager will maintain records that document adequately that the patients were provided the doses specified by the CTP and reconcile all investigational product(s) received from the sponsor. At the time of return to the sponsor, the investigator / pharmacist / investigational drug storage manager must verify that all unused or partially used drug supplies have been returned by the clinical trial patient and that no remaining supplies are in the investigator’s possession. For non-investigational medicinal products (salbutamol/albuterol) specific drug accountability requirements need to be fulfilled. Refer to Section 4.2.1.1 for details. ADDITIONAL INFORMATION FOR JAPAN ONLY The investigator / pharmacist / investigational drug storage manager should return the unused and collected investigational drugs (including empty boxes) to the sponsor (OPU) after unblinding the trial. In case investigational drugs are returned before unblinding of the trial, the investigator / pharmacist / investigational drug storage manager should seal the opened box (excluding empty boxes) for the patient, and before returning the unused and collected investigational drugs (including empty boxes) to the sponsor. When returning the investigational drugs, the investigator / pharmacist / investigational drug storage manager should exercise utmost caution to assure that the sponsor and other relevant trial staff members remain blinded to the patient's name on the package (box or label) of the investigational drugs. Upon completion of the trial, the investigator / pharmacist / investigational drug storage manager submits to the sponsor a copy of the investigational drug dispensing and return log. When submitting the copy, the investigator / pharmacist / investigational drug storage manager should exercise caution to assure that the sponsor and other relevant trial staff members remain blinded to the patient's name. 4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT The investigator must record all medication used by the patient in the three months prior to Visit 1 and throughout the trial on the Concomitant Therapy electronic case report form (eCRF). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 202 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 49 of 149 4.2.1 Rescue medication, emergency procedures, and additional treatment(s) 4.2.1.1 Rescue medication Administration of rescue medication is allowed at any point during the trial. Open-label salbutamol (albuterol) HFA MDI (100 µg per puff) will be provided as rescue medication (non-investigational medicinal product). During the complete trial period including screening, treatment and follow-up period, only salbutamol (albuterol) MDI provided by BI is allowed for PRN rescue medication use. Formoterol, alone or in fixed combinations with an ICS such as Symbicort® (budesonide and formoterol), is not allowed as rescue medication in this trial. During the screening and treatment period, patients must record the number of inhalations (puffs) of rescue medication used during the daytime and the nighttime in their electronic diary. If rescue medication is administered during a 3 or 24h PFT visit day, the visit will be discontinued and the patient will not complete the remainder of the pulmonary function testing. If rescue medication is administered during a PK visit, pulmonary function tests may be discontinued, but blood and urine collection for PK evaluation should be completed. Discontinued visits due to rescue medication intake will not be rescheduled. The medication used, dosage, route, date and 24-hour clock time of administration will be recorded on the Rescue Medication eCRF page. If rescue medication is administered on a visit day within 8 hours prior to the pre-dose PFT, the visit will be re-scheduled once. Further rescheduling should be discussed with the local clinical monitor. Salbutamol (albuterol) is considered a non-investigational medicinal product. Source data documentation and full drug accountability in regard to dispensed and returned medication to investigational site and to patients are required. 4.2.1.2 Emergency procedures There are no special emergency procedures to be followed. 4.2.1.3 Additional treatments Medications allowed to control acute asthma exacerbations as medically necessary during the screening, treatment and follow-up period: 1. PRN salbutamol (albuterol) HFA inhalation aerosol (MDI) provided by BI and to be recorded in the patient’s electronic diary. 2. Temporary addition of systemic corticosteroids is allowed during the study period. Pulmonary function testing should not occur within four weeks of the last administered dose of the addition (see Section 6.1 for visit schedule). 3. Temporary increases in the dose of inhaled corticosteroids are allowed during the study period. Pulmonary function testing should not occur within three weeks of the last Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 203 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 50 of 149 administered dose of an increase (see Section 6.1 for visit schedule). Patients should, whenever possible, return to the ICS medication and dose used prior to the exacerbation after the recovery from the exacerbation. 4. Temporary addition of theophylline preparations is allowed during the study period. Pulmonary function testing should not occur within seven days of the last administered dose of an increase or addition (see Section 6.1 for visit schedule). 5. The use of antibiotics is not restricted and may be used as medically necessary for asthma exacerbations and/or other infections. Pulmonary function testing should not occur within seven days of the last administered dose of an increase or addition of antibiotics if given for an asthma exacerbation or respiratory tract infection (see Section 6.1 for visit schedule). The treatment of asthma exacerbations including initiation of systemic corticosteroids should be done according to the investigator´s or treating physician´s medical judgement and should be in line with national and international recommendations. In the case of life-threatening exacerbations, any and all therapies deemed medically necessary may be prescribed. Medications allowed prior to and throughout the trial: 1. Maintenance treatment with medium doses inhaled corticosteroids (required for study entry; refer to inclusion criterion no. 6). 2. Leukotriene modifiers (if stabilised for at least 4 weeks prior to the trial and remains stable throughout the trial). 3. Mucolytic agents not containing bronchodilators. 4. Any orally inhaled rapid-acting beta-adrenergic agent is allowed prior to Visit 0. During the screening and randomised treatment periods and during the follow-up period, only salbutamol (albuterol) MDI provided by BI is allowed for PRN rescue medication use. The washout requirements before clinic visits need to be followed. 5. Antihistamines. Oral beta-adrenergics and beta blockers may be re-introduced during the follow-up period. However, it is not allowed to start with oral beta-adrenergics and beta blockers if not already prescribed prior to study entry. Treatment with pulmonary medications should remain stabilised as far as possible throughout the trial period. Please refer to Table 4.2.2.1: 1 for more information on medication permitted during the follow-up period. Refer to Section 4.2.2.1 for washout periods prior to pulmonary function testing during the study (including Visit 1). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 204 Page U12-2466-01 5 Dec 2011 Page 51 of 149 Trial Protocol 4.2.2 Restrictions 4.2.2.1 Restrictions regarding concomitant treatment The following table provides an overview of required, permitted and restricted medication. Table 4.2.2.1: 1 Overview of required, permitted and restricted medication Medications prescribed for asthma may be washed out after Visit 0 (after signing informed consent) and prior to Visit 1 to comply with the criteria in the table below. Study Period Drug Class Sub-class Prior to study Screening Period Treatment Period Follow up Period Corticosteroids Inhaled corticosteroids1 REQUIRED Patients must have been on maintenance treatment with a medium, stable dose for at least 4 weeks prior to Visit 1 Permitted Maintenance treatment with a medium, stable dose REQUIRED Maintenance treatment with a medium, stable dose REQUIRED Maintenance treatment with a medium, stable dose REQUIRED Permitted Permitted Permitted NOT permitted for at least four weeks prior to Visit 1 NOT permitted Temporary addition to treat exacerbations is allowed.1 NOT permitted Temporary addition to treat exacerbations is allowed. 1 Permitted Inhaled shortacting betaadrenergics Permitted Rescue (prior to all visits at least 8-hour washout) Rescue (prior to all visits at least 8-hour washout) Rescue Inhaled longacting betaadrenergics Permitted NOT permitted from 24 hours prior to Visit 1 Study medication Permitted Topical nasal steroids Systemic (including oral) corticosteroids Betaadrenergics / Beta-blockers Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 205 Page U12-2466-01 5 Dec 2011 Page 52 of 149 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class Sub-class Betaadrenergics / Beta-blockers Anticholinergics Miscellaneous Prior to study Screening Period Treatment Period Follow up Period Oral and patch beta-adrenergics NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted Permitted (only reintroduction is allowed. NOT allowed to start if not used prior to trial entry) Beta blockers NOT permitted for at least four weeks prior to Visit 1 Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. NOT permitted Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. NOT permitted Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. Permitted Short-acting anticholinergics: inhalation aerosol and nasal spray Permitted NOT permitted from 8 hours prior to Visit 1 Not permitted Permitted Long-acting inhaled anticholinergics NOT permitted for at least four weeks prior to Visit 1 NOT permitted Study medication NOT permitted All other (longacting) anticholinergics (e.g. for the treatment of overactive bladder) NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted Other investigational drugs NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted (only reintroduction is allowed. NOT allowed to start if not used prior to trial entry) Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 206 Page U12-2466-01 5 Dec 2011 Page 53 of 149 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class Sub-class Prior to study Screening Period Treatment Period Follow up Period Combination ICS/LABA (e.g. Advair®/ Seretide®; Symbicort®; Foster®) Permitted NOT permitted Permitted Combination ICS/SABA (e.g. Butasol®) Permitted NOT permitted Permitted Combination short-acting anticholinergic/ SABA (e.g. Berodual®, Combivent®, Duovent®) Permitted NOT permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 24 hours prior to Visit 1 NOT permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 8 hours prior to visit 1 NOT permitted from 8 hours prior to Visit 1 NOT permitted Permitted NOT permitted for at least two weeks prior to Visit 1 NOT permitted NOT permitted Permitted Permitted Permitted Permitted Permitted NOT permitted for at least two weeks prior to Visit 1 NOT permitted Temporary addition of theophylline to treat exacerbations is allowed1 NOT permitted Temporary addition of theophylline to treat exacerbations is allowed1 Permitted Cromone Antihistamines Methylxanthines /phosphodiesterase 4 inhibitors Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 207 Page U12-2466-01 5 Dec 2011 Page 54 of 149 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class 1 Sub-class Prior to study Screening Period Treatment Period Follow up Period Mucolytics Permitted Permitted Permitted Permitted Leukotriene modifiers Permitted To be stabilised for four weeks prior to Visit 1 and throughout the trial. Permitted Permitted Permitted Anti-IgE treatment (e.g. Omalizumab) NOT permitted for at least 6 months prior to Visit 1 NOT permitted NOT permitted Permitted ´Experimental´, non-approved asthma medications (e.g TNF-alpha blockers) NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted Refer to Section 4.2.1.3 for washout period prior to PFTs in case of treatment of an asthma exacerbation. Medication restrictions for pulmonary function testing (including Visit 1): 1. At least a 24-hour washout of long-acting beta-adrenergic bronchodilators prior to Visit 1 (not allowed between Visit 1 and 6). 2. At least a 24-hour washout of combination products, long-acting beta-adrenergic bronchodilators/corticosteroid prior to Visit 1 (not allowed between Visit 1 and 6). Patients should be switched to the inhaled steroid mono-product without changing the steroid dose at least 24 hours prior to Visit 1. 3. At least an 8-hour washout of short-acting beta-adrenergic bronchodilators prior to PFTs. 4. At least an 8-hour washout of short-acting anticholinergic bronchodilators prior to Visit 1 (not allowed between Visit 1 and 6). 5. At least an 8-hour washout of combination short-acting anticholinergic/SABA prior to Visit 1 (not allowed between Visit 1 and 6) 6. At least an 8-hour washout of combination products ICS/SABA prior to Visit 1 (not allowed between Visit 1 and 6). Patients should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 8 hours prior to Visit 1 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 208 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 55 of 149 7. On a visit day, the evening doses of the patient's regular ICS therapy, LTRA (if applicable) and trial medication should be taken after the visit day pre-dose PFT (i.e. at the clinic and not at home). 4.2.2.2 Restrictions on diet and life style Restrictions prior to PFT visits 1. Medication washout restrictions should be adhered to as described in Section 4.2.2.1. 2. The patient must remain in the building where the pulmonary function testing is performed and must return to the laboratory at least ten minutes prior to the start of each test. 3. On pulmonary function test days (including the Screening Visit), patients must refrain from strenuous activity for at least 12 hours prior to pulmonary function testing and throughout the testing period. Patients should also avoid cold temperatures, environmental smoke, dust or areas with strong odours (e.g. perfumes). 4. Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and icecold beverages are not allowed at least 2 hours prior to and during the pulmonary function testing period at clinic visits. Decaffeinated beverages are acceptable. 5. If a patient (re-)starts smoking during the trial, smoking should be discouraged for the 12 hours prior to pulmonary function testing and throughout the test day and will not be permitted in the 30-minute period prior to spirometry. Additional restrictions for patients participating in PK subset Patients who participate in pharmacokinetic sampling are not allowed to take any fruit juices (e.g. oranges, grapefruits), as well as products containing St. John´s wort (Hypericum perforatum) 72 hours before the pharmacokinetic sampling at Visits 2, 2A, 2B, 2C and 3. 4.3 TREATMENT COMPLIANCE The patient will complete an eDiary confirming that trial medication has been taken and indicating the number of puffs of salbutamol (albuterol) MDI use. The investigator will review these records with the patient at each visit (Visits 2 to 6) to assess treatment compliance. Compliance should be emphasised with a goal of at least 80% compliance rate. However, randomised patients will not be discontinued for lack of compliance without prior discussion with the local clinical monitor. On visit days, compliance will be guaranteed by administration of the trial drug under supervision of the investigating physician or designee. Each patient will be trained in the correct use of the Respimat® inhaler at Visit 1 and Visit 2. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 209 Page U12-2466-01 Trial Protocol 5. VARIABLES AND THEIR ASSESSMENT 5.1 EFFICACY - CLINICAL PHARMACODYNAMICS 5.1.1 Endpoint(s) of efficacy 5 Dec 2011 Page 56 of 149 Combined data of the two twin trials 205.418 and 205.419 will be used to ensure an adequate number of patients for the endpoints ACQ, time to first severe asthma exacerbation and time to first asthma exacerbation. These endpoints will be comprehensively analysed in a metaanalysis, the individual reports will only provide basic descriptive displays regarding these endpoints. 5.1.1.1 Primary Endpoints The co-primary endpoints are 1. Peak forced expiratory volume in one second (FEV1) response (within 3 hours post dosing) determined at the end of the 24-week treatment period. 2. Trough FEV1 response determined at the end of the 24-week treatment period. Peak FEV1 is defined as the highest FEV1 reading observed within 3 hours after administration of the evening dose of each randomised treatment. Peak FEV1 response is defined as the change from baseline in peak FEV1. Trough FEV1 is defined as the FEV1 measured (in the evening) at the -10 minute time point at the end of the dosing interval (24 hours post drug administration). Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline is the pre-treatment FEV1 measured at Visit 2 in the evening 10 minutes prior to the evening dose of patient’s usual inhaled corticosteroid controller medication (if regular posology), leukotriene modifier (LTRA) (if applicable) and first dose of trial medication (inhalation via MDI followed by inhalation via Respimat® inhaler). Meta-Analysis: The primary endpoint is the responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period on combined data from the two twin trials 205.418 and 205.419. The following definition for responder will be used. A patient is said to be a responder if for that patient an improvement of at least 0.5 for the ACQ was observed. The minimum clinical important difference (MCID) for the ACQ is 0.5. 5.1.1.2 Secondary Endpoints In a subgroup of patients FEV1, FVC and PEF readings are also available at 5 and 15 minutes post-dose, these readings will be analysed as mentioned in endpoint no. 11. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 210 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 57 of 149 1. Peak (within 3 hours post dosing) and trough forced vital capacity (FVC) determined at the end of the 24-week treatment period (as defined above for FEV1). 2. FEV1 (AUC0-3h) and FVC (AUC0-3h) at the end of the 24-week treatment period. The AUC0-3h will be calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough values will be assigned to zero time. FEV1 AUC 0−3h = 1 4 1 ∑ ( FEV1 (t i−1 ) + FEV1 (t i )) * (t i − t i −1 ) 3h i =1 2 (Trapezoid rule) where FEV1(ti) = FEV1 reading at planned time ti t0 = pre-dosing (= 0 min), t1 = 0.5h, …t4 = 3h FVC (AUC0-3h) is defined in the same way as FEV1 (AUC0-3h). 3. Individual in-clinic FEV1, FVC and PEF measurements at all time-points including peak, trough and AUC0-3h during the 24-week treatment period. 4. Quality of Life as assessed by standardised Asthma Quality of Life Questionnaire (AQLQ (S)) at all clinic visits during the 24-week treatment period. 5. PEF am/pm: change from baseline in mean weekly pre-dose morning and evening PEF measured by patients at home in the last week of the 24-week treatment period. Baseline is defined as the last week prior to randomization. 6. Use of PRN salbutamol (albuterol) rescue medication during the 24-week treatment period: number of puffs of rescue therapy used per day (i.e. the full 24 hour period, the daytime and the nighttime; weekly means will be compared). 7. Asthma symptoms as assessed by the patient’s electronic diary during the 24-week treatment period. Analysis with regard to daytime and nocturnal symptoms will be done. 8. Asthma symptom free days as assessed by the patient’s electronic diary during the 24week treatment period: asthma symptom free day is defined as a day with no reported symptoms and no use of rescue medication. 9. The responder rate as assessed by the ACQ determined at the end of the 24-week treatment period for each trial separately. Additionally in a subset of patients: 10. FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC1224h), FVC (AUC0-24h) after 24-week treatment FEV1 AUC n − mh = 1 k 1 ( FEV1 (t i −1 ) + FEV1 (t i )) * (t i − t i −1 ) ∑ i= j mh 2 (Trapezoid rule) Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 211 U12-2466-01 Trial Protocol 5 Dec 2011 Page 58 of 149 where FEV1(ti) = FEV1 reading at planned time ti t0 = pre-dosing (= 0 min), t1 = 0.5h, …t16 = 23.5h and tj-1=nh, tk=mh FVC (AUCn-mh) is defined in the same way as FEV1 (AUCn-mh). The FEV1 (AUC0-12h), FEV1 (AUC12-24h), and FEV1 (AUC0-24h) will be calculated as described above for FEV1 (AUC0-3h). The same method applies to the different areas under the curve for FVC. 11. Individual FEV1 and FVC measurements at 5 and 15 minutes post dose including peak and AUC0-3h. Peak and AUC0-3h are defined as described above, including the 5 and 15 minutes recordings. Meta-Analysis: The secondary endpoints on combined data from the two twin trials 205.418 and 205.419 are: 1. Time to first severe asthma exacerbation during the 24-week treatment period. 2. Time to first asthma exacerbation during the 24-week treatment period. 3. The ACQ value at each visit during the 24 week treatment period 5.1.1.3 Other Endpoints Three additional pulmonary function endpoints will be analysed: 1. PEF am/pm: weekly mean pre-dose morning and evening PEF measured by patients at home (weekly means will be compared) from baseline to the last week of the 24-week treatment period. Baseline is defined as the last week prior to randomization. 2. FEV1 am/pm: mean pre-dose morning and evening FEV1 measured by patients at home (weekly means will be compared) from baseline to the last week of treatment. Baseline is defined as the last week prior to randomization. 3. PEF variability: PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values (weekly means will be compared) during the 24-week treatment period. 5.1.2 Assessment of efficacy Pulmonary Function Testing (PFT) on study visits ( formerly known as MasterScope® CT spirometers ( Germany) will be provided to sites for the in-clinic spirometry measurements. The spirometers and their use, including daily calibration, must meet ATS/ERS criteria [P05-12782]. Spirometry will be conducted with the patient in a seated position having abstained from medications as specified in Section 4.2.2.1, and it is preferable that the same trained individual performs the PFTs for a given patient. The best of Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 212 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 59 of 149 three efforts will be defined as the highest FEV1, the highest FVC and the highest PEF each obtained on any of three blows meeting the ATS criteria (with preferably a maximum of five manoeuvres: however, a maximum of eight manoeuvres would be acceptable). The highest FEV1, FVC and PEF will be selected regardless of whether they come from different spirometric manoeuvres or from the same manoeuvre. At the 24-hour PFT test-day (Visit 6), patients participating in this subset should be woken 40 minutes (± 10 minutes) prior to the start of the initial morning PFT (11h50’ time point). For each patient, pulmonary function testing will always start at approximately the same time of the day and depending on the time of dosing. At Visit 1 pulmonary function testing will be performed between 06.00 and 08.00 pm. At Visits 2 to Visit 6, visits and PFTs will be scheduled to enable dosing between 6:00 pm and 8:00 pm. At Visits 3 to Visit 6 pulmonary function testing should start with ± 30 minutes maximum difference between the start of the tests on Visit 2 and the tests conducted on subsequent test days . The end of the 2nd inhalation of evening dose of study medication from the Respimat® will be regarded as time point zero for pulmonary function testing. At Visits 2 to 6, the 10 minute pre-dose measurement will be obtained in the period from 25 minutes to 5 minutes prior to the evening dose of ICS and study medication. The 30 and 60 minute measurements will be obtained within ± 5 minutes of the specified time point; and measurements made from 2-24 hours post-dose will be performed within ± 10 minutes of the scheduled time point. If a patient is unable to complete the PFTs during a visit, the local clinical monitor should be notified as soon as possible. The eCRF will be completed indicating the reason for stopping testing. Refer to Section 4.2.1.1 for more details on conduction of trial procedures if rescue medication was administered during a visit day. Patients who are unable to complete the trial visit may leave the clinic only upon instruction from the supervising physician. Refer to Section 4.1.4 (Trial medication at clinic visits) for more information on medication intake times that will be captured with the Masterscope® CT spirometer. Refer to Section 4.2.2.1 for restrictions regarding concomitant therapy prior to PFTs. Refer to Section 4.2.2.2 for restrictions on diet and life style prior to PFTs. Refer to the Flow Chart for the time schedule. Asthma Control Questionnaire (ACQ) The Asthma Control Questionnaire (ACQ) developed by Elizabeth Juniper [R00-1157] has 6 patient self-administered questions for the time period of the last week prior to the visit and one question concerning pre-bronchodilator FEV1 to be completed by a member of the clinic staff. Each question has a 7-point scale. The ACQ will be completed from Visit 1 to Visit 6 and should be the first questionnaire completed during Visit 2 to 6 and should precede any discussion with a health professional (physician, nurse or study co-ordinator). Question 7 will be completed after pulmonary function testing. The questions in the questionnaire are weighted equally, the score is the mean of the responses to all 7 questions. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 213 U12-2466-01 Trial Protocol 5 Dec 2011 Page 60 of 149 The ACQ is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Please refer to Appendix 10.6 for an example of the questionnaire. Electronic peak flow meter with electronic diary (Asthma Monitor® AM3) formerly known as The patients will receive an Asthma Monitor® AM3 ( , Germany) which combines the features of an electronic peak flow meter (measurement of both PEF and FEV1) and an electronic diary in one device. , Patients will receive the AM3 at Visit 1 and instructions for the use of the device at Visit 1 and Visit 2. They will use the device during the screening and treatment period (Visit 1 to Visit 6). The device will be used twice daily to first record questions related to asthma symptoms and quality of life, use of rescue salbutamol (albuterol), use of trial medication (during the treatment period only), and then to measure PEF and FEV1. The patient will be alerted by the AM3 to contact the investigator in case of one of the following situations: • A decrease of patient's best morning PEF of ≥ 30% from the patient's mean morning PEF for at least two consecutive days During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. • The patient used 12 or more puffs of rescue medication for at least two consecutive days All PEF/FEV1 and eDiary data saved in the AM3 will be downloaded at each visit after Visit 1 (except at Visits 2A, 2B and 2C) and transmitted via the MasterScope® CT to central data management of the vendor. At each trial visit the investigator receives a print-out of all downloaded AM3 data for review. Details and instructions for use are given in the Appendix 10.9 and the ISF. Electronic diary (eDiary) at home The diary part of the AM3 will be used to record the answers to the questions raised in the daily diary. The eDiary includes questions on asthma symptoms, quality of life and number of puffs of rescue medication. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 214 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 61 of 149 Morning and evening recordings should be performed at approximately the same time of the day (± 30 minutes) between 6:00 and 08:00 am and 6:00 and 08.00 pm, respectively. An alarm will sound at 8:00 and 8:30 am and pm to remind the patient to use the AM3. When the patient forgot to use the AM3 between 06:00 and 08:00, the patient should be instructed to use the AM3 if it is still before 11:59 (am or pm). The diary must be answered in the morning immediately upon arising (after the patient has cleared out mucus) and in the evening both prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication (and rescue medication if needed). Trial medication taken during the treatment period (morning and evening) will also be recorded in the AM3. Peak flow measurements at home The patient will record twice-daily PEF and FEV1 during the screening and treatment period (Visit 1 to Visit 6) with the AM3 immediately after answering the eDiary questions. The morning measurement should be performed upon arising after the patient has cleared out mucus and prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication (and rescue medication if needed). The evening measurement will be performed prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication (and rescue medication if needed). The patient should perform three peak expiratory flow manoeuvres in the standing position with the AM3. All acceptable PEF and FEV1 values are stored in the AM3 with date and time of the reading. The highest PEF and the highest FEV1 out of up to three acceptable blows, but not necessarily from the same blow, will be used for evaluation. Peak flow measurements and eDiary at Visit days 2 to 6 The morning recordings at home should be done as usual. In the afternoon/evening, patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic between -1:00 and -0:30h and prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication. The medication should be administered at the clinic after the pre-dose pulmonary function testing with the MasterScope® CT. Peak flow measurements and eDiary at 24 hour visits (Visit 2, 3 and/or 6 at selected sites) The morning recordings at home and on the following morning in the clinic should be done as usual. Also see the Flow Chart. The afternoon/evening recordings should be done in the clinic as described above. On the following afternoon/evening (at the end of the visit), patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic prior to Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 215 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 62 of 149 administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication and prior to leaving the clinic. Peak flow measurements and eDiary at Visits 2A, 2B and 2C at selected sites The morning recordings at home should be done as usual. In the afternoon/evening, patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic between -1:00 and -0:30h and prior to administration of maintenance ICS (if regular posology), their leukotriene modifier (LTRA) (if applicable) and trial medication.The medication administration should be performed at the clinic after the pre-dose PK sample has been drawn. Asthma Exacerbations The patient will document any worsening of asthma symptoms during the screening and treatment period in the electronic diary of the AM3 and measure the PEF twice daily (see Appendix 10.9). In addition, the patient will receive a paper patient diary card to document specific asthma symptoms, required medical treatment (e.g. change in asthma medication, need for medical care) or lost working days due to the asthma worsening (see Appendix 10.8). The investigator will review the patient’s entries and enter the relevant information from the paper patient diary card in the eCRF. The paper patient diary card will remain at the site. A new patient diary card should be dispensed at every visit as needed. The investigator should collect all information regarding asthma exacerbations including review of the electronic and paper diary. Specific questions should be raised to capture any asthma worsening, any changes in concomitant asthma medication including the introduction of systemic corticosteroids or any unplanned need for medical care due to asthma or lost working days that have not been documented in the patient’s diaries. It is the investigator’s responsibility to report any deterioration of asthma as an AE regardless if the sponsor’s definition of asthma exacerbations is fulfilled or not. The treatment of asthma exacerbations including initiation of systemic corticosteroids should be done according to the investigator´s or treating physician´s medical judgement and should be in line with national and international recommendations. If systemic corticosteroids are required, the GINA guidelines recommend to initially dose oral glucocorticosteroids between 0.5 to 1 mg of prednisolone or equivalent /kg body weight during 24-hours [P10-03196]. Whenever feasible, the following scheme is recommended for the trial: 30 mg/day prednisolone or prednisolone equivalent for 7 days. The onset of an asthma exacerbation should be defined by the onset of the first worsened symptom respectively PEF deterioration. The end of an asthma exacerbation should be recorded as defined by the investigator. Courses of systemic corticosteroids that are separated by one week or more should be treated as separate exacerbations. Refer to Appendix 10.10 for the BI definition of an asthma exacerbation in general and a severe asthma exacerbation. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 216 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 63 of 149 Asthma Quality of Life Questionnaire (AQLQ (S)) The standardised Asthma Quality of Life Questionnaire (AQLQ (S)) developed by Elizabeth Juniper [R08-0092] is administered on every visit from Visit 2 to 6. The AQLQ (S) is patient self-administered. The AQLQ (S) has 32 questions for the time period of the last two weeks prior to the visit and each question has a 7-point scale. Eleven questions refer to activity limitations, twelve questions refer to symptoms, five questions to emotional function and another four questions to environmental stimuli. The AQLQ (S) should be the second questionnaire completed (ACQ is completed first) and should precede any discussion with a health professional (physician, nurse or trial co-ordinator). The AQLQ (S) is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Challenges to inconsistent responses (pronounced outliers) should only be done very infrequently and with very careful consideration. Please refer to Appendix 10.5 for an example of the questionnaire. 5.2 SAFETY 5.2.1 Endpoint(s) of safety 1. All adverse events. 2. Vital signs: pulse rate and blood pressure (seated) recorded in conjunction with spirometry until 3 hours post-dose. 3. Vital status information of prematurely discontinued patients to be collected for all randomised patients on the originally planned follow up visit date (Visit 7). 5.2.2 Assessment of adverse events 5.2.2.1 Definitions of adverse events Adverse event An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. The event does not necessarily have to have a causal relationship with this treatment. Serious adverse event A serious adverse event (SAE) is defined as any AE which results in death, is immediately life-threatening, results in persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an important medical event when based upon appropriate medical judgement which may jeopardise the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above definitions. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 217 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 64 of 149 Additional information for Japan: An AE which possibly leads to disability will be reported as an SAE. Every new occurrence of cancer will be reported as a SAE regardless of the duration between discontinuation of the drug and the occurrence of the cancer. Significant Adverse Events No events have been classified as "significant" for this trial. Significant events The following are considered as significant events: • Hepatic injury defined by the following alterations of liver parameters: an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the same blood draw sample. Significant events are to be reported in an expedited manner similar to SAEs, even if they do not meet any of the seriousness criteria (for details see Section 5.2.2.2). Intensity of adverse event The intensity of the AE should be judged based on the following: • • • Mild: Moderate: Severe: Awareness of sign(s) or symptom(s) which is/are easily tolerated Enough discomfort to cause interference with usual activity Incapacitating or causing inability to work or to perform usual activities Causal relationship of adverse event Medical judgment should be used to determine the relationship, considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant medication, concomitant diseases and relevant history. Assessment of causal relationship should be recorded in the case report forms. Additional information for Japan: The reason for the decision on causal relationship needs to be provided in the eCRF. • • Yes: There is a reasonable causal relationship between the investigational product administered and the AE. No: There is no reasonable causal relationship between the investigational product administered and the AE. If a SAE is reported from a still blinded trial, the causal relationship must be provided by the investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. any active comparator or placebo according to the trial design). Worsening of underlying disease or other pre-existing conditions Worsening of the underlying disease or of other pre-existing conditions will be recorded as an (S)AE in the (e)CRF. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 218 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 65 of 149 Expected fluctuations or expected deterioration of the underlying disease and other preexisting conditions should not be recorded as an AE unless at least one of the following criteria is met: − the worsening of the disease constitutes an SAE, − the investigational drug is discontinued or the dose is reduced or increased, − additional treatment is required, i.e. concomitant medication is added or changed. − an unexpected deterioration from baseline has occurred in the opinion of the investigator. Changes in vital signs, ECG, physical examination, and laboratory test results Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator. Changes in vital signs including blood pressure, pulse rate, ECG, physical examination, and laboratory tests will be only then recorded as AEs if they are not associated with an already reported AE, symptom or diagnosis, and the investigational drug is either discontinued, reduced or increased, or additional treatment is required, i.e. concomitant medication is added or changed. Listed Adverse Events Please refer to Section 8.4.1 for more information. 5.2.2.2 Adverse event and serious adverse event reporting All adverse events, serious and non-serious, occurring during the course of the clinical trial (i.e., from signing the informed consent onwards through the observational phase and until 21 days after the last dose of trial medication) will be collected, documented and reported to the sponsor by the investigator on the appropriate CRF(s) / eCRFs / SAE reporting forms. Reporting will be done according to the specific definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File. All AEs, including those persisting after trial completion must be followed up until they have resolved or have been sufficiently characterised. For each adverse event, the investigator will provide the onset date, end date, intensity, treatment required, outcome, seriousness, and action taken with the investigational drug. The investigator will determine the relationship of the investigational drug to all AEs as defined in Section 5.2.2.1. If not stipulated differently in the ISF, the investigator must report the following events via telephone/fax using the SAE form immediately (within 24 hours or the next business day whichever is shorter) to the sponsor: SAEs and non-serious AEs occurring at the same time as an SAE and/or which are medically related to the SAE(s). BI has set up a list of AEs which are defined to be always serious. In order to support the investigator with the identification of these “always serious adverse events”, if a non serious AE is identified to be serious per BI definition, a query will be raised. The Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 219 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 66 of 149 investigator must verify the description and seriousness of the event. If the event description is correct, the item “serious” needs to be ticked and an SAE has to be reported in expedited fashion following the same procedure as above. The list of these adverse events can be found via the Remote Data Capture (RDC)system. Additional information for Japan: This information must be also reported immediately to the head of the trial site. With receipt of any further information to these events, a follow-up SAE report has to be provided. SAEs and non-serious AEs must include a causal relationship assessment made by the investigator. The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU (country-specific contact details will be provided in the Investigator Site File). This immediate report is required irrespective of whether the investigational product has been administered or not and irrespective of causal relationship. It also applies if new information to existing SAEs becomes available. Vital status information After any premature withdrawal of patients that took at least one dose of trial medication, the vital status information (dead or alive) will be collected on the originally planned visit date of the follow up visit (Visit 7). Any death during the vital status observation period needs to be reported as SAE by the investigator according to the Boehringer Ingelheim SAE procedures. Pregnancy In rare cases, pregnancy might occur in clinical trials. Once a female subject has been enrolled into the clinical trial, after having taken study medication, the investigator must report immediately any drug exposure during pregnancy to the sponsor. Drug exposure during pregnancy has to be reported immediately (within 24 hours or next business day whichever is shorter) to the defined unique entry point for SAE forms of the respective BI OPU (country-specific contact details will be provided in the Investigator Site File). The outcome of the pregnancy associated with the drug exposure during pregnancy must be followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B). 5.2.3 Assessment of safety laboratory parameters Clinical laboratory testing Clinical laboratory testing will be conducted on all patients at Visit 1 (to determine patient's eligibility) and Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. Lab parameters will be analysed by the local laboratory of each participating site. Please refer to Appendix 10.11 for methodological details. At Visit 1, the white blood cell count, eosinophil count (absolute and relative), total serum IgE and creatinine levels will be recorded on the eCRF. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 220 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 67 of 149 Pregnancy testing A pregnancy test will be conducted at Visit 1 and Visit 6 (or at the withdrawal visit if the patient does not complete all trial visits) in all women of childbearing potential. It will be sufficient to use a urine test kit (provided by BI or by the investigator/hospital). 5.2.4 Electrocardiogram A standard 12-lead electrocardiogram (ECG) will be performed on all patients at Visit 1 (to obtain information about the patient's baseline condition and to determine patient's eligibility) and at Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. All clinically significant findings at screening (Visit 1) will be recorded on the Medical History/Baseline Condition page in the eCRF. New clinically significant findings or worsening of screening conditions detected at Visit 6 (or at a withdrawal visit) will be recorded as adverse events on the appropriate eCRF page. An explanation of the aetiology of clinically significant abnormal findings must be made on the eCRF. All relevant abnormal findings have to be followed up until they have normalised or have been sufficiently characterised. 5.2.5 Assessment of other safety parameters Vital signs Pulse rate, systolic and diastolic blood pressure will be measured and recorded in conjunction with pulmonary function testing at Visit 2 to Visit 6 and prior to inhalation of medication and until 3 hours post-dose. Measurements will always be obtained immediately before pulmonary function testing with the patient seated and rested for a minimum of five minutes. The same person using the same blood pressure instrument on the same arm should perform all recordings. Physical examination A complete, head-to-toe physical examination will be completed on all patients at the screening visit (Visit 1) and at Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. The physical examination will also include measurements of systolic and diastolic blood pressure and pulse rate, which will be measured with the patient seated after having rested for at least 5 minutes. All clinically significant findings at screening (Visit 1) will be recorded on the Medical History/Baseline Condition page in the eCRF. New clinically significant findings or worsening of screening conditions detected at Visit 6 (or at a withdrawal visit) will be recorded as adverse events on the appropriate eCRF page. An explanation of the aetiology of clinically significant abnormal physical findings must be made on the eCRF. All relevant abnormal physical findings have to be followed up until they have normalised or have been sufficiently characterised. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 221 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 68 of 149 Vital status Vital status information (dead or alive) will be collected at the originally planned visit date of the follow up visit (Visit 7) for discontinued patients following randomisation. The vital status eCRF will be completed. Collection of vital status information does not require a patient visit. If no information can be collected despite at least 3 (documented) phone calls and at least one registered letter have remained unanswered, the patient will be regarded as lost to follow-up. 5.3 OTHER 5.3.1 Other endpoints Health economic analysis For the purpose of a separate health economic analysis (for example cost-effectiveness analysis including the clinical endpoint as effectiveness parameter), health care resource utilisation (HCRU) data will be collected and Quality of Life will be assessed at all time points during the 24-week treatment period. The economic evaluation of the HCRU and EQ-5D data will not be part of the clinical trial report. PASAPQ In a subset of patients the satisfaction and acceptance of the device will be investigated using the PASAPQ. The following PASAPQ-endpoints will be analyzed: • • • • • • • 5.3.2 The performance domain score (Q1-Q5, Q10-Q11) The convenience domain score (Q6-Q9, Q12-Q13) The total score (Q1-Q13) The overall satisfaction question score (Q14) The score for device preference question (Q15) The score for willingness to continue question (Q16) The score for 13 individual items (Q1-Q13) Other assessments HCRU data Resource use related to asthma will be captured within the trial in order to estimate and compare cost of treatment across treatment arms. HCRU data will be collected from Visit 2 to 6. Resource use data collected for calculating direct costs will include, e.g. number of days in hospital, number of unscheduled health care provider visits, number of visits in emergency room, number of days in intensive care unit, concomitant medications, and lost working days due to asthma. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 222 U12-2466-01 Trial Protocol 5 Dec 2011 Page 69 of 149 EQ-5D The EQ-5D self-report questionnaire was developed by the ( ) and is a standardised instrument for use as a measure of health outcome [R96-2382]. The EQ-5D is patient self-administered and will be completed from Visit 2 to 6. The questionnaire essentially consists of 2 pages. The first page is the descriptive system with 5 questions to the patient’s health state today. Each question captures one dimension of health (e.g. mobility, self-care) and has three levels to answer. The second page records the patient’s self-rated health status of today on a vertical graduated (0-100) visual analogue scale. The EQ-5D should be the third questionnaire completed and should precede any discussion with a health professional (physician, nurse or study co-ordinator). The EQ-5D is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. In instances where a patient cannot give or decide upon a response, no response should be recorded. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Please refer to Appendix 10.7 for an example of the questionnaire. PASAPQ The PASAPQ will be self-administered at Visit 6 in selected countries. The Patient Satisfaction and Preference Questionnaire (PASAPQ) is a multi item measure of respiratory inhalation device satisfaction and preference designed to be easy to understand and administer to asthma patients [P05-02607]. The PASAPQ is a two part questionnaire. Part I consists of 14 questions, the first 13 generating the Performance, Convenience and Total Score domains. The 14th question is a stand alone question for Overall Satisfaction. Part II consists of stand alone questions concerning a subject’s device preference and willingness to continue use. The PASAPQ should be the fourth questionnaire completed and should precede any discussion with a health professional (physician, nurse or study coordinator). Scoring will be according the methods used in the validation of the questionnaire (refer to PASAPQ User Manual) and will be described in detail in the TSAP. The PASAPQ is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. Patients should be requested to complete the Patient Satisfaction questionnaire as completely and as accurately as possible. If the patient requests help or clarification, the investigator will instruct the patient to re-read the instructions and to give the best answer possible to each question. The investigator will not provide the patient with an answer to any question or review their responses for accuracy. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Please refer to Appendix 10.13 for an example of the questionnaire. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 5.3.3 Page 223 U12-2466-01 Trial Protocol 5 Dec 2011 Page 70 of 149 Pharmacogenetic evaluation Exploratory genetic investigations in respiratory diseases might be done after complete anonymisation of the patient’s blood sample. 5.3.3.1 Methods of sample collection To allow pharmacogenetic analyses, all patients (who signed a separate informed consent) will be asked for one blood sample after successful randomisation at Visit 2 (or at any other subsequent Visit after randomisation). The samples will be taken and stored in accordance with local ethical and regulatory requirements. Participation in the pharmacogenetics part is voluntary and not a prerequisite for participation in the trial. The blood sample will be completely anonymised. The anonymisation procedure will guarantee a very high level of data protection for the donor. Once the anonymisation has been carried out, there will be no legal way to trace back to the identity of the donor. The anonymised DNA may be analysed at a later time to identify whether there are genetic factors that could contribute to a better therapeutic outcome or a higher risk of developing treatment related adverse drug reactions. Genetic investigations will be limited to the investigation of the effects of genetic variations on respiratory diseases, and on efficacy, safety and pharmacokinetics of the trial drug. After anonymisation, the blood sample (or the DNA derived thereof) will be stored at Boehringer Ingelheim for 15 years after the end of the clinical trial or until there is no more material available for tests. 5.3.3.2 Analytical determinations Genomic DNA will be extracted from blood samples according to standard molecular genetics methods. 5.4 APPROPRIATENESS OF MEASUREMENTS Pulmonary function tests are a validated and well established measurement tool for lung function testing. Pulmonary function tests will be conducted at clinic visits using the MasterScope® CT Spirometer ( formerly known as , Germany). FEV1 is a standard measurement for the assessment of lung function. The AM3 device ( formerly known as , Germany) will be used for measurement of PEF and FEV1 and to record the data of the eDiary. The AM3 complies with the regulations of European Medical Device Directive and the FDA guidelines in the United States. The EQ-5D, AQLQ(S) and ACQ are well established and validated questionnaires. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 5.5 224 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 71 of 149 DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS A subset of at least 80 patients will participate in the PK part of the trial. Plasma and urine concentration monitoring of tiotropium will be performed in order to assess drug exposure and to characterise the pharmacokinetics of tiotropium bromide in this patient population. A separate informed consent will be signed by the patients in accordance with local ethical and regulatory requirements. 5.5.1 Pharmacokinetic endpoint(s) The following pharmacokinetic parameters will be determined at Visit 2 (day 1) in relation to the administration of the first dose of tiotropium, when feasible: 1. Cmax (maximum concentration of tiotropium in plasma) 2. tmax (time from dosing to maximum tiotropium plasma concentration) 3. AUC0-tz (area under the concentration-time curve of tiotropium in plasma over the time interval from 0 to the last quantifiable data point within the first dosing interval) 4. Aet1-t2 (amount of tiotropium that is eliminated unchanged in urine from the time point t1 to time point t2) 5. fet1-t2 (fraction of tiotropium dose excreted in urine from time point t1 to t2) 6. AUCt1-t2 (area under the concentration-time curve of tiotropium in plasma over the time interval t1 to t2) 7. AUC0-∞ (area under the concentration-time curve of tiotropium in plasma over the time interval from 0 extrapolated to infinity) 8. %AUCtz-∞ (the percentage of the AUC0-∞ that is obtained by extrapolation) 9. λz (terminal rate constant of tiotropium in plasma) 10. t½ (terminal half-life of tiotropium in plasma) 11. MRTih (mean residence time of tiotropium in the body after inhalation) 12. CL/F (apparent clearance of tiotropium in the plasma after extravascular administration) 13. Vz/F (apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose) 14. CLR,t1-t1 (renal clearance of tiotropium in plasma from the time point t1 to time point t2) A pre-dose blood sample will be obtained at Visits 2A, 2B and 2C and will be reported as Cpre,N (pre-dose concentration of tiotropium in plasma). Similarly, a blood sample will be Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 225 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 72 of 149 obtained 5 minutes post-dosing at Visits 2A, 2B and 2C and will be reported as C0.083,N (tiotropium plasma concentration 5 minutes post-dosing). At Visit 3 (week 4) tiotropium steady state will be assumed and the following parameters will be determined, when feasible: 1. AUCt1-t2,ss (area under the concentration time curve of tiotropium in plasma over the time interval t1 to t2 at steady state) 2. AUCτ,ss (area under the plasma concentration-time curve at steady state over a uniform dosing interval τ at steady state) 3. Cmax,ss (maximum measured concentration of tiotropium in plasma at steady state) 4. tmax,ss (time from dosing to the maximum concentration of tiotropium in plasma at steady state) 5. λz,ss (terminal rate constant in plasma at steady state) 6. t½,ss (terminal half-life of tiotropium in plasma at steady state) 7. MRTih,ss (mean residence time of tiotropium in the body after inhalational administration to steady state) 8. CL/F,ss (apparent clearance of tiotropium from plasma after extravascular administration to steady state) 9. Vz/F,ss (apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose) 10. Aet1-t2,ss (amount of tiotropium that is eliminated in urine from the time point t1 to time point t2 (Ae0-2, Ae2-6 at steady state) 11. fet1-t2, ss (fraction of tiotropium eliminated in urine from time point t1 to time point t2 (fe02, fe2-6 at steady state) 12. CLR,t1-t2,ss (renal clearance of tiotropium from the time point t1 until the time point t2) (CLR,0-2, CLR, 2-6 at steady state) 13. Cpre,ss (predose concentration of tiotropium in plasma at steady state) 14. Cmin,ss (minimum concentration of tiotropium in plasma at steady state) In addition, the linearity index (LI) and the following accumulation ratios of the analyte in plasma following 28 doses over a uniform dosing interval τ will be calculated: 15. RA,Cmax,28 based on Cmax 16. RA,AUC based on AUC Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 226 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 73 of 149 Further pharmacokinetic parameters may be calculated as appropriate. Details on the pharmacokinetic methods can be found in Appendix 10.12. The pharmacokinetic parameters will be included in the clinical trial report. 5.5.2 Methods of sample collection Date and exact clock time of pharmacokinetic sampling have to be recorded and documented in the eCRFs by the site personnel. Clocktime of the MasterScope® CT should be used at Visit 2 and Visit 3. The time point zero for pharmacokinetic sampling is defined as end of last inhalation from the Respimat®. For handling of medication administration at clinic visits and collection of medication administration time points, please refer to Section 4.1.4. The pre-dose PK blood sample will be obtained 15 minutes before trial drug administration. A planned time of -0:15 will be used for data base set-up. The pre-dose urine sample collection interval will be the hour prior to trial drug administration. A planned start time of -1:00 and a stop time of 0:00 will be used for data base set-up. At Visit 2 and 3, the patient may leave the clinic after the morning inhalation of trial medication (or, if preferred by the patient, after the 6 hour post-dose sample has been drawn) and should return 30 minutes prior to the planned time for the last PK sample. Patients should continue urine collection at home and take the container with them from and to the clinic. All urine fractions must be kept cold at all times, i.e., during collection and transport. This includes the 6-24 hour urine fraction which will be taken home by the patient. A cold box will be provided to the patients for this purpose. Blood sampling For quantification of tiotropium plasma concentrations, at each sampling time point about 6 mL (Vacutainer®) or 4.9 mL (Monovette®) blood will be taken from a forearm vein using a Monovette or Vacutainer collection tube containing EDTA (ethylenediaminetetraacetic acid) as anticoagulant. Blood samples shall be drawn as close to the planned time as possible. Two aliquots of plasma will be prepared from each blood sample. The sampling/collection tubes will be labeled with at least patient number, visit number and planned sampling time. A total amount of approximately 150-180 mL blood will be taken per patient during the trial for pharmacokinetic purposes. Refer to the Flow Chart for the time schedule. Detailed instructions for pharmacokinetic sampling, handling and shipment of plasma samples are provided in the ISF/labmanual. Urine sampling All urine voided during the collection intervals will be collected in containers. The urine bladder will be voided within 5 minutes before the beginning of each collection interval. In order to enable a sufficient urine flow patients might be asked to drink at least 150-200 mL of a non-caffeinated beverage 15 minutes prior to the end of each urine fraction in order to support a miction in time. The collection containers and tubes will be labeled with at least patient number, visit number and planned sampling time. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 227 U12-2466-01 Trial Protocol 5 Dec 2011 Page 74 of 149 Urine container weights (i.e. tare and gross) and times of collection will be documented in the eCRFs (weight will be set equal to volume without correction for specific gravity of urine when calculating the urine weight for analysis). Refer to the Flow Chart for the time schedule. Detailed instructions for pharmacokinetic sampling, handling and shipment of urine samples are provided in the ISF/labmanual. Prevention of contamination Tiotropium is known to be a very adhesive substance. In order to avoid contamination of plasma and urine samples PK blood sampling, urine collection and plasma and urine preparation procedures must NOT take place in the same room where priming of the Respimat® inhaler or drug inhalation takes place. Also, the priming and drug inhalation must be carried out in different rooms. More than one patient must not be present in a room at the time of drug inhalation on the pharmacokinetic days. Patients and study personnel should handle the Respimat® inhaler with gloves on, and these gloves should be changed and discarded immediately after a patient has completed inhalation and before any container for PK samples is handled. The urine containers, plasma vials and transfer pipettes should not be touched with the same gloves already used for blood sampling. Plasma and urine vials/containers should be stored closed and should only be opened if necessary for the procedure. The patients must be advised to handle the urine containers with gloves on or to wash hands thoroughly before and after urine collection. The site of cannulation should remain covered (e.g. use of overalls) during the time the patient remains in the room where drug inhalation is planned. The covering should only be removed once the patient is moved to the room where blood sampling etc is planned. 5.5.3 Analytical determinations Plasma and urine concentrations of tiotropium will be determined by validated HPLC/MS/MS assays (high performance liquid chromatography) [U10-1855-01]. The analysis will be performed by (formlery known as ( , Germany) and will be described in an Appendix in the clinical trial report. Plasma concentration measurement of samples from the salmeterol and placebo treatment will be restricted to the blood samples taken before treatment and taken at Cmax (i.e. plasma sample taken at 5 minutes after inhalation). Similarly, urinary concentrations of samples from salmeterol and placebo treatment will be restricted to pre-dose and 0-2 hour intervals (Visits 2 and 3). Only if one of these samples reveals tiotropium, the remaining samples of that particular patient will be analysed as well. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 5.6 228 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 75 of 149 BIOMARKER(S) Not applicable to this trial. 5.7 PHARMACODYNAMICS Not applicable to this trial. 5.8 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP Not applicable to this trial. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 229 Page U12-2466-01 Trial Protocol 6. INVESTIGATIONAL PLAN 6.1 VISIT SCHEDULE 5 Dec 2011 Page 76 of 149 This trial consists of a screening period, a treatment period and a follow-up period. Following the screening visit (Visit 1) and the four-week screening period, patients will be randomised into the double-blind portion of the study (Visit 2). Additional visits will be scheduled after 4, 8, 16 and 24 weeks of therapy (Visits 3, 4, 5 and 6) and once 21 days post-treatment (Visit 7). For patients participating in the pharmacokinetic evaluations, additional visits will be scheduled after 1, 2 and 3 weeks of therapy (Visit 2A, 2B, and 2C). Patients should make every attempt to complete the study as specified. Investigators should encourage patient treatment compliance and adherence to other protocol specific activities. All deviations from the planned visit schedule will be documented. Rescheduling in general • A patient may be rescheduled twice (within two weeks of the scheduled visit date) due to lack of medication washout compliance. Rescheduling prior to randomization • The screening period (between Visit 1 and Visit 2) may be extended by an additional 4 weeks for administrative reasons. • If a patient experiences an asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1, the visit will be postponed until 4 weeks following recovery from the infection or exacerbation. • If a patient experiences an asthma exacerbation or respiratory tract infection during the screening period (between Visit 1 and 2), randomisation will be postponed until 4 weeks following recovery from the infection or exacerbation. • If the screening period is extended by more than an additional 4 weeks, but not more than an additional 8 weeks (calculated from the initial Visit 1 if the reversibility test and ACQ are repeated as described below), the screening examination has to be repeated prior to randomisation. The repeat screening examination will include a physical examination, vital signs (blood pressure and pulse rate), 12-lead ECG and clinical laboratory evaluation (haematology, serum chemistry, and pregnancy test). The patient should return for these evaluations 2 weeks prior to the re-scheduled randomisation visit (Visit 2). All adverse events and concomitant therapies will be recorded. If the screening period is to be extended more than an additional 8 weeks, the clinical monitor should be contacted. • If at Visit 1 the reversibility criterion (inclusion criterion 5) is not met, the reversibility test may be repeated once within two weeks. The ACQ should in this Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 230 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 77 of 149 case also be repeated (prior to any discussion with a health professional and prior to pulmonary function testing) and this ACQ score should be used to assess patient eligibility. Visit 2 must be scheduled 4 weeks after the repeated reversibility test of Visit 1. • If on Visit 2, the eDiary completion compliance is below 80%, rescheduling of Visit 2 is required. Patients may continue the trial if they show an eDiary completion compliance of at least 80% at the randomisation visit (Visit 2). Rescheduling of Visit 2 (for two weeks) is allowed twice. eDiary Completion Compliance is derived from the number of acceptable sessions. A session is either a set of morning data entries, or evening data entries. An acceptable session during the screening period is one in which at least two acceptable PEFs at the morning and evening session were stored and all diary data were entered. The calculation of the compliance during the screening period will be based on the last 10 days prior to Visit 2. • If on Visit 2, the inclusion criteria of an ACQ mean score of ≥ 1.5 or of the FEV1 variation within ± 30% between the pre-bronchodilator value of Visit 1 as compared to the pre-dose FEV1 of Visit 2 (absolute values of FEV1) are NOT met, Visit 2 can be repeated once within two weeks. If a respiratory tract infection or asthma exacerbation in the screening period was the reason for the FEV1 deterioration resulting in a FEV1 variation from Visit 1 of below 30%, Visit 2 may be repeated four weeks following recovery from the infection or exacerbation. At the repeated Visit 2, both criteria must be met; otherwise the patient is considered as non-eligible. Refer to Section 4.2.1.3 for details on medications allowed to control acute asthma exacerbations and restrictions for these medications prior to PFTs. Rescheduling after randomization • If rescheduling of visits after randomisation is necessary, the total daily doses of the Respimat® inhaler and MDI (i.e. 30 days) need to be obeyed and the need to take reserve medication should be avoided. If possible an additional intermediate visit to dispense the new drug supply should be planned in order to avoid use of the reserve trial medication. Refer to the Flow Chart for the rescheduling time windows. • If rescue medication is administered during a visit day within 8 hours prior to the pre-dose PFT, the visit will be rescheduled once. Further rescheduling should be discussed with the local clinical monitor. • Subsequent visits should always be planned to take place at the originally scheduled dates to assure a 24 week treatment period. Refer to Section 4.2.1.3 for details on medications allowed to control acute asthma exacerbations and restrictions for these medications prior to PFTs. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 231 Page U12-2466-01 Trial Protocol 6.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS 6.2.1 Screening and run-in period(s) 5 Dec 2011 Page 78 of 149 Informed Consent Visit (Visit 0) • • • • • • Informed Consent will be obtained prior to patient participation in the trial, which includes any medication washout procedures or restrictions. Upon obtaining Informed Consent, the patient will be instructed on the medication washout and other restrictions needed for the screening pulmonary function test at Visit 1. At sites capable of performing 24h PFT: patients will be asked to give Informed Consent for the 24-h PFT at visit 6. At selected sites: patients will be asked to give Informed Consent for the PK analyses. Patients will be asked to give Informed Consent to the pharmacogenomic analyses. The patient will receive directions on the as needed use of the salbutamol (albuterol) MDI (as rescue medication) that will be dispensed at this visit. A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid unnecessary washout procedures in non-eligible patients. Observations and procedures at Visit 1 • • • • • • • • • • Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms prior to any discussion with a health professional and prior to pulmonary function testing. Medication washout compliance will be verified. Demographic data (sex, race, date of birth, height, weight, duration of asthma, asthma background characteristics, pack years, smoking and employment status) will be recorded. Medical history regarding cardiovascular disorders, CVAs, urinary/renal disorders/diseases, cancer and narrow-angle glaucoma will be recorded. Current conditions and conditions for which therapy is given in the last 3 months prior to Visit 1 as well as any chronic disease (excluding asthma) will be recorded (baseline conditions). Physical examination including vital signs (blood pressure and pulse rate) will be conducted and a 12-lead ECG will be recorded. The vital signs (seated) and ECG should be conducted following five minutes of rest and prior to the PFT measurements. All adverse events experienced since signed Informed Consent will be reviewed and recorded. Concomitant therapy for the previous three months will be recorded. Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. Blood samples need to be taken prior to the salbutamol (albuterol) dosing. A urine pregnancy test will be conducted (if applicable). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • • • • • • 232 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 79 of 149 Pulmonary function testing with the MasterScope® CT spirometer will be conducted in the evening between 06.00 and 08.00 pm immediately prior to (-10 min) and 15 to 30 minutes after the inhalation of 4 puffs of salbutamol (albuterol). Question 7 of the ACQ questionaire (regarding pre-bronchodilator FEV1 predicted) will be completed by qualified site staff. Inclusion and exclusion criteria will be reviewed. Patients will be trained in the use of the Respimat® inhaler. The patient's ability to perform technically acceptable pulmonary function tests and their ability to use the Respimat® inhaler will be assessed. Patients qualified to enter the 4-week screening period of the trial will be issued - an electronic peak flow meter with integrated electronic diary (AM3) - a paper patient diary card (and a PK Visit Card, if applicable) - additional rescue medication if needed Patients will receive training and instructions on - the use of the AM3 (including performance of PEFs and completing the eDiary) - the use of rescue medication - medication restrictions and washout requirements for the screening period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Screening Period Patients who qualify on Visit 1 will measure twice-daily PEF and record their asthma symptoms and the number of puffs of rescue medication (daytime and nighttime) in the eDiary during the 4-week screening period. If there is any indication during the screening period that the patient is not stable enough to complete the trial or that the patient is non-compliant with the trial medication or restrictions, the patient should not be randomised. This evaluation should take place by the investigator after PEF and eDiary data saved in the AM3 have been downloaded and reviewed. Details of any patient who is screened for the trial but is found to be ineligble must be entered in the Enrolment log and documented in the eCRF. 6.2.2 Treatment period(s) Observations and procedures at Visit 2 • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic. AM3 data will be downloaded and reviewed by the investigator. eDiary compliance should be reviewed (see inclusion criterion 12 and Section 6.1). Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • • • • • • • • • • • 233 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 80 of 149 Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional. Medication washout compliance will be verified. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. Patients will be trained in the use of the Respimat® inhaler. Note: the patient should NOT inhale from a placebo inhaler at this visit. Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. The variation from the pre-bronchodilator FEV1 at Visit 1 will be determined (must not exceed ± 30%). Question 7 of the ACQ questionnaire (regarding pre-bronchodilator FEV1 predicted) will be completed by qualified site staff. Vital signs will be conducted in conjunction with the pre-dose PFT measurement. Inclusion and exclusion criteria will be reviewed to determine eligibility. Patients who meet all inclusion criteria and violate none of the exclusion criteria will be assigned to treatment according to the following procedure: 1. Randomise patient using IVRS. 2. Allocate the appropriate medication kits using IVRS. • • • • • • Blood samples will be drawn from patients who consented to participate in the genotyping investigation. If blood sampling is not possible at this visit, it is also allowed at any subsequent visit. For a subset of patients at selected sites: blood and urine samples will be collected for evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). Refer to the Flow Chart for the time schedule. Patients will be issued - study medication including reserve medication - additional rescue medication if needed - a new paper patient diary card if needed (and a PK Visit Card, if applicable) Patients will receive training and instructions on - the use of the AM3 (including performance of PEFs and completing the eDiary) Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 234 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 81 of 149 - the use of rescue medication - medication restrictions and washout requirements for the treatment period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Observations and procedures at Visits 2A, 2B and 2C. • • • For a subset of patients at selected sites: blood samples will be collected for the evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic prior to inhalation of medication. eDiary data will NOT be downloaded. Observations and Procedures at Visits 3, 4 and 5 • • • • • • • • • • • • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic. AM3 data will be downloaded and reviewed by the investigator. Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered questionnaire. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional. Medication washout compliance will be verified. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. Study medication from the previous visit will be collected prior to study medication administration and new study medication will be dispensed. Allocate the appropriate medication kits (including new reserve medication if needed) using IVRS. Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. Question 7 of the ACQ questionnaire (regarding prebronchodilator FEV1 predicted) will be completed by qualified site staff. For a subset of patients at selected sites at Visit 3: blood and urine samples will be collected for evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • • • 235 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 82 of 149 Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). Refer to the Flow Chart for the time schedule. Patients will be issued - new study medication (including reserve medication if needed). - additional rescue medication if needed - a new paper patient diary card if needed Patients will receive instructions on - medication restrictions and washout requirements for the treatment period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Observations and Procedures at Visit 6 • • • • • • • • • • • • • • • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic. AM3 data will be downloaded and reviewed by the investigator. Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional (physician, nurse or study coordinator). PASAPQ will be patient self-administered in selected countries. The PASAPQ should be the fourth questionnaire completed during a clinic visit and should precede any discussion with a health professional (physician, nurse or study coordinator). Medication washout compliance will be verified. The AM3 will be collected. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. The patient's smoking status will be assessed. A 12-lead ECG will be recorded Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. A urine pregnancy test will be conducted (if applicable). Study medication from the previous visit will be collected after study medication administration and no new study medication will be dispensed. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 • • • • • • 6.2.3 236 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 83 of 149 Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. Question 7 of the ACQ questionnaire (regarding prebronchodilator FEV1 predicted) will be completed by qualified site staff. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). PFTs will be performed until 24 hours post-dosing in patients who consented to this. Refer to the Flow Chart for the time schedule. Physical examination including vital signs (blood pressure and pulse rate) will be conducted. Patients will be issued additional rescue medication if needed. Patients will receive instructions for the follow-up period. End of trial and follow-up period Observations and Procedures at Visit 7 The patient will visit the clinic 21 days after the last dose of trial medication. Any adverse events or changes in concomitant therapies that have occurred will be recorded in addition to the trial completion information. Any ongoing (serious) adverse events should be followed until the event is resolved or there is a mutual agreement between the investigator and CML that follow-up is sufficient. Rescue medication will be collected. Observations and Procedures in case of premature withdrawal The following procedures should be performed after any premature withdrawal of patients that took at least one dose of trial medication • • • • • • • • • • Physical examination including vital signs (blood pressure and pulse rate) will be conducted A 12-lead ECG will be recorded Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. A urine pregnancy test will be conducted (if applicable). Adverse events (including exacerbations and HCRU data) and changes in concomitant therapies will be recorded. Any ongoing (serious) adverse events should be followed until the event is resolved or there is a mutual agreement between the investigator and CML that follow-up is sufficient. All SAEs that occur within 21 days after a patient terminates trial medication must be reported according to Boehringer Ingelheim SAE procedures. Smoking status will be assessed. Study medication (used and unused) will be collected. AM3 data will be downloaded and reviewed by the investigator. The AM3 will be collected. Patient's paper diary card will be collected and reviewed. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 237 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 84 of 149 The investigator should make every effort to perform the follow-up visit 21 days after the last dose of study medication on patients that withdrew prematurely. Vital status information After any premature withdrawal of patients that took at least one dose of trial medication, the vital status information (dead or alive) will be collected on the originally planned visit date of the follow up visit (Visit 7). The vital status eCRFs will be completed. Collection of vital status information does not require a patient visit. Patients will be asked to consent to telephone follow-up at their normal exit date from the trial. If death occurs, the investigator will review the circumstances, including the relevant medical records to ascertain the most likely primary and secondary causes. Any death during the vital status observation period needs to be reported as SAE by the investigator according to the Boehringer Ingelheim SAE procedures. Collection of vital status information will be performed in accordance with national ethical and regulatory guidelines. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 7. 238 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 85 of 149 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE This trial is one of two twin trials with identical protocols (BI trial numbers 205.418 and 205.419). The analysis described below will be performed for this trial and detailed in the Clinical Trial Report. In addition, a meta-analysis will comprise the analyses on combined data from the twin studies. This comprehensive meta-analysis, specifically indicated below, will be performed on the combined data in order to take advantage of the larger sample size. Separate documentation will be produced for each of the above. 7.1 STATISTICAL DESIGN - MODEL Design This is a randomised double-blind, placebo- and active-controlled, multinational, parallelgroup trial to evaluate the efficacy and safety of 2.5 and 5 µg of tiotropium inhalation solution delivered by the Respimat® inhaler (once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in moderate persistent asthma patients treated with at least medium doses of inhaled corticosteroids. The comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. Primary objective The primary objective of the trial is to demonstrate superiority of tiotropium (2.5 µg and 5 µg) with regard to primary pulmonary function endpoints after 24 weeks of treatment as compared to placebo. Meta-analysis: the primary objective of the meta-analysis is to demonstrate superiority in terms of asthma control (primary ACQ endpoint) of tiotropium (2.5 µg and 5 µg) over placebo after 24 weeks of treatment, on pooled data from the twin trials 205.418 and 205.419. Any comparison of tiotropium versus salmeterol and placebo versus salmeterol will only provide basic descriptive displays and will be used for descriptive purposes only. Primary Endpoints There are two co-primary variables in this trial (Peak FEV1 and trough FEV1) as lung function endpoints measured in relation to the evening dose. The first co-primary efficacy endpoint is the peak FEV1 response (within 3 hours post dosing) determined at the end of the 24-weeks treatment period. Peak FEV1 is defined as the maximum value of the FEV1 measurements within 3 hours post evening dosing. Peak FEV1 response is defined as the change from baseline in peak FEV1. Baseline is the pre-treatment FEV1 measured at Visit 2 in the evening just prior to the evening dose of patient’s usual asthma medication and first dose of trial medication. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 239 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 86 of 149 The second co-primary endpoint is the trough FEV1 response determined at the end of the 24week treatment period. Trough FEV1 is defined as the pre-evening-dose FEV1 measured in the clinic just prior to the inhalation of the evening doses. Trough FEV1 response is defined as the change from baseline in trough FEV1. Meta-analysis The primary endpoint is the responder as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period on combined data from the two twin trials 205.418 and 205.419. The two trials will be combined to get an adequate number of patients for this endpoint. The two trials will run concurrently. Responder is defined as an improvement with at least the minimum clinically important difference (MCID) in the ACQ which is defined as 0.5. Please refer to Section 5 for the list of secondary and safety endpoints. Baseline For all clinical spirometry endpoints, the pulmonary function test in the evening of the randomisation visit (Visit 2), measured just prior to the evening dose of patient’s usual ICS medication and first administration of the randomised treatment, is defined as baseline. For AQLQ (S) and ACQ, baseline is defined as the value obtained at the randomisation visit (Visit 2). For all endpoints measured with the AM3, the average of the data obtained in the week immediately preceding Visit 2 will be used as baseline. Response Response is defined as the change from baseline. Centre Centres might be pooled for analysis if necessary. The detailed strategy for pooling will be specified in the statistical analysis plan prior to database lock and unblinding. 7.2 NULL AND ALTERNATIVE HYPOTHESES The hypothesis will be tested in a stepwise manner to control the probability of Type I error: firstly, to establish the efficacy of tiotropium 5 µg over placebo, and secondly, to establish the efficacy of tiotropium 2.5 µg over placebo. The following hypotheses (α = 0.025 onesided) will be tested for the first co-primary endpoint: H01: H11: Peak FEV1(response) (tiotropium 5 µg) ≤ Peak FEV1(response) (placebo) versus Peak FEV1 (response) (tiotropium 5 µg) > Peak FEV1 (response) (placebo) If the null hypothesis H01 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 H02: H12: 240 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 87 of 149 Trough FEV1 (response) (tiotropium 5 µg) ≤ Trough FEV1 (response) (placebo) versus Trough FEV1 (response) (tiotropium 5 µg) > Trough FEV1 (response) (placebo) If the null hypothesis H02 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: H03: H13: Peak FEV1(response) (tiotropium 2.5 µg) ≤ Peak FEV1(response) (placebo) versus Peak FEV1 (response) (tiotropium 2.5 µg) > Peak FEV1 (response) (placebo) If the null hypothesis H03 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: H04: H14: Trough FEV1 (response) (tiotropium 2.5 µg) ≤ Trough FEV1 (response) (placebo) versus Trough FEV1 (response) (tiotropium 2.5 µg) > Trough FEV1 (response) (placebo) Each step will only be considered confirmatory providing all the previous steps were successful. If any of the previous steps were not successful the analysis of the current step will be considered descriptive. Comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. Meta-analysis The primary endpoint (ACQ) will be tested on pooled data from the two twin-trials 205.418 and 205.419 only. The hypothesis will be tested in a stepwise manner to control the probability of Type I error: firstly, to establish the efficacy of tiotropium 5 µg over placebo, and secondly, to establish the efficacy of tiotropium 2.5 µg over placebo. It will not be used in the sequential testing for US registration. The following hypotheses (α = 0.025 one-sided) will be tested for this endpoint: H0M1: H1M1: Number of ACQ responders (tiotropium 5 µg) ≤ Number of ACQ responders (placebo) versus Number of ACQ responders (tiotropium 5 µg) > Number of ACQ responders (placebo) If the null hypothesis H0M1 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested on pooled data from both twin trials: H0M2: H1M2: Number of ACQ responders (tiotropium 2.5 µg) ≤ Number of ACQ responders (placebo) versus Number of ACQ responders (tiotropium 2.5 µg) > Number of ACQ responders (placebo) Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 241 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 88 of 149 Comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. 7.3 PLANNED ANALYSES The efficacy analyses and the summary of safety data will be based on all randomised patients that received at least one dose of trial medication; this set of patients will be the Treated Set. The efficacy analyses and the summary of safety data will be based on all randomised patients that received at least one dose of trial medication; this set of patients will be the Treated Set (TS), the Full Analysis Set (FAS) includes all patients of the TS for which at least one post-baseline efficacy measurement is available.Full and clear definitions of each analysis set will be provided in the Trial Statistical Analysis Plan (TSAP). All individual data will be listed. Adherence to the protocol (e.g., inclusion/exclusion criteria, times of measurement, completeness and consistency of data, etc.) will be checked using the data recorded. Standard statistical parameters (number of non-missing values, mean, standard deviation (SD), median, quartiles, minimum, and maximum) or frequency tables will be calculated where appropriate. In general, these parameters or frequencies will be calculated separately for each treatment. Data from subjects who are screened but not treated will be listed, but not included in summary statistics. 7.3.1 Primary analyses The primary analysis will be performed on the FAS. The primary FEV1 endpoints (change from baseline) will be analyzed using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Analyses will include the fixed, categorical effects of treatment, centre, visit, and treatmentby-visit interaction, as well as the continuous, fixed covariates of baseline value and baseline value-by-visit-interaction. An unstructured (co)variance structure will be used to model the within-patient errors. If this analysis fails to converge, the following structures will be tested Compound Symmetry, Autoregressive Model (AR (1)) or Spatial Covariance. The (co)variance structure converging to the best fit, as determined by Akaike’s information criterion, will be used as the primary analysis. The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. Significance tests will be based on leastsquares means using a two-sided alpha=0.05 (two-sided 95/% confidence intervals). The primary comparison will be the contrast between treatments at week 24. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. For sensitivity analysis of the primary endpoint an Analysis of Covariance Model (ANCOVA) of the 24-week response data will be performed with baseline, centre and Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 242 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 89 of 149 treatment as main effects. Centre will be included as random main effect. Missing data wil be imputed according the rules in Section 7.4. Meta-analysis The analysis on the primary ACQ endpoint will be conducted after combining the data from the two twin trials 205.418 and 205.419. The number of responders (responder as defined in section 5.1.1.1) wil be analysed using Fisher’s Exact test. The odds ratio and corresponding 95% confidence interval will be presented along with the p-value. 7.3.2 Secondary analyses PFT Parameters The PFT parameters Peak FVC, trough FVC and AUC0-3h FEV1/FVC (change from baseline) and PEF variability will be analysed as detailed above for the co-primary FEV1 endpoint (24 weeks after treatment). In addition individual FEV1, FVC and PEF measurements at all time-points (4, 8, 16 and 24 weeks after treatment) including peak, trough and AUC0-3h will be analysed as mentioned above. The mean pre-dose morning and evening PEF and FEV1 measured with the AM3 device by the patients at home (weekly mean and overall mean) will be compared using the same method as mentioned above. For a subset of patients the endpoints FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h) will be analysed as detailed above for the co-primary FEV1 endpoint (after 24-week treatment). For a subset of patients the 5 and 15 minutes post dose endpoints FEV1 peak response, FEV1 (AUC0-3h), FVC peak response and FVC (AUC0-3h) will be analysed using an Analysis of Covariance Model (ANCOVA) with centre and treatment as main effects. Centre will be included as random main effect. No imputation of missing data will take place. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. AQLQ These parameters (change from baseline) will be analysed as detailed above for the coprimary FEV1 endpoint at all clinic visits during the 24 week treatment period. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 243 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 90 of 149 Use of PRN salbutamol The number of puffs rescue therapy used per day (i.e. daytime, night-time and the full 24 hour period) will be analysed using Poisson regression with log exposure as offset and adjusting for overdispersion. In case Poisson regression gives a bad fit due to large amount of zeros, negative binomial regression will be used for the analysis. Asthma symptoms Nocturnal and daytime asthma symptoms as well as the number of asthma free days will be analysed in the same way as detailed above for the co-primary FEV1 endpoint. Meta-analysis Time to first (severe) asthma exacerbation The analysis of (severe) asthma exacerbations will be conducted after combining the data from the two twin trials 205.418 and 205.419. Treatment groups will be compared with respect to the time to first (severe) asthma exacerbation during the 24 week randomised treatment period. Only (severe) asthma exacerbations with an onset during randomised treatment will be included in the analysis. The analysis will be performed using Cox's proportional hazards regression model with only treatment fitted as an effect. The hazard ration and corresponding 95% confidence interval will be presented along with the p-value. Kaplan-Meier estimates of the probability of not experiencing a (severe) asthma exacerbation over the treatment period will be plotted by treatment group. ACQ These parameters (change from baseline) will be analysed as detailed above for the coprimary FEV1 endpoint at all clinic visits during the 24 week treatment period, for each trial separately and on pooled data from the two twin trials 205.418 and 205.419. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. 7.3.3 Safety analyses All treated patients will be included in the safety analysis. In general, safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis testing is planned prospectively. Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary. Standard BI summary tables and listings will be produced to compare the incidence of adverse events across the treatment groups. All events with an onset after the first dose of trial medication up to a period of 30 days after the last dose of trial Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 244 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 91 of 149 medication will be assigned to the treatment period for evaluation. Other adverse events will be assigned either to the screening or post study period as appropriate. Changes from baseline in vital signs will be summarized by treatment group and compared descriptively. 7.3.4 Interim analyses No interim analysis is planned. 7.3.5 Pharmacokinetic analyses Tiotropium will be analysed in blood and urine samples collected from a subset of patients in this trial with the objective of determining the pharmacokinetics of tiotropium in patients with moderate persistent asthma. Pharmacokinetics of tiotropium will be determined following the administration of a single dose and multiple doses of 2.5 and 5 µg tiotropium via Spiriva® Respimat®. Also, pre- and 5 minutes post-dose blood samples will be obtained at visits 2A, 2B and 2C to determine time needed to reach steady-state. It is not planned to test any statistical hypothesis with respect to the pharmacokinetic parameters. Instead, they will be presented in their entirety and evaluated by descriptive statistical methods 7.3.6 Pharmacodynamic analyses Not applicable. 7.3.7 Pharmacogenetic analyses Not applicable. 7.3.8 Health economic analyses The details of HCRU and EQ-5D analysis will be determined in a separate analysis plan. This HCRU and EQ-5D analysis will not be part of the clinical trial report. 7.3.9 PASAPQ analysis An Analysis of Covariance Model (ANCOVA) will be performed with centre and treatment as main effects. Centre will be included as random main effect. Missing data will be imputed according the rules in Section 7.4. 7.4 HANDLING OF MISSING DATA Every effort will be made to collect FEV1 data at the specified time points, except if the patient has used rescue medication. Post-baseline missing FEV1 values will be replaced with the least favourable FEV1 value if a patient withdraws due to worsening of asthma. Randomly missing data after inhalation of study medication for which there are data from that visit both before and after inhalation will be linearly interpolated. Randomly missing data Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 245 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 92 of 149 with no subsequent non-missing values for that visit will be imputed using the last observation carried forward (LOCF) technique to calculate peak and AUC. Data missing due to worsening of asthma or need of rescue medication will be replaced with the least favourable data for that visit (including pre-dose values). Completely missing data at a post-baseline visit, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used. Completely missing data at the baseline visit, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used. No post baseline data available at all, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used from previous visit. For Patient Daily Record data, when the number of salbutamol (albuterol) doses is missing but other data are filled out on any given day then these data will be imputed by zero (because the presence of other data is interpreted as meaning that the patient was not having a problem). Before calculating the baseline and treatment means, the following data will be excluded: • • • • • data with a missing Patient Daily Record date, PEF data which is less than 50 L/min, duplicate data for the same date Daily Record data for days after drug was discontinued, Patient Daily Record data for the period during which oral steroids or theophylline doses were increased because of an exacerbation of asthma. Missing AQLQ (S), ACQ and PASAPQ data will be imputed according the methods used in the validation of the respective questionnaire and will be described in detail in the TSAP. Methods to handle any other exceptional cases will be considered only before unblinding the data and will be applied in a manner consistent with other trials of this type. Full details on the handling of missing data will be provided in the TSAP. 7.5 RANDOMISATION Patients will be randomized 1:1:1:1 to 2.5 µg tiotropium inhalation solution, or 5 µg tiotropium inhalation solution, or salmeterol HFA-MDI, or placebo over the 24-week treatment period. The sponsor will arrange for the randomisation as well as packaging and labelling of trial medication. Each patient will have a single randomisation number indicating the allocated treatment. Medication numbers will be assigned at a visit level. The randomisation list will be generated using a validated system involving a pseudo-random number generator and a supplied seed number, thereby ensuring that the resulting allocation Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 246 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 93 of 149 to a treatment is both reproducible and nonpredictable. The seed numbers will be documented in the report. An Interactive Voice Response System (IVRS) and/or an Interactive Web Response System (IWRS) will be used. BI will provide the randomisation and medication number lists to the IVRS/IWRS provider and the sites will contact the IVRS/IWRS to obtain the next medication numbers to be dispensed to the patient. 7.6 DETERMINATION OF SAMPLE SIZE For the first two co-primary variables sample size estimation is performed under the following assumptions. For the first co-primary variable peak FEV1 a SD between 310mL and 370mL was observed as worst case SD in period 1 of trial 205.341 for change from baseline. For the second coprimary variable trough FEV1 a SD between 290mL and 350mL was observed in trial 205.342 and between 266mL and 277mL in period 1 of trial 205.341 for change from baseline. Sample size is calculated using a two-group t-test with a power of 90% and a type I error probability of 2.5% (one-sided). The following Table 7.6.: 1 provides several sample size considerations based on a two group t-test with a power of 95% and a type I error of 2.5% (one-sided), to get on overall power for the first co-primary endpoints of about 90% (0.95 x 0.95 = 0.9025) considerations depending on number of patients per group using different scenarios. Table 7.6: 1 Number of patients necessary for the first two co-primary endpoints (Nquery, version 6.01) Endpoint peak FEV1 Delta 150 135 120 SD 310 340 370 310 340 370 310 340 370 N per group 112 135 160 139 166 197 175 210 249 trough FEV1 Delta SD 270 140 310 350 270 120 310 350 270 100 310 350 N per group 98 129 164 133 175 223 191 251 320 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 247 Page U12-2466-01 5 Dec 2011 Page 94 of 149 Trial Protocol With a sample size of 250 patients per group one is able to detect a delta of 120mL and 100mL for peak FEV1 and trough FEV1, respectively under the expectation to have a SD for change from baseline of 370mL in peak FEV1 and 310mL in trough FEV1. Sample size consideration for the third co-primary variable ACQ is based on the endpoint of the relative frequency of patients who reached the minimum clinically important difference (MCID) in the ACQ which is defined as 0.5 (i.e. ACQ score difference to baseline ≥ 0.5 then responder) [R09-1589]. Assuming a delta of 10% in responder rate in comparison to placebo, the following number of patients per group based on a pooling the data of the two trials would be necessary depending on the expected placebo rate. Table 7.6: 2 Number of patients necessary for the third co-primary endpoint ACQ (Nquery, version 6.01) under the assumption of a power of 90% Expected placebo response rate Sample Size per group 20% 392 30% 477 40% 519 With 500 patients per treatment group, the power is 91.34% for the pooled analysis assuming a placebo response rate of 30%. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 8. 248 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 95 of 149 INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS The trial will be carried out in compliance with the protocol, the principles laid down in the Declaration of Helsinki, version as of October 1996 (as long as local laws do not require to follow other versions), in accordance with the ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the treating physician of the patient. The investigator should inform the sponsor immediately of any urgent safety measures taken to protect the study subjects against any immediate hazard, and also of any serious breaches of the protocol/ICH GCP and, for Japan, the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997). The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract. As a general rule, no trial results should be published prior to finalisation of the Clinical Trial Report. Insurance Cover: The terms and conditions of the insurance cover are made available to the investigator and the patients via documentation in the ISF (Investigator Site File). 8.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT This trial will be initiated only after all required legal documentation has been reviewed and approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and competent authority (CA) according to national and international regulations. The same applies for the implementation of changes introduced by amendments. Prior to patient participation in the trial, written informed consent must be obtained from each patient (or the patient’s legally accepted representative) according to ICH GCP and to the regulatory and legal requirements of the participating country. Each signature must be personally dated by each signatory and the informed consent and any additional patientinformation form retained by the investigator as part of the trial records. A signed copy of the informed consent and any additional patient information must be given to each patient or the patient’s legally accepted representative. The patient must be informed that his/her personal trial-related data will be used by Boehringer Ingelheim in accordance with the local data protection law. The level of disclosure must also be explained to the patient. The patient must be informed that his / her medical records may be examined by authorised monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities. ADDITIONAL INFORMATION FOR JAPAN The investigator must give a full explanation to trial patients including the items listed below in association with the use of the patient information form, which is prepared avoiding the Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 249 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 96 of 149 use of technical terms and expressions. The patient is given sufficient time to consider participation in the trial. The investigator obtains written consent of the patient's own free will with the informed consent form after confirming that the patient understands the contents. The investigator must sign (or place a seal on) and date the informed consent form. If a trial collaborator has given supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the informed consent. The following items need to be included: 1. That the clinical trial involves research, i.e. testing of drugs. 2. The objectives of the clinical trial. 3. The clinical trial procedures (including those aspects of the clinical trial that are experimental, patient inclusion criteria, specific fasting requirements for laboratory, and the probability for random assignment to each treatment. 4. Anticipated benefits of the investigational product and anticipated risks to the patient. 5. The expected duration of the patient's participation in the clinical trial. 6. The approximate number of patients involved in the clinical trial. 7. The reasonably foreseeable risks or inconveniences to the patient. If there is no intended clinical benefit to the patient, the patient should be made aware of this. 8. The alternative procedure(s) or course(s) of treatment that may be available to the patient, and their important potential benefits and risks. 9. The patient's primary physician will be informed by the investigator about participation in the trial. 10. The compensation and/or treatment available to the patient in the event of trial-related injury. 11. That the patient's participation in the clinical trial is voluntary and that the patient may refuse to participate in or withdraw from the clinical trial at any time, without penalty or loss of benefits to which the patient is otherwise entitled. 12. That the patient or the patient's proxy consenter will be informed in a timely manner if information becomes available that may be relevant to the patient's willingness to continue participation in the clinical trial. 13. The foreseesable circumstances and/or reasons under which the patient's participation in the clinical trial may be terminated. 14. That the monitor(s), the auditor(s), the IRB, and the regulatory authority(ies) may be provided direct access to the patient's original medical records. In such cases, the confidentiality of the patient should be protected, and by signing and sealing an informed consent form, the patient or the patient's proxy consenter is authorising such access. 15. The type of the IRB which is used for the reviews and deliberations in regard to the appropriate conduct of the clinical trial. The information to be reviewed by each IRB and any other topics concerning the IRBs involved in the clinical trial. 16. If the results of the clinical trial are published, the patient's identity will remain confidential. 17. The anticipated expenses, if any, to the patient for participating in the clinical trial. 18. The anticipated prorated payment, if any, to the patient for participating in the clinical trial. 19. The name, title, and address of the investigator or the sub-investigator to contact. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 250 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 97 of 149 20. The person(s) to contact for further information regarding the clinical trial and the rights of patient, and whom to contact in the event of a trial-related injury. 21. That necessary treatment is available to the patient in the event of trial-related injury and all other issues in regards to compensation in the event of any trial-related injury. 22. The patient's responsibilities. 8.2 DATA QUALITY ASSURANCE A quality assurance audit/inspection of this trial may be conducted by the sponsor or sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance auditor will have access to all medical records, the investigator’s trial-related files and correspondence, and the informed consent documentation of this clinical trial. The data management procedures to ensure the quality of the data are described in detail in the trial data management and analysis plan (TDMAP) available in the CTMF. 8.3 RECORDS Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on paper or via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to Section 4.1.8. 8.3.1 Source documents Source documents provide evidence for the existence of the patient and substantiate the integrity of the data collected. Source documents are filed at the investigator’s site and could for example be physician's notes in patient files, ECG results (original or copies of printouts), lung function test results, worksheets or patient diaries. Data entered in the eCRFs must be derived from source documents and must be consistent with the source documents or the discrepancies must be explained. The investigator may need to request previous medical records or transfer records, depending on the trial; also current medical records must be available. 8.3.2 Direct access to source data and documents The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review and regulatory inspection, providing direct access to all related source data / documents. CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and medical test results must be available at all times for review by the sponsor’s clinical trial monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by reviewing the documents described in Section 8.3.1. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 8.3.3 251 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 98 of 149 Storage of records ADDITIONAL INFORMATION FOR JAPAN ONLY Storage period of records Trial site(s): The trial site(s) must retain the source documents and essential documents for a period defined by the Japanese GCP regulation and the sponsor's SOP. Sponsor: The sponsor must retain the essential documents according to the sponsor's SOPs. When it is no longer necessary for the trial site to retain the source documents and essential documents, the sponsor must notify the head of trial site. 8.4 LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS 8.4.1 Listedness To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. Therefore a unique reference document for the evaluation of listedness needs to be provided. For the 2.5 and 5 µg tiotropium bromide inhalation solution this is the current version of the Investigator’s Brochure (U92-0551). For the salmeterol xinafoate metered dose inhaler this is the EU SP (Serevent Evohaler). For the non-investigational medicinal product salbutamol/albuterol, the reference document is the US-PI (Proair HFA). The current versions of these reference documents are to be provided in the ISF. No AEs are classified as listed for matching placebo, study design, or invasive procedures. 8.4.2 Expedited reporting to health authorities and IECs/IRBs Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local regulatory requirements. Further details regarding this reporting procedure are provided in the Investigator Site File. 8.5 STATEMENT OF CONFIDENTIALITY Individual patient medical information obtained as a result of this trial is considered confidential and disclosure to third parties is prohibited with the exceptions noted below. Patient confidentiality will be ensured by using patient identification code numbers. Treatment data may be given to the patient’s personal physician or to other appropriate medical personnel responsible for the patient’s welfare. Data generated as a result of the trial need to be available for inspection on request by the participating physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities, i.e. the CA. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 8.6 252 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 99 of 149 COMPLETION OF TRIAL ADDITIONAL INFORMATION FOR JAPAN ONLY When the trial is completed, the investigator should inform the head of the trial site of the completion in writing, and the head of the trial site should promptly inform the IRB and sponsor of the completion in writing. ADDITIONAL INFORMATION FOR EU MEMBER STATES The EC/competent authority in each participating EU member state needs to be notified about the end of the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the CTP) or early termination of the trial. 8.7 PROTOCOL VIOLATIONS ADDITIONAL INFORMATION FOR JAPAN ONLY The investigator or sub-investigator should record all CTP violations. The investigator should provide and submit the sponsor and the head of the trial site the records of violations infringing the Japanese GCP or violations to eliminate an immediate hazard to trial subjects and for other medically inevitable reasons. 8.8 COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL RELATED INJURY ADDITIONAL INFORMATION FOR JAPAN ONLY In the event of health injury associated with this trial, the sponsor is responsible for compensation based on the contract signed by the trial site. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 253 Page U12-2466-01 Trial Protocol 9. REFERENCES 9.1 PUBLISHED REFERENCES 5 Dec 2011 Page 100 of 149 P86-0614 Beck R, Robertson C, Galdes-Sebaldt M, Levison H Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma. J Pediatr 107, 605 - 608 (1985) P97-9482 Beakes DE The use of anticholinergics in asthma. J Asthma 34 (5) 1997: 357368 P98-7763 Lanes SF, Garrett JE, Wentworth CE, Fitzgerald JM, Karpel JP. The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma: a pooled analysis of three trials. Chest 114 (2) 1998: 365-372 P98-9345 Plotnick LH, Ducharme FM. Should inhaled anticholinergics be added to beta2 agonists for treating acute childhood and adolescent asthma? A systematic review. Br Med J 317 (7164) 1998: 971-977 P99-02952 Rodrigo G, Rodrigo C, Burschtin O. A meta-analysis of the effect of ipratropium bromide in adults with acute asthma. Am J Med 107 (4) 1999: 363-370 P04-11193 Israel E, et al. Use of regulary scheduled albuterol treatment in asthma: genotype statified, randomised, placebo-controlled cross-over trial. Lancet 364 (9444) 2004: 1505-1512 P05-01207 Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev (3) 2004 [P05-02607] Kozma CM, Slaton TL, Monz BU, Hodder R, Reese PR. Development and validation of a patient satisfaction and preference questionnaire for inhalation devices. Treat Respir Med 4(1) (2005): 41-52 P05-05129 Gosens R, Bos IS, Zaagsma J, Meurs H: Protective effects of tiotropium bromide in the progression of airway smooth muscle remodelling, Am J Respir Crit Care Med 2005; 71:1096-1102 P05-08960 Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systemic review with metaanalysis. Thorax 2005; 60 (9): 740-746 P05-11064 Profita M,Di Giorgi R, Sala A, Bonanno A, Riccobono L, Mirabella F, Gjomarkaj M, Bonsignore G, Bousquet J, Vignola: Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients; Allergy 2005; 60:1361-1369 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 254 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 101 of 149 P05-12782 Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J Standardisation of spirometry. Eur Respir J 26 (2) , 319-338 (2005) P06-03400 Wechsler ME, Lehman E, Lazarus SC, Lemanske RF, Boushey HA, Deykin A, et al. Beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173 (5):519-526. P07-10315 Bos IST, Gosens R, Zuidhof AB, Schaafsma D, Halayko AJ, Meurs H, Zaagsma . Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison. Eur Respir J 2007, 30 (4), 653-661 P07-12448 Buehling F, Lieder N, Kuehlmann UC, Waldburg N, Welte T. Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro. Respir Med 2007, 101 (11), 2386-2397 P08-00177 Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 370 (9605), 2118 - 2125 (2007) P09-07838 Asthma Clinical Research Network (ACRN) Long Acting beta agonist Response by GEnotype (LARGE). See website: acrn.org/large.html (access date: 15.06.2009) (2009) P10-03196 Global strategy for asthma management and prevention, Global Initiative For Asthma (GINA) 2009. Available from website: ginasthma.org. R94-1408 Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows.Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J 1993 ;6 (Suppl 16) :5 -40. R96-2382 EuroQol - a new facility for the measurement of health-related quality of life. Health Policy 1990; 16: 199-208 R00-1157 Juniper EF, O´Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999; 14: 902-907 R05-0813 Sato E, Koyama S, Okubo Y, Kubo K, Sekiguchi M Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am J Physiol (Lung Cell Mol Physiol 18) 1998; 274: L970-L979 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 255 U12-2466-01 Trial Protocol 5 Dec 2011 Page 102 of 149 R05-2327 Koyama S, Sato E, Nomura H, Kubo K, Nagai S, Izumi T: Acetylcholine and substance P stimulate bronchial epithelial cells to release eosinophil chemotactic activity. J Appl Physiol. 1998; 84(5):1528-34 R06-0573 Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, et al. Systematic review and meta-analysis of the association between beta2adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol 2005 ;162 (3) :201 -211. R06-0585 Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JPA. Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol 2005 ;115 (5) :963 -972. R08-0092 Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999, 115: 1265-1270. R08-5197 Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P Relationship of the type of tobacco and inhalation pattern to pulmonary and total mortality. Eur Respir J 5, 1111 - 1117 (1992) R09-1589 Juniper E. Asthma Control Questionnaire: background, administration and analysis. See website: qoltech.co.uk; Bosham: QOL Technologies 2005 9.2 UNPUBLISHED REFERENCES U92-0551 . Investigator´s Brochure - Tiotropium Bromide, Ba 679 BR (tiotropium bromide inhalation powder and tiotropium bromide inhalation solution). BPO5601. Version 01 March 2008 U96-0240 . A double-blind, placebo-controlled, crossover study to determine the effect of inhaled Ba 679 BR (tiotropium) on methacholine responsiveness in patients with mild asthma. 205.121. 03 June 1996. U97-2651 . Ba 679 BR: in vitro inhibition studies on cytochrome P450 dependent metabolic reactions. B820. 09 October 1997 U98-3174 The effect of twenty-one day dosing of tiotropium on bronchomotor tone in patients with moderate to severe asthma (a randomized, double-blind, placebo-controlled, parallel study). 205.201. 17 August 1998 U98-3274 . The effect of tiotropium in patients with nocturnal asthma (a randomized, double-blind, double- Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 256 U12-2466-01 Trial Protocol 5 Dec 2011 Page 103 of 149 dummy, placebo and active-controlled, parallel study). 205.202. 09 November 1998 U99-1004 New mathematical model for the determination of the slow dissociation kinetics of the long antimuscarinic Tiotropium bromide and BEA 2108 BR in comparison to ipratropium bromide from human muscarinic receptors. BC5.A06. 15 October 1998 U99-1019 . The protective effect and safety of 36 µg inhaled tiotropium (Ba 679) against exercise-induced bronchoconstriction in patients with bronchial asthma (double-blind, randomised, placebo-controlled, parallel study). 205.203. 20 October 1998 U02-1222 . Evaluation of local tolerability of an acidic (pH=2.7) ® solution for inhalation administered via the RESPIMAT device in 32 asthmatic adults. A single-dose (4 puffs), cross-over randomized study. 205.248. 22 Jan 2002 U07-1752 . Ba 679 BR (Tiotropium bromide): Partial validation of an existing LC-MS/MS method for the determination in acidified human urine. PA614. 23 July 2007. U08-2081 . A Randomised, DoubleBlind, Placebo-Controlled, Crossover Efficacy and Safety Evaluation of 8Week Treatment Periods of Two Doses [5 µg (2 actuations of 2.5 µg) and 10 µg (2 actuations of 5 µg)] of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler as Add-on Therapy in Patients with severe persistent Asthma. 205.341. 22 Oct 2008. U09-1701 . A 16-week randomised, placebo-controlled, double-blind, double-dummy, parallel-group study comparing the efficacy and safety of tiotropium inhalation solution delivered by the Respimat inhaler (2 puffs of 2.5 mcg once daily) with that of salmeterol from… 205.342. 14 Aug 2009. U10-1855-01 Revalidation of an existing LCMS/MS method for the determination of tiotropium in human EDTA plasma with lowered LLOQ. TA409B. 22 March 2010. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10. APPENDICES Page 257 U12-2466-01 Trial Protocol - 5 Dec 2011 Page 104 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.1 258 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 105 of 149 INSTRUCTIONS FOR THE USE OF THE RESPIMAT INHALER Instructions for Use Respimat® inhaler How to use your Respimat® inhaler This leaflet explains how to use and care for your Respimat® inhaler. Please read and carefully follow these instructions. The Respimat® inhaler releases medication slowly and gently, making it easy to inhale it into your lungs. The Respimat® inhaler enables you to inhale the medicine contained in a cartridge. You will need to use this inhaler only ONCE A DAY. Each time you use it take two PUFFS. In the box you will find the Respimat® inhaler and the Respimat® cartridge. Before the Respimat ® inhaler is used for the first time, the cartridge provided must be inserted. Respimat® inhaler and the Respimat® cartridge Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 259 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 106 of 149 Inserting the cartridge and preparation for use The following steps 1-6 are necessary before first use: 1) With the grey cap closed, press the safety catch (E) and pull off the clear base (G). 2) Take the cartridge (H) out of the box. Push the narrow end of the cartridge into the inhaler until it clicks into place (2a). The cartridge should be pushed gently against a firm surface to ensure that it has gone all the way in (2b). Do not remove the cartridge once it has been inserted into the inhaler. 3) Replace the clear base (G). Do not remove the clear base again. Safety catch 1 2a 2b 3 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 260 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 107 of 149 To prepare the Respimat® inhaler for first-time use 4) Hold Respimat® inhaler upright, with the grey cap (A) closed. Turn the clear base (G) in the direction of the red arrows on the label until it clicks (half a turn). 5) Open the grey cap (A) until it snaps fully open. 6) Point the Respimat® inhaler towards the ground. Press the dose release button (D). Close the grey cap (A). 4 5 Repeat steps 4, 5 and 6 until a cloud is visible. Then repeat steps 4, 5 and 6 three more times to ensure the inhaler is prepared for use. 6 Your Respimat® inhaler is now ready to use. These steps will not affect the number of doses available. After preparation your Respimat® inhaler will be able to deliver 60 puffs. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 261 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 108 of 149 Using the Respimat® inhaler You will need to use this inhaler only ONCE A DAY. Each time you use it take two PUFFS. I) Hold Respimat® inhaler upright, with the grey cap (A) closed, to avoid accidental release of dose. Turn the clear base (G) in the direction of the red arrows on the label until it clicks (half a turn). I II) II III) Open the grey cap (A) until it snaps fully open. Breathe out slowly and fully, and then close your lips around the end of the mouthpiece without covering the air vents (C). Point your Respimat® inhaler to the back of your throat. While taking in a slow, deep breath through your mouth, press the dose release button (D) and continue to breathe in slowly for as long as you can. Hold your breath for 10 seconds or for as long as comfortable. Repeat steps I and II one more time so that you get the full dose. You will need to use this inhaler only ONCE A DAY. Close the grey cap until you use your Respimat® inhaler again. If the Respimat® inhaler has not been used for more than 3 days release one puff towards the ground. If the Respimat® inhaler has not been used for more than 21 days repeat steps 4 to 6 until a cloud is visible. Then repeat steps 4 to 6 three more times. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 262 Page U12-2466-01 5 Dec 2011 Page 109 of 149 Trial Protocol When to get a new Respimat® inhaler The Respimat® inhaler contains 60 puffs (30 doses). The dose indicator shows approximately how many doses are left. When the pointer enters the red area of the scale, there is, approximately, medication for 15 puffs (7 days) left. Once the dose indicator has reached the end of the red scale (i.e., all 60 doses have been used), the Respimat® inhaler is empty and locks automatically. At this point, the base cannot be turned any further. What if... What if... Reason What to do I can’t turn the base easily. a) The Respimat® inhaler is already prepared and ready to use. a) The Respimat® inhaler can be used as it is. b) The Respimat® inhaler is locked after 60 puffs (30 doses). b) Prepare and use your new Respimat® inhaler. I can’t press the dose release button. The clear base has not been turned. Turn the clear base until it clicks. (half a turn) The clear base springs back after I have turned it. The clear base was not turned far enough. Prepare the Respimat® inhaler for use by turning the clear base until it clicks. (half a turn) I can turn the clear base past the point where it clicks. Either the dose release button With the grey cap closed, has been pressed, or the clear turn the base until it clicks. base has been turned too far. (half a turn) How to care for your inhaler Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at least once a week. Any minor discoloration in the mouthpiece does not affect the performance of your Respimat® inhaler. If necessary, wipe the outside of your Respimat® inhaler with a damp cloth. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 263 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 110 of 149 Further information The Respimat® inhaler must not be disassembled after inserting the cartridge and replacing the clear base. Do not touch the piercing element inside the base. Keep out of the reach and sight of children. Do not freeze. Boehringer Ingelheim Pharma GmbH & Co. KG D - 55216 Ingelheim Germany 0123 HI-Master-Version-Respimat-20080831 PLEASE ALWAYS ENTER THE DATE OF FIRST PRIMING ON THE MEDICATION LABEL! Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.2 264 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 111 of 149 INSTRUCTIONS FOR THE USE OF THE MDI Instructions for Use Please read and carefully follow these instructions. You will need to use this inhaler only TWICE A DAY (morning and evening). Each time you use it take two PUFFS. There is enough trial medication for 30 days when the MDI is used according to the directions for use. Testing the inhaler 1. When using the inhaler for the first time or when you have not used the inhaler for a week or more, test that it is working properly. Remove the mouthpiece cover (gently squeeze the sides with your thumb and forefinger and pull apart). Hold MDI as illustrated in the figure below and shake well. Point mouthpiece away from you and release four puffs into the air by pressing the MDI. Using the MDI inhaler 1. Remove the mouthpiece cover. 2. Hold MDI as illustrated in the figure below and shake the inhaler 4 or 5 times to ensure the contents of the inhaler are evenly mixed. 3. Hold the MDI upright between fingers and thumb with your thumb on the base, below the mouthpiece. Breathe out as far as is comfortable and then place the mouthpiece in your mouth between your teeth and close your lips around it. Do not bite. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 265 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 112 of 149 4. Breath in through your mouth. Just after starting to breathe in, press down on the top of the MDI to release a puff while still breathing in steadily and deeply. 5. While holding your breath, take the MDI from your mouth and take your finger from the top of the MDI. Continue holding your breath as long as is comfortable. 6. Keep the MDI upright and wait about half a minute before repeating steps 1-5 to inhale the second puff from the MDI. 7. After use always replace the mouthpiece cover (by firmly pushing until it snaps into place) to keep out dust and fluff. How to care for your inhaler It is important to clean the MDI at least once a week to prevent the inhaler from blocking up. To clean the MDI: 1. Remove the mouthpiece cover. 2. The metal canister should NOT be removed from the plastic casing at any time. 3. Wipe the outside and inside of the mouthpiece and the plastic casing with a dry cloth or tissue. 4. Replace the mouthpiece cover. NEVER put the metal canister in water. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.3 Page 266 U12-2466-01 Trial Protocol 5 Dec 2011 Page 113 of 149 INSTRUCTIONS FOR RETURN OF MALFUNCTIONING RESPIMAT INHALERS Respimat® inhalers, with the used cartridge in situ, that appeared to malfunction, will be returned to the Boehringer Ingelheim OPU responsible for packaging and labeling as soon as possible. The name, address and contact person are listed below: Boehringer Ingelheim Pharma GmbH & Co. KG Business Unit Development Dpt. Quality & Records Management 55216 Ingelheim am Rhein Germany The following information should be included when the inhaler is returned: a) Medication number b) Visit number c) Date of malfunction d) Description of malfunction and cause of malfunction (if known) e) Person identifying malfunction f) Malfunctioned after amount of days or weeks of treatment g) BI personnel contacted and date contacted h) Date shipped to Boehringer Ingelheim i) Trial number / country j) Investigator’s name/ center number l) Date of return to the investigator The original of the Product/Device Complaint Form should be included with the returned inhaler. In parallel, a scanned copy of the form should be send to the responsible CTSU coordinator of the trial via email. A copy of the form should be filed with the Drug Dispensing Log. All inhalers and cartridges should be wrapped in bubble wrap or a similar packing material, placed in a secure shipping box (not a packing envelope) and shipped by overnight express. Any questions regarding shipping and handling should be directed to the local Clinical Monitor. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.4 267 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 114 of 149 ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA Classification of medium ICS doses Table 10.4: 1 Definition of medium daily doses of ICS adapted from GINA 2009 [P10-03196] Drug Medium daily Dose (µg) Beclomethasone dipropionate Budesonide Ciclesonide Flunisolide Fluticasone Mometasone furoate Triamcinolone acetonide ≥500 and ≤1000 ≥400 and ≤800 ≥160 and ≤320 ≥1000 and ≤2000 ≥250 and ≤500 ≥400 and ≤800 ≥1000 and ≤2000 As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the investigator for the equivalent correct dosage. There are specific requirements per country. Please refer to the ISF for a detailed list. Reversibility testing [P05-12782] At the screening visit (Visit 1), following the completion of three acceptable prebronchodilator forced expiratory manoeuvres, salbutamol (albuterol) will be administered to each patient in order to document the degree of reversibility. Immediately after (within 10 min) pre-bronchodilator forced expiratory manoeuvres and after a gentle and incomplete expiration, a dose of 100 µg of salbutamol (albuterol) is inhaled in one breath to total lung capacity (TLC). The breath is then held for 5–10 s before the subject exhales. Four separate doses (total dose 400 µg) are delivered at approximately 30-s intervals (this dose ensures that the response is high on the salbutamol dose–response curve). Three additional, acceptable post-bronchodilator forced expiratory manoeuvre tests are recorded ≥15 min and up to 30 min later after the last dose of salbutamol (albuterol) is inhaled. Calculation of predicted normal values according to ECSC [R94-1408] For height measured in inches Males: FEV1 predicted (L) = 4.30 x [height (inches)/39.37] - 0.029 x [age (yrs)] - 2.49 Females: FEV1 predicted (L) = 3.95 x [height (inches)/39.37] - 0.025 x [age (yrs)] - 2.60 For height measured in meters Males: FEV1 predicted (L) = 4.30 x [height (m)] - 0.029 x [age (yrs)] - 2.49 Females: FEV1 predicted (L) = 3.95 x [height (m)] - 0.025 x [age (yrs)] - 2.60 Patients with ages 18-25 will have predicted FEV1 calculated with age 25. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 268 Page U12-2466-01 5 Dec 2011 Page 115 of 149 Trial Protocol The race correction factors in table 10.4: 2 will apply. Table 10.4: 2 Race correction factors Correction factor FEV1 Races / Ethnicities Caucasian Orientals Hong Kong Chinese Orientals Japanese Americans Polynesians North Indians & Pakistanis South Indians African Descent Other Correction factor FVC 1.0 1.0 0.89 0.9 0.9 0.87 0.87 1.0 1.0 1.0 1.0 0.9 0.9 0.87 0.87 1.0 Calculation of variation of absolute FEV1 values The value of Visit 1 is regarded as 100% and the following formula applies: FEV1 variation (%) = FEV1 pre-dose at Visit 2 (L) FEV1 pre-bronchodilator at Visit 1 (L) x 100 - 100 Calculation of number of pack years Pack years = Number of cigarettes/day 20 x years of smoking The following equivalents for the tobacco content should be used for smokers other than cigarettes smokers [R08-5197]: • • • • One plain or filter cigarette = 1 gram of tobacco One cigar = 5 grams of tobacco One cheroot or cigarillo = 3 grams of tobacco One gram of pipe tobacco = 1 gram of tobacco Calculation of pack years based on tobacco contents: Pack years = Number of gram/day 20 x years of smoking Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.5 Page 269 U12-2466-01 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S)) 5 Dec 2011 Page 116 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 270 U12-2466-01 5 Dec 2011 Page 117 of 149 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID - - - - - - - DATE _ _ _ _ _ _ _ _ __ SELF-ADMINISTERED Page 1 oi5 Please complete all q ue stions by circling the number that best des cribes how you have been d uring the last 2 w eeks as a re-sult of you r asth ma . HOW LIM ITED HAVE YOU BEEN DURING THE LAST 2 WEEKS IN THES E ACTIVITIES AS A RESU LT OF YOUR ASTHMA? 1. 2. 3. O:xtremety v~ Modet~t~ Limite d Lirritt'd li.rnitation Some Umito1tion limit~~ioto A Li~tte No~ ~t 'J limited STRENUOUS A CTIVITIES (suc h as hurrying, exercising, running up stairs, sports} 2 3 4 5 6 7 MODERA TE ACTIVITIES (such as w alking, houseworl<. gardening, shopping, c limbing stairs) 2 3 4 5 6 7 pets/children, visiting f riends/relativ es) 2 3 4 5 6 7 WORK-RELATED ACTIVITIES !tasks y ou have to do at work~) 2 3 4 5 6 7 6 7 SOCIAL ACTIVITIES I such a s t a lking. pla ying with 4. '"If 5. you are not employed or $E!tf-employed, these should be tasks y ou have to do most days. SLEEPING 2 4 3 5 HOW M UCH DISCOMFORT OR DISTRESS HAVE YOU FELT DURING THE LAST 2 WEEKS? A Very Gre;t Oe;~~l 6. How m uch d iscomfort or distress hav e y ou felt over the last 2 weeks as a result of CHEST TIGHTNESS? AGru t De'! A Good M o<ler;t'=' Oul Amou nt 2 3 4 Som• Very None Li~1f..e 5 6 7 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 271 U12-2466-01 - 5 Dec 2011 Page 118 of 149 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATIENT ID SELF-ADMINISTERED DATE Page 2oi5 IN GENERAL. HOW MUCH OF THE TIME DURING THE LAST 2 WEEKS DID YOU: All of the Time 7. 8. 9. Mo$t of the A Good Si~ oi the Some of the Time A L~de ~he of Time H~rdly Any o f the TJmc ..... None Ti~ Time Feel CONCERNED ABOUT HAVING ASTHMA? 2 3 4 5 6 7 Feel SHORT OF BREATH as a result of y our asthma? 2 3 4 5 6 7 Experience asthm a symptom s as a RESULT OF BEING EXPOSED TO CIGARETTE SMOKE? 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 10 . Experience a WHEEZE in y our chest? T ime 11 . Feel you had to AV OID A SITUATION OR ENVIRONMENT BECAUSE OF CIGARETTE SMOKE? HOW M UCH DISCOMFORT OR DISTRESS HAVE YOU FELT DURING THE LAST 2 WEEKS? A Ve-ry G.rut Oc ~1 1 2 . How much d iscomfort or distress have y ou felt over the last 2 weeks as a result of COUGHING? A Grcrt A Good Moc!ero1~c ""' Ou l Amouf'lt 2 3 4 Som• v •.., Not~c Li~tk 5 6 7 IN GENERAL, HOW M UCH OF THE TIM E DURING THE LAST 2 WEEKS DID YOU: ... A!l of Mon of the Tim~~: T<me 13. Feel FRUSTRATED as a result of y our ast hma? 14 . Experience a feeling of CHEST HEA VINESS? 2 A Good Sit ~he r~. of Som• o f the A Little Hardly of the Any o f Time Ti~ the TJme ..... None T ime 2 3 4 5 6 7 2 3 4 5 6 7 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 272 U12-2466-01 - 5 Dec 2011 Page 119 of 149 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID SELF-ADMINISTERED DATE Page 3of 5 IN GENERAL, HOW M UCH Of THE TIM E DURING THE LAST 2 WEEI<S DID YOU: A!l of th< Mo~ of :be Time Time H~rdly A Good Sit Som< A Lrtt!e of :he o f tl'lc of the Any o f r~• Time Time the rune ...... Nol'\e T ime 1 5 . Feel CONCERNED ABOUT THE NEED TO USE M EDICATION for your asthma? 2 3 4 5 6 7 1 6 . Feel t he need to CLEAR Y OUR THROAT? 2 3 4 5 6 7 1 7. Experience asthma symptom s as a RESULT Of BEING EXPOSED TO DUST? 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 20. WAKE UP IN THE MORNING WITH ASTHMA SYMPTOMS? 2 3 4 5 6 7 21 . Feel A FRAID Of NOT HAVING YOUR ASTHMA MEDICATION AVAILABLE? 2 3 4 5 6 7 22 . Feel bothered by HEA VY BREATHING? 2 3 4 5 6 7 23. Experience asthma symptom s as a RESULT Of THE WEATHER OR AIR POLLUTION OUTSIDE? 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 18 . Experience DIFFICULTY BREATHING OUT as a result of y our asthma? 19. Feel y ou nac to A V OI D A SITUATION OR ENVIRONMENT BECAUSE Of DUST? 24. Were y ou WOKEN AT NIGHT by your asthma? 2b. A V U IU UH LIM I I (jO JN(j U U I ~I Ut BECAUSE Of THE WEATHER OR AIR POLLUTION? 3 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 273 U12-2466-01 - 5 Dec 2011 Page 120 of 149 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID SELF-ADMINISTERED DATE Page 4 oi 5 IN GENERAL, HOW M UCH OF THE TIM E DURING THE LAST 2 WEEKS DID YOU: ... Atl of Mo~ ~he of Tin t Time A G ood Sit Some A Litfte of the Time o f the Time oh h< T irM H::~.rdl•t Any o f tfle r~me ...... Nolle Time 26 . Experience asthm a symptom s as a RESULT OF BEING EXPOSED TO STRONG SM ELLS OR PERFUME? 2 3 4 5 6 7 Feel AFR.AID OF GETTING OUT OF BREATH? 2 3 4 5 6 7 28. Feel y ou had t o AV OID A SITUATION OR ENVIRONMENT BECAUSE OF STRONG SMELLS OR PERFUME ? 2 3 4 5 6 7 29. Has y our asthma INTERFERED W ITH GETTING A GOOD NIGHT'S SLEEP? 2 3 4 5 6 7 30. Have a feeling of FIGHTING FOR AIR? 2 3 4 5 6 7 27. HOW LIM ITED HAVE YOU BEEN DURING THE LAST 2 WEEKS? Sever ~ Very Few NotOOl'\e Not Gone No Umit .ltlon 3 1. Think of the OVERALL RANGE Of ACTIVITIES t hat you would have liked to have done during the last 2 weeks. How much has your range of actN ities been lim ited by your asthma? 2 4 3 4 5 6 7 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 274 U12-2466-01 - 5 Dec 2011 Page 121 of 149 Trial Protocol ASTHMA QUALITY OF LI FE QUESTIONNAIRE (S) PATI ENT ID - - - - - - - DATE _ _ _ _ _ _ _ _ _ ___ SELF-ADMINISTERED Page5oi 5 HOW LIMITED HAVE YOU BEEN DURING THE LAST 2 WEEKS? Extreme~ lirA ted 32. Overall, among ALL THE ACTIVITIES that you have done during the last 2 weeks, how limited have you IJeen by your asthma? 2 3 Moderate Some A U We Net at al lirnitat:oo Limita:on Limita:ion limito:d 4 5 6 7 DOMAIN CODE: Symptoms: 6, 8, 10, 121 14: 16! 18, 20, 22, 24, 29, 30 Activity Limitation: 1! 2! 3, 4, 5, 11, 19 , 25, 28, 31., 32 Emotional Function: 7, 13:, 151 21,27 Environmental Stillluli : 9 1 171 231 26 5 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.6 Page 275 U12-2466-01 Trial Protocol ASTHMA CONTROL QUESTIONNAIRE (ACQ) 5 Dec 2011 Page 122 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 276 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 123 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 277 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 124 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.7 Page 278 U12-2466-01 Trial Protocol EQ-5D HEALTH QUESTIONNAIRE ~Q-50 He.nlth Questionnnit·e (Euglish vcnio11 for the US) - 5 Dec 2011 Page 125 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 279 U12-2466-01 Trial Protocol 5 Dec 2011 Page 126 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 280 U12-2466-01 Trial Protocol 5 Dec 2011 Page 127 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.8 281 Page U12-2466-01 Trial Protocol PAPER PATIENT DIARY CARD 5 Dec 2011 Page 128 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.9 AM3 PATIENT INSTRUCTION CARD 282 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 129 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 283 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 130 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 284 U12-2466-01 Trial Protocol - 5 Dec 2011 Page 131 of 149 Vacation Card AM3 Tnlsvacation cara aescrlt:>es now to use tne AM3 aurlng your vacation. The AM3 has been programmed with a new time zone by your study doctor. The clock on the AM3 will be adjusted accordingly once the •vacation mode" is activated. If you have any problems using the AM3, please call your study doctor as soon as possible for help. Using t he AM3 at Home When using the AM3 while you are still at home, the following screen will appear when the AM3 is turned on. I I Are you at home? Yes No ESC 0 I = = Selecting"Yes• starts the scheduled session. Selecting "No" turns off the AM3. I:J OK Please note that t11e clock on the AM3 is still set to your home time zone. V-782034_USEN Final Version 02.00 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 285 U12-2466-01 Trial Protocol - 5 Dec 2011 Page 132 of 149 Using the AM3 During Your Vacation As soon as you arrive at your travel desti nation, please activate t he "vacation mode": 1. Press and h ol d t he • /:::t button. 2. While holdin g th e button, press and hold t he "ESC" button. 3 . Hold both buttons for approximately 2 seconds. ESC ·C::t The following screen wi ll appear: Do you want to I change to - i 1--------.,-,-------t= vacation mode? Yes I No Selecting "Yes" sets the clock t o t he local time zone of your t ravel destination. • If you select"No",the clock w ill not be changed. : OK Durin g your vacation t h e followin g screen w ill app ear every time you t urn on the AM3: I Are you on vacation? ; Yes : • Selecting "Yes" starts w ith the scheduled session. • Selecting "No" t urns off the AM3. I No I• I ' - - - - - - - - - . , -"""! _,I O! ESC Using t he AM3 When You Ret urn Home ESC As soon as you return h om e, please activat e the" hom e mode": 1. Press and h ol d t he • £::,.· button. 2. While holdin g th e •/:::t button, press and hold t he "ESC" button. 3. Hold bot h buttons for approximately 2 seconds. The following screen will appear: Do you want to change to home mode? ;;; • 1-----:-: Ye- s- - - - - j I ! No ESC Page 2 • Selectin g "Yes" sets the clock to your home time zone. • If you select "No",the clock will not be changed. !! 0( V·782034_USEN Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.10 286 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 133 of 149 DEFINITION ASTHMA EXACERBATION Asthma exacerbation For the purposes of this trial, an asthma exacerbation in general is defined by the sponsor as • an episode of progressive increase in one or more asthma symptoms, like shortness of breath, cough, wheezing, or chest tightness, or some combination of these symptoms. Respiratory distress is common. The symptoms should be outside the patient´s usual range of day-to-day asthma and should last for at least two consecutive days and/or • a decrease of patient´s best morning PEF of ≥ 30% from the patient´s mean morning PEF for at least two consecutive days. Relevant PEF deteriorations are marked on the AM3 data reports downloaded at each visit. During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. Severe asthma exacerbation Severe asthma exacerbations are defined by the sponsor as a subgroup from all asthma exacerbations according to sponsor´s definition given above that require an initiation of treatment with systemic (including oral) corticosteroids for at least 3 days. PEF decreases marked on AM3 report A asymptomatic PEF-decrease as described above is considered an asthma exacerbation per protocol, regardless of being accompanied by asthma symptoms, need for additional asthma medication or if considered medically relevant or not. At every AM3 download, the report includes an alert section summarizing all relevant PEF-decreases (PD alerts) that occurred since the last visit. The investigator needs to discuss the report with the patient and decide which PD-alerts are valid (explained by decreased lung function) and which are not valid (e.g. explained by non-compliance as for instance device was used by other person than patient or PEF measurement done incorrectly). For each valid PD alert, the investigator needs to document this finding as adverse event in the eCRF. If symptomatic, examples of AE verbatims would be asthma aggravation, asthma Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 287 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 134 of 149 exacerbation or bronchitis. If asymptomatic, the AE verbatim would be ´asymptomatic peak expiratory flow decrease´ if no symptoms were reported. In addition, the Asthma exacerbation verification page in the eCRF needs to be entered. Note: if a respiratory tract infection without asthma worsening was the reason of PEF decrease (e.g. bronchitis), then this would only be documented as AE, not as asthma exacerbation per protocol. For each non-valid PD alert, the investigator needs to document the rationale on the AM3report. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.11 288 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 135 of 149 CLINICAL LAB PARAMETERS Laboratory specimens will be collected in the evening. Blood samples need to be taken prior to the salbutamol (albuterol) dosing. Lab parameters will be analysed by the local laboratory of each participating site. Lab samples may be stored overnight. The local lab should be contacted to discuss the required overnight storage conditions (fridge or room temperature). The haematological parameters will include the following: • • • • • • Haemoglobin Haematocrit Absolute and relative eosinophil count (to be recorded on eCRF) Red blood cell count White blood cell count (to be recorded on eCRF) including differential test (neutrophils, lymphocytes, monocytes, eosinophils, basophils) Platelet count The blood chemistry parameters will include the following: • • • • • • • • • • • Total serum IgE (at Visit 1 only; to be recorded on eCRF) LDH γ-GT SGOT (AST) SGPT (ALT) Calcium Inorganic phosphorus Creatinine (to be recorded on eCRF) Potassium Sodium Chloride Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.12 Page 289 U12-2466-01 Trial Protocol 5 Dec 2011 Page 136 of 149 PHARMACOKINETIC METHODS 10.12.1 Planned analyses for pharmacokinetic evaluations Concentrations will be used for calculations in the format that is reported in the bioanalytical report. The data format for descriptive statistics of concentrations will be identical with the data format of the respective concentrations. For the calculation of pharmacokinetic parameters, only concentrations within the validated concentration range will be used. The actual sampling times will be used for the evaluation of plasma concentrations. If the actual sampling time was not recorded or is missing for a certain time point, the planned time should generally be used for this time point instead. For pre-dose samples, the actual sampling time will be set to zero. Noncompartmental pharmacokinetic parameters will be determined using the WinNonlinΤΜ software program (Professional version 4.1 or higher, , or another validated program. The following descriptive statistics will be calculated for analyte concentrations as well as for all primary and secondary pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. The descriptive statistics of pharmacokinetic parameters will be calculated using the individual values with the number of decimal places as provided by the evaluation program. Then the individual values as well as the descriptive statistics will be reported with three significant digits in the clinical trial report. Plasma concentrations will be plotted graphically versus time for all patients as listed in the drug plasma concentration-time tables. For the presentation of the mean profiles, the arithmetic mean and the planned blood sampling times will be used. 10.12.2 Handling of missing data Drug concentration-time profiles: Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not analyzed), BLQ (below the limit of quantification) and NOP (no peak detectable) will be ignored and not replaced by zero at any time point (including the lag phase). Descriptive statistics of concentrations at specific time points will be calculated only when at least 2/3 of the individuals have concentrations within the validated concentration range. The overall sample size to decide whether the '2/3' rule is fulfilled will be based on the total number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, NOA, NOP will be included). Pharmacokinetic parameters: During the noncompartmental analysis, concentration data identified with NOS, NOR, and NOA will not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag phase is defined as the period between time zero and the first time point with a concentration above the quantification limit. All other BLQ and/or NOP values of the profile will be ignored. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 290 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 137 of 149 If the predose concentration before the first dose is less than or equal to 5% of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements and calculations (i.e. the predose value will not be changed to zero). If the predose value before the first dose is greater than 5% of Cmax, the subject will be dropped from all statistical evaluations. The individual pharmacokinetic parameters will be calculated and listed separately. Every effort will be made to include all concentration data in an analysis. If that were not to be possible, a case to case decision iwill be taken as to whether the value should only be excluded from half-life estimation or the complete analysis. ∗ If a concentration is only excluded from half-life determination, it will be used for all other calculations (e.g. descriptive statistics) and for graphical presentation. ∗ If a concentration value is excluded from all calculations, it will not be presented graphically or used for the calculation of descriptive statistics and parameter determination. However the excluded concentration itself will be listed in the clinical trial report associated with an appropriate flag. Descriptive statistics of parameters are calculated only when at least 2/3 of the individual parameter estimates of a certain parameter are available. If the actual sampling time will not be recorded or will be missing for a certain time point, the planned time will generally be used for this time point instead. Pharmacokinetic parameters which cannot be determined will be identified by "not calculated" (NC). 10.12.3 Derivation of PK parameters Individual Cmax(,ss), tmax(,ss), Cmin(,ss), and Cpre,N values will be directly determined from the plasma concentration time profiles of each patient. If the same Cmax(,ss) concentration occurs at different time points, tmax(,ss) is assigned to the first occurrence of Cmax(,ss). Estimation of λz(,ss): The apparent terminal rate constant λz(,ss) will be estimated from a regression of ln(C) versus time over the terminal log-linear disposition portion of the concentration-time profiles. At least three data points should be used in the calculation of λz(,ss). In addition, the lower (tλz,start(ss)) and upper (tλz,end(ss)) limit on time for values to be included in the calculation of λz,ss will be listed. t1/2(ss): The terminal half-life will be calculated from the terminal rate constant using the equation t1/2(ss) = ln2 λ z(ss) AUC: The area under the curve will be calculated using the linear up/log down algorithm. If an analyte concentration is equal to or higher than the preceding concentration, the linear trapezoidal method will be used. If the analyte concentration is smaller than the preceding concentration, the logarithmic method will be used. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 291 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 138 of 149 Linear trapezoidal rule (t2 > t1 and Ct2 ≥ Ct1): The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by: AUCt1- t2 = 0.5 × (t 2 − t1 )× (C t1 + C t2 ) Logarithmic trapezoid rule (t2 > t1 and Ct2 < Ct1): The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by: AUC t1− t2 = (t 2 − t 1 ) × (C t2 − C t1 ) ln (C t2 /C t1 ) AUCτ,ss: The area under the plasma concentration-time curve at steady state over a uniform dosing interval τ will be calculated using the extra- or interpolated concentration at time tτ (time at the end of the dosing interval). The actual sampling time of the trough value Cpre,N will be set to 0. MRTih(,ss): MRTih(,ss) calculation in the steady state will be performed according to the following equation: MRTih,ss = AUMCss AUC τ,ss AUMCss is the area under the first moment curve at steady state. CL/F,ss: The apparent clearance at steady state following extravascular multiple dose administration will be calculated as follows: CL/F,ss = Dose AUCτ ,ss Vz/F,ss: The apparent volume of distribution during the terminal phase after (multiple) extravascular administration (at steady state) will be determined according to the following equation: Vz F(,ss ) = CL F(,ss) λ z(,ss) fet1-t2,ss: The fraction excreted is calculated according to fe t1- t2(,ss) = Ae t1- t2(,ss) Dose ×100 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 292 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 139 of 149 where Aet1-t2,ss is the total quantity of the analyte that is excreted in urine over the time interval t1 to t2 (at steady state). This may represent the product of urine volume and urine analyte concentration for one time interval, as well as the cumulative amounts excreted calculated as the sum of the excreted amounts of subsequent time intervals. CLR,t1-t2,ss: The renal clearance (CLR) will be calculated as the quotient of the quantity of the analyte that is excreted in urine from the time point t1 until the time point t2 (Aet1-t2(,ss)) and the area under the concentration-time curve within the same time interval (AUCt1-t2(,ss)). CL R, t1− t2(,ss) = Ae t1− t2(,ss) AUCt1− t2(,ss) RA: The accumulation ratio RA will be calculated as follows: RA,Cmax = C max,ss C max RA,AUC = AUC τ ,ss AUC τ LI: The linearity index (LI) will be calculated as follows: LI = AUC τ ,ss AUC 0−∞ gMean, gCV: The geometric mean (gMean) and coefficient of variation, gCV (given in %), will be calculated by the formulae: [ ⎡ n ⎤ gMean = exp ⎢ 1n ∑ ln(x i )⎥ = exp ln(x i ) ⎣ i =1 ⎦ gCV(%) = 100 ⋅ exp [Var(ln(x i ))] − 1 where Var(ln(x i )) = [ 1 n ∑ ln(x i ) − ln(x i ) n − 1 i =1 ] 2 ] Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 10.13 293 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 140 of 149 PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 294 U12-2466-01 ·- 5 Dec 2011 Page 141 of 149 Trial Protocol PART 1: RATING OF SATISFACTION WITH Il'I"HALER ATTRIBUTES Instru ctions : For the following questions, please check the response that. best describes how satisfied you are with each of the following items. Please take as much ti:me as you need to answer each question. ~ Q) -g~ o;: .~ IJJ .... ~ Q) ;;::: IJJ IJJ ~ (:-VI Q) ~ Q) ;.;:: .!!l >O ... ~ Q) IJJ ... IJJ .r; n! :::$ Q) n! E IJJ .r;O 0 1/)0 0 .!!l ... 1/) 1/) n! IJJ IJJ IJJ :; :;:: .~ nl'"' n! ·.r; .... :;::; :;: Q) · - ~ 'Q) z 0 c: n! ::: Q) E 0 1/) ~ Q) ;;::: ..., IJJ n! 1/) ~ Q) ~~ Q) n! >II) H ow satisfied are you ... 1. With the overall feeling of inhaling your medicine? ~espima~®l 2. With the feeling that the inhaled dose goes to your hutg.~? ~espimar~l 3. That you can tell the amo\utt of medication left in your inhaler? ~e;pima~l ~ ~ ~ 4. That the inhaler works reliably? ~e~pima~l ~ 5. With the ease of inhaling a dose from the inhaler? ~espimar~l ~ 6. With the iustn1ction~ for use? ~esyima~l ~ 7. With the size of your inhaler? Respimat~l 8. That the inhaler is durable (hard wea ring)? ~e;pima~l ~ ~ T D 0 D 0 D D D 0 D 0 D D D 0 D 0 D 0 D 0 D 0 D D D D D 0 D 0 D 0 Please go to the next page @Boehringer Ingelheim F:"IINSnTUT\CUlTAOA?\Fi\OJE-....'""T\!S36'.S11J~·4536'J'fn31_vers:br.$IPASAFO:ng-tfSO~.cJoc· 18.'Q4.12Ql)8 0 0 D 0 0 D 0 0 0 0 0 D D 0 0 0 0 0 D 0 0 D 0 0 0 0 0 D D 0 0 0 D 0 0 D 0 0 D D D 0 D 0 D D D 0 D 0 D 0 D 0 D 0 D D D D D 0 D 0 D 0 D 0 0 D 0 0 0 0 0 D D 0 0 0 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 295 U12-2466-01 - 5 Dec 2011 Page 142 of 149 Trial Protocol ~"0 ~ .~ VI'>- "0 "0 "' "' :;:; ~ ;;:: VI <0 i:':'VI iii VI VI "' .!!! Ci >O 9. With the ease of cleaning your inhaler? Rewimat®! 10. With using the inhaler? Re;pimat®! 11 With the speed at which medicine comes out of the inhaler? IRe;pimat®! 12. With the ease of holding the inhaler during \Lse? Re•pimar~! 13. With the overall convenience of carrying the inhaler with you? IRespimar~! ~ ~ ~ ~ ~ 14. Overall, how satisfied are you with your inhaler? Respimat®! ~ T D D D D D D "0 ~"' <0 ·- j~ Q) <0 VI E 0 .!!! eno :;:; .~ co~ en co VI ,_ VI Q) · - ~0 .~ Q) z ...0 r::: "0 ;;= "'VI ~ en ~ <0 ~ ~ "C "0 E "' ~~"' :;:; en "' <0 en >en Q) 0 ~ VI <0 D D D 0 D D D 0 D D 0 0 D D D D D D D D D D D D D D D D 0 0 D D 0 D D D D D D D 0 0 D D D D D D D D D D D 0 0 D 0 0 D 0 0 D D D D 0 0 D 0 0 Please go to the next page ©Boehringer Inge.lheim f jjNSTITUT\CUlTADA~M.O...~CT'.f.538'l$lUCiy.:!SJe'.Rnli_Wt'$iOr.£~?ASAFQer.g.tJSO(lq.OOc.- ta<NJ20t!8 D D 0 0 D D 0 0 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 296 U12-2466-01 ·- 5 Dec 2011 Page 143 of 149 Trial Protocol PART II: R<\.TING OF PREFERENCE Al'il> WILLINGNESS TO CO!\'TINUE WITH Il'HIALER 15. Comparing the two inhalers that you have used during the study, overall, would you prefer io use Respimat® or MDI? Please che.c.k one box D D D I prefer Respimat® I prefer MDI No preference 16. Comparing the two inhalers that you have used during the study, overall, how would you feel about continuing to use Respimat® or MDI? Plea~e indicate your willingness to continue using each of the inhalers that you used during the study by providing a value between 0 and I 00. 0 indicates that you would not be willing to continue using this inhaler and 100 indicates that you would definitely be willing to continue . Please write Ul a number in each box thai is between 0 and 100. Respimat® ~mi Both boxes should c.ontain a number between 0 amllOO. 'f Please go to the next page ©Boehru1ger Ingelheim F::'tiNSllTUT\CUllAD,A,?'\P.''\O!ECNSJ6\$1Udy~S36\Rnai_Vef'6:.0r!$.\PASAF~n.g-OSOrlq.Cioc-1MI4J2008 D D Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 297 U12-2466-01 Trial Protocol THANK YOU VERY MUCH FOR COMPLETING THIS SURVEY. PLEASE RETURN THIS SURVEY TO THE STUDY COORDINATOR. ©Boe.h ringer Ingelheim F:.INSlllUT\CUlTA.C,4.;r,F.RO.:~~ S3e'.s11Jely453e\Frnll_versi0r.&\PASAPC-er:g-t!SO~.cJce-18JD4i201l8 - 5 Dec 2011 Page 144 of 149 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 11. 298 Page U12-2466-01 Trial Protocol 5 Dec 2011 Page 145 of 149 SUMMARY OF CLINICAL TRIAL PROTOCOL MODIFICATIONS Summary of Clinical Trial Protocol Modifications Sheet (SOMS) Number of CTP modification Date of CTP modification EudraCT number BI Trial number BI Investigational Product(s) Title of protocol To be implemented only after approval of the IRB/IEC/Competent Authorities To be implemented immediately in order to eliminate hazard – IRB / IEC / Competent Authority to be notified of change with request for approval Can be implemented without IRB/IEC/ Competent Authority approval as changes involve logistical or administrative aspects only 1 19 January 2011 2009-018004-18 205.418 - 2.5 µg tiotropium bromide - 5 µg tiotropium bromide - 50 µg salmeterol xinafoate - Placebo inhalation solution (Respimat®) - Placebo metered dose inhaler A Phase III randomised, double-blind, placebocontrolled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Section to be changed Description of change 299 Page U12-2466-01 Trial Protocol I) 5 Dec 2011 Page 146 of 149 Synopsis, flow chart (including footnotes), abbreviations, section 1.2.1, section 3.2, section 3.3.3, section 4.1.4 (Trial medication administration at clinic visits), section 4.2, section 4.2.1.3, table 4.2.2.1: 1, section 5.1.1.1, section 5.1.1.2, section 5.1.2, section 5.3.2, section 5.4, section 5.5.2, section 5.5.3, section 6.2.2, section 7.1 (Design), section 7.3.1, section 7.6 II) Synopsis, flow chart (including footnotes), timing of trial procedures 3 hour PFT, timing of trial procedures 24 hour PFT, section 3.1, section 3.3, section 5.3.1, section 5.3.2, section 6.2.2 (Observations and procedures Visit 6), section 7.3.9, section 9.1, appendix 10.13 III) Timing of trial procedures 3 hour PFT, section 2.2, section 3.3, section 3.3.2, section 5.1.1.2, section 7.3.2 IV) Section 4.1.4 (Instructing the patient) V) Section 5.1.2 (Electronic peak flow meter with electronic diary) VI) Section 5.1.2 VII) Section 3.3.2, section 6.2.1 (Observations and procedures Visit 1), Appendix 10.4 VIII) Section 3.3.2, section 6.1 VIIII) Section 4.1.4 (Testing of the MDI), Appendix 10.2 IV) Section 5.5.2, section 5.5.3, section 9.2. I) Administrative changes, corrections and added clarifications. II) Implementation of PASAPQ III) Implementation of PFT subset at Visit 5 IV) Change of time windows for medication administration at home in the evenings and mornings in case a patient missed a dose. V) Change in time windows for eDiary use at home in the evenings and mornings in case a patient forgot to use the eDiary. VI) Change in the maximum number of attempts for Pulmonary Function Testing. VII) Extension of time window for reversibility testing. VIII) Addition of option to repeat reversibility test (Visit 1). VIIII) Change in the number of priming puffs. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 300 Page U12-2466-01 Trial Protocol IV) Rationale for change I) II) III) IV) V) VI) VII) VIII) 5 Dec 2011 Page 147 of 149 Change in blood volume PK samples. More detailed instructions to prevent possible contamination of PK samples. Administrative changes/corrections/clarifications. To measure patient satisfaction and preference for the devices used in this study. To explore the onset of action of the study medication. To increase patient treatment compliance. To add instructions in case a patient forgot to use the Asthma Monitor®AM3 within the specified time window. To be consistent with the ATS/ERS criteria and with other studies within the same project (Tiotropium in Asthma). To allow patients who reverse after 30 minutes to participate in the study. To allow patients who do not reverse during the first test, but do during the repeat test to participate in the study. VIIII) To make sure the device is working properly. IV) To increase the quality of the PK analysis. Bioanalytical method has been revalidated. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 301 Page U12-2466-01 Trial Protocol 2 5 December 2011 2009-018004-18 205.418 - 2.5 µg tiotropium bromide - 5 µg tiotropium bromide - 50 µg salmeterol xinafoate - Placebo inhalation solution (Respimat®) - Placebo metered dose inhaler A Phase III randomised, double-blind, placebocontrolled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Number of CTP modification Date of CTP modification EudraCT number BI Trial number BI Investigational Product(s) Title of protocol To be implemented only after approval of the IRB/IEC/Competent Authorities To be implemented immediately in order to eliminate hazard – IRB / IEC / Competent Authority to be notified of change with request for approval Can be implemented without IRB/IEC/ Competent Authority approval as changes involve logistical or administrative aspects only Section to be changed 5 Dec 2011 Page 148 of 149 I) II) III) IV) V) VI) VII) VIII) Abbreviations Section 5.2.2.1 Section 5.2.2.2 Section 5.3.1 Section 6.1 Section 6.1 Flowchart and Section 6.2.3 Appendix 10.11 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Description of change Rationale for change 302 Page U12-2466-01 Trial Protocol I) II) III) IV) V) VI) VII) VIII) I) II) III) IV) V) VI) VII) VIII) 5 Dec 2011 Page 149 of 149 Administrative correction/additions. Administrative change and clarification. Administrative change. Administrative correction. Clarification. Clarification. Administrative change. Clarification. Administrative correction/additions. Administrative change regarding reporting of significant events. Clarification of (S)AE reporting. Administrative change regarding reporting of always serious AEs. Deletion of invalid endpoint. Clarification start of screening period. Clarification scheduling Visit 2 after repeated reversibility test. Administrative change regarding collection of HCRU data. Clarification. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 303 U12-2466-01 5 Dec 2011 Page 2 of 149 Trial Protocol CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety oftiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 Jlg once daily) compared with placebo and salmeterol HFA MDI (50 Jlg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.418 I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial rotocol. Name: Affiliation: Date: 2 J I; Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Page 304 U12-2466-01 19 Jan 2011 Page 2 of147 Trial Protocol CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 Jlg once daily) compared with placebo and salmeterol HF A MDI (50 Jlg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.418 I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial Name: Trial Master File Affiliation: Date: Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 305 U12-2466-01 !1.i\ Boehringer ~1lllnJ lngelheim Clinical Trial Protocol Local Amendment Local Amendment Number: China Date: 29Mar2011 D EudraCT No.: 2009-018004-18 D BI Trial No.: 205.418 Local Amendment I To be implemented only after documented approval of the IRB I IEC I Competent Authorities To be implemented immediately in order to eliminate hazard IRB I IEC I Competent Authority to be notified of change with request for approval Can be implemented without IRB Investigational Product(s): Tiotropium Inhalation Solution, Title: A Phase ill randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety oftiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 J.lg once daily) compared with placebo and salmeterol HFA MDI (50 J.lg twice daily) over 24 weeks inpatients with moderate persistent asthma. Rationale for Local Amendment: Not all sites in China are certified to analyse total serum IgE in their local laboratory. The samples of these sites will be analysed at a certified site. Respimat® inhaler I IEC I Competent Authority X approval as changes involve logistical or administrative aspects onlv Page 1 of5 Proprietary confidential information. © 2011 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. R I 001-MCS-40-106 RD-04(9.0)/Savedon: 11 Mar2010I Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 306 U12-2466-01 nuennnger •ngetnetm BI Trial No.: 205.418 Protocol Local Amendment 1 China Page 2 of5 SIGNATURE PAGE(S) This amendment ~ Concerns administrative matters only so that the coordinating investigator's signature will not be obtained. D Concerns matters dealing with design elements of the study, in-/exclusion criteria, observations, or safety or efficacy related study elements so that the coordinating investigator's signature needs to be obtained. -- Trial Clinical Monitor Date Boehringer Ingelheim bv, The Netherlands/ Medical department Trial Statistician Date Boehringer Ingelheim Phanna GmbH & Co. KG, Biberach/ C MED Clinical Operations + BDM Team Member Medicine Date Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ Dep. Clinical Research, Respiratory Diseases Trial Clinical Pharmacokineticist -- (if applicable) Date Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ Development Germany Proprietary confidential information. © 2011 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. I 001-MCS-40-106 RD-04 (9.0) I Saved on: 11 Mar 20101 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 307 U12-2466-01 HI Trial No.: 2U5.4UI Protocol Local Amendment 1 China Page 3 of5 SIGNATURES (PRINCIPAL INVESTIGATOR OF SITE AND CLINICAL MONITOR LOCAL) Clinical Monitor Local: Date Name -· Boehringer Ingelheim Int'l Trading (Shanghai) Co.,Ltd I Medical Dept. I herewith certify that I agree to adhere to the trial protocol amendment and to all documents referenced in the trial protocol amendment. Principal Investigator (site): Date Name Full name Organisation/Department Proprietary confidential information. © 2011 Boehringer lngelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part- be passed on, reproduced, published or otherwise used without prior written pennission. I 001 MCS-40-106 RD 04 (9.0) I Saved on: 11 Mar 20101 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 308 U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 309 U12-2466-01 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 310 U12-2466-01 Boehringe•· Ingelheim Bl Trial No.: 205.419 Dmft, 29Ma•·2011 Protocol Local Amendment 1 China Page 2 of5 SIGNATURE PAGE(S) This amendment IZI Concems administrative matters only so that the coordinating investigator's signah1re will not be obtained. D Concerns matters dealing with design elements of the study, in-/exclusion criteria, observations, or safety or efficacy related study elements so that the coordinating investigator's signature needs to be obtained. Trial Clinical Monitor department Trial Statistician Boehringer lngelheim Pharma GmbH & Co. KG, Biberach/ C MED Clinical Operations+ BDM Team Member Medicine '2JAfr,:_f <. o111 Date Boehringer lngelheim Pharma GmbH & Co. KG, Biberach/ Dep. Cliuical Resea1eh, ~~~~ D~sh~d Ajjo/rf i{Of M Trial Clinical Pharmacokineticist (if applicable) Boehringer lngelheim Pharma GmbH & Co. KG, Biberach/ ~ntGermany lr.,.,s/p-1,,...,.) ~·o.-.:.. P r oprietary confidential information. © 2011 Boeh r inger lngelheim International GmbH or one or more of its affilia ted companies. All r ights reserved. This documenlmay no!- in lull or in pan- be passed on, reproduced, published or olhcrwisc used wilhoul prior writlen permission. I 001·MCS·40-106 R0.04 (9.0} I Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments 311 Page U12-2466-01 CLINICAL TRIAL PROTOCOL LOCAL AMENDMENT Clinical Trial Protocol Local Amendment Doc. No.: U10-1634-AM1 Local Amendment Number: Local Amendment 1 Date: 28 June 2010 EudraCT No.: 2009-018004-18 BI Trial No.: 205.418 Investigational Product(s): Tiotropium Inhalation Solution, Title: A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Rationale for Local Amendment: To adapt the international clinical trial protocol for use in Japan Japan ® Respimat inhaler ■ To be implemented only after documented approval of the IRB / IEC / Competent Authorities □ To be implemented immediately in order to eliminate hazard – IRB / IEC / Competent Authority to be notified of change with request for approval □ Can be implemented without IRB / IEC / Competent Authority approval as changes involve logistical or administrative aspects only Page 1 of 12 Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 Page 312 U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 2 of 12 SIGNATURE PAGE(S) This amendment concerns administrative matters only so that the coordinating investigator's signature will not be obtained. concerns matters dealing with design elements of the study, in-/exclusion criteria, observations, or safety or efficacy related study elements so that the coordinating investigator's signature needs to be obtained. Trial Clinical Monitor Date Boehringer Ingelheim bv, The Netherlands/ Medical department Trial Statistician Date Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ C MED Clinical Operations + BDM Team Member Medicine Date Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ Dep. Clinical Research, Respiratory Diseases Trial Clinical Pharmacokineticist (if applicable) Date Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ Development Germany Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 Page 313 U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 3 of 12 CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.418 I herewith certify that I agree to adhere to the trial protocol amendment and to all documents referenced in the trial protocol amendment. Name: , MD Affiliation: , The Netherlands Signature: ______________________________ Date: ___________________________ Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 Page 314 U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 4 of 12 SIGNATURES (PRINCIPAL INVESTIGATOR OF SITE AND CLINICAL MONITOR LOCAL) Clinical Monitor Local: Date Name Nippon Boehringer Ingelheim Co., Ltd./ Clinical Research Department I herewith certify that I agree to adhere to the trial protocol amendment and to all documents referenced in the trial protocol amendment. Principal Investigator (site): Date Name Full name Organisation/Department Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 Change 1: regulatory. 315 Page U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 5 of 12 Add explanations of administrative structure required as per local Change 1.1: Section 3.1.1 Administrative structure of the trial Sponsor: Clinical trial drug supplies including trial, training and rescue medication will be provided by the sponsor. Co-ordinating Investigator: The co-ordinating investigator was selected by the sponsor. He will review the trial protocol, any subsequent amendments to the protocol and the (draft) Clinical Trial Report (CTR). He will provide his signature on the final protocol signature page and amendments and will provide his signature on the (draft) Clinical Trial Report (CTR) indicating that, to the best of Co-ordinator’s knowledge, the final CTR accurately describes the conduct and results of the Trial. Targeted group of Investigators: Pulmonologists/qualified sites with access to the requested patient population. The following local facilities/equipment are required at the investigational site: clinical laboratory, ECG, scale and sphygmomanometer. The sites have to be able to perform the 3 hour PFT measurements in the evening. Selected sites have to be able to perform the (24 hour) PK and/or 24 hour PFT measurements. DSMB: A DSMB will not be implemented on trial level, but might be implemented on project level. If so, safety review meetings will be held as per separate DSMB charter Central laboratory: The sample transport logistics (from site to sponsor) for PK and pharmacogenetic samples will be the responsibility of the central lab. The central lab will provide sampling and shipment materials. IVRS: An interactive voice response system (IVRS) will be used for randomisation to a treatment group in this trial and for appropriate re-supply of medication to patients. The ability to unblind will be available to the investigator via the IVRS. CROs: A CRO will provide MasterScope® CT and AM3® devices for the complete duration of the trial. All contracts and relevant meeting minutes will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). Was changed to: Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 316 Page U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 6 of 12 Sponsor: The trial is sponsored by Nippon Boehringer Ingelheim Co., Ltd. Boehringer Ingelheim will appoint a Trial Clinical Monitor, responsible for writing and preparing the Core documents for the conduct of the trial (Clinical trial Protocol, Core consent, etc.), for directing the Clinical Trial Team in the preparation, conduct and reporting of the trial, for ordering Clinical Trial Supplies and materials necessary for the trial, for ensuring appropriate information and training of CMLs / CRAs / investigators of participating countries, for ensuring timely cleaning of data, DataBaseLock and delivery of results and for writing the Clinical Trial Report or overseeing preparation of associated publications. Data Management and Statistical evaluation will be done by BI according to BI SOPs. For these activities, a Trial Data Manager and a Trial Statistician will be appointed. Tasks and functions assigned in order to organise, manage, and evaluate the trial will be defined according to BI SOPs. A list of responsible persons will be given in the clinical trial master file (CTMF) document. List of co-ordinating investigators, CROs, and NBI personnel is available as Attachment 1 and that of participating investigational sites and investigators is available as Attachment 2 The organisation of the trial in the participating countries will be done by the respective local BI-organisation (OPU) or a by a Contract Research organization (CRO) with which the responsibilities and tasks have been agreed and a written contract has been filed before initiation of the clinical trial. In each local BI-organisation (OPU) participating in this study, a local clinical monitor (CML) will be appointed responsible for coordinating the activities required in order to manage the trial in accordance with applicable regulations and internal SOPs in the countries covered by the respective BI OPU. Clinical trial drug supplies including trial, training and rescue medication will be provided by the sponsor. Co-ordinating Investigator: A Co-ordinating Investigator will be nominated to coordinate investigators at different sites participating in this multicentre trial. Tasks and responsibilities for the Coordinating Investigator will be defined in a contract. The co-ordinating investigator was selected by the sponsor. He will review the trial protocol, any subsequent amendments to the protocol and the (draft) Clinical Trial Report (CTR). He will provide his signature on the final protocol signature page and amendments and will provide his signature on the (draft) Clinical Trial Report (CTR) indicating that, to the best of Co-ordinator’s knowledge, the final CTR accurately describes the conduct and results of the Trial. Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 317 Page U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 7 of 12 Targeted group of Investigators: Pulmonologists/qualified sites with access to the requested patient population. The following local facilities/equipment are required at the investigational site: clinical laboratory, ECG, scale and sphygmomanometer. The sites have to be able to perform the 3 hour PFT measurements in the evening. Selected sites have to be able to perform the (24 hour) PK and/or 24 hour PFT measurements. Documents on participating (Principal) investigators and other important participants, especially their curricula vitae, will be filed in the CTMF document. DSMB: A DSMB will not be implemented on trial level, but might be implemented on project level. If so, safety review meetings will be held as per separate DSMB charter Central laboratory: The sample transport logistics (from site to sponsor) for PK and pharmacogenetic samples will be the responsibility of the central lab. The central lab will provide sampling and shipment materials. IVRS: An interactive voice response system (IVRS) will be used for randomisation to a treatment group in this trial and for appropriate re-supply of medication to patients. The ability to unblind will be available to the investigator via the IVRS. CROs: A CRO will provide MasterScope® CT and AM3® devices for the complete duration of the trial. All contracts and relevant meeting minutes will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). CROs: A CRO will provide CRAs for the complete duration of the trial. All contracts and relevant meeting minutes will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). Details on handling of the trial supplies including responsible institutions are given in chapter 4. of this protocol. The Investigator Site File (ISF) document will be kept in print-out version at the sites as far as required by local regulation and BI-SOP. A copy of the ISF documents will be kept as an electronic Clinical Trial Master File (CTMF) document according to BI SOPs. Reason For Change 1: Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 318 Page U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 8 of 12 To adapt the international clinical trial protocol for use in Japan. Change 2: Add exclusion criteria and a precautionary statement to avoid enrolling patients with narrow-angle glaucoma and/or micturition disorder due to prostatic hyperplasia. Change 2.1: Section 3.3.3 Exclusion criteria none Was changed to: 26. Patients with narrow-angle glaucoma and/or micturition disorder due to prostatic hyperplasia. Change 2.2: Section 3.3.3 Precautionary statement As an anticholinergic drug, tiotropium may potentially worsen symptoms and signs associated with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction and should be used with caution in patients with any of these conditions. Was changed to: As an anticholinergic drug, tiotropium may potentially worsen symptoms and signs associated with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction and should be used with caution in patients with any of these conditions. Tiotropium should not be used in patients with narrow-angle glaucoma and/or micturition disorder due to prostatic hyperplasia etc. Reason For Change 2: Consistent description with Japanese package insert for COPD patients deemed necessary. Change 3: Add required action when an emergency key code is unblinded. Change 3.1: Section 4.1.5.2 Procedures for emergency unblinding The ability to unblind will be available to the investigator via the IVRS. Unblinding must only be used in emergency situations when the identity of the study drug must be known by the investigator to provide appropriate medical treatment. Each site receives a manual from the IVRS provider that contains instructions on how to unblind the treatment of a patient via the IVRS (via 24-hour Emergency helpline). If possible, the Clinical Monitor Local (CML) Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 319 Page U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 9 of 12 and Trial Clinical Monitor (TCM) must be contacted prior to the site unblinding a patient's treatment. Patients unblinded to treatment will be withdrawn from the trial. Was changed to: The ability to unblind will be available to the investigator via the IVRS. Unblinding must only be used in emergency situations when the identity of the study drug must be known by the investigator to provide appropriate medical treatment. Each site receives a manual from the IVRS provider that contains instructions on how to unblind the treatment of a patient via the IVRS (via 24-hour Emergency helpline). In case, emergency unblinding is conducted, the site must contact Operative unit of BI and write the reasons for unblinding and the initial of the person who unblinds the code and the date of unblinding in eCRF or worksheet. If possible, the Clinical Monitor Local (CML) and Trial Clinical Monitor (TCM) must be contacted prior to the site unblinding a patient's treatment. Patients unblinded to treatment will be withdrawn from the trial. Reason For Change 3: It is due to local regulatory requirement. Change 4: Remove the statement of disposable mouthpieces and sharing the training Respimat among patients. Change 4.1: Section 4.1.6 Packaging, labelling, and re-supply Open-label supplies Boehringer Ingelheim will provide the following open-label supplies: Respimat® inhalers, placebo cartridges and disposable mouthpieces for training purposes. A training device may be used for more than one training session. The training Respimat® can be used until 3 months after priming or until the device is empty. The date of first priming should be entered on the medication label of the Respimat®. A new mouthpiece should be used for each patient. Was changed to: Open-label supplies Boehringer Ingelheim will provide the following open-label supplies: Respimat® inhalers, placebo cartridges for training purposes. A new training Respimat® should be used for each patient. The training Respimat® can be used until 3 months after priming or until the device is empty. The date of first priming should be entered on the medication label of the Respimat®. Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 320 Page U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 10 of 12 Reason For Change 4: In Japan, a training Respimat can not be shared among patients even though a new mouthpiece is used. A new training Respimat is always provided to each patient and disposable mouthpieces will not be provided to the sites. Change 5: Add anti-allergic drug to the restricted medication in concomitant therapy of Antihistamines. Change 5.1: Section 4.2.1.3 Additional treatments Medications allowed prior to and throughout the trial: 1. … 5. Antihistamines. Was changed to: Medications allowed prior to and throughout the trial: 1. … 5. Antihistamines and anti-allergic drug (except cromone and leukotriene modifiers). Change 5.2: Section 4.2.2.1 Restrictions regarding concomitant treatment Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class Sub-class Prior to study Miscellaneous Other investigational drugs Combination ICS/LABA (e.g. Advair®/ Seretide®; Symbicort®; Foster®) Screening Period Treatment Period Follow up Period NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted Permitted NOT permitted NOT permitted Permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 24 hours prior to Visit 1 Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 Combination ICS/SABA 321 Page U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Permitted NOT permitted Permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 8 hours prior to visit 1 (e.g. Butasol®) Combination short-acting anticholinergic/ SABA NOT permitted Page 11 of 12 Permitted NOT permitted from 8 hours prior to Visit 1 NOT permitted Permitted NOT permitted for at least two weeks prior to Visit 1 NOT permitted NOT permitted Permitted Permitted Permitted Permitted Permitted (e.g. Berodual®, Combivent®, Duovent®) Cromone Antihistamines Was changed to: Study Period Drug Class Sub-class Prior to study Miscellaneous Other investigational drugs Combination ICS/LABA Screening Period Treatment Period Follow up Period NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted Permitted NOT permitted NOT permitted Permitted NOT permitted Permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 24 hours prior to Visit 1 (e.g. Advair®/ Seretide®; Symbicort®; Foster®) Combination ICS/SABA (e.g. Butasol®) Permitted NOT permitted Patient should be switched to the inhaled Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 322 Page U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 12 of 12 steroid monoproduct without changing the steroid dose at least 8 hours prior to visit 1 Combination short-acting anticholinergic/ SABA Permitted NOT permitted from 8 hours prior to Visit 1 NOT permitted Permitted NOT permitted for at least two weeks prior to Visit 1 NOT permitted NOT permitted Permitted Permitted Permitted Permitted Permitted (e.g. Berodual®, Combivent®, Duovent®) Cromone Antihistamines and Antiallergic drug (except cromone and leukotriene modifiers) Reason For Change 5: In Japan, there is a category of anti-allergic drugs which includes not only antihistamines but also leukotoriene modifiers and cromone. We need to clarify how to handle anti-allergic drugs in the clinical trial protocol because they are often used for asthmatic patients in Japan. Anti-allergic drugs other than antihistamines and with the exception of cromone and leukotriene modifiers are permitted throughout the trial.. Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 001-MCS-40-106_RD-04 (9.0) / Saved on: 11 Mar 2010 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.418 Doc. No.: U10-1634-AM1 Page 323 U12-2466-01 Final 28 Jun 2010 Protocol Local Amendment 1 Japan Page 2 of12 SIGNATURE PAGE(S) This amendment 0 concerns administrative matters only so that the coordinating investigator's signature will not be obtained. cg) concerns matters dealing with design elements of the study, in-/exclusion criteria, observations, or safety or efficacy related study elements so that the coordinating investigator's signature needs to be obtained. Trial Clinical Monitor (.;<; ).A.\ 2010 Date Trial Statistician Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ C MED Clinical Operations+ BDM Team Member Medicine 121,j} 2o1o Dat Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ Dep. Clinical Research, Re~;piratOJ-y Diseases Trial Clinical Pharmacokineticist (if applicable) Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/ Development Germany Proprietary confidential information. © 2010 Boehringer lngelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part- be passed on, reproduced, published or otherwise used without prior written permission. I 001-MCS-40-106 RD-04 (9.0) I Saved on: 11 Mar 201g Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 324 U12-2466-01 /@\Ill Boehri~ger \J1llhv Ingelhe1m Clinical Trial Protocol Local Amendment Local Amendment Number: Local Amendment I Date: FINAL I7 November 20 I 0 X EudraCT No.: 2009-0 I 8004-1 8 0 BI Trial No.: 205.4I8 USA To be implemented only after documented approval of the IRB I JEC I Com]J!tent Authorities To be implemented immediately in order to eliminate hazard IRB I IEC I Competent Authority to be notified of change with request for approval 0 Can be implemented without IRB Investigational Product(s): Tiotropium bromide Inhalation Solution Title: A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety oftiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 J.tg once daily) compared with placebo and salmeterol HFA MDI (50 J.tg twice daily) over 24 weeks in patients with moderate persistent asthma. Rationale for Local Amendment: I IEC I Competent Authority approval as changes involve logistical or administrative aspects onlv Change of time windows for medication administration at home in the evenings and mornings in case a patient missed a dose. Change in time windows for eDiary use at home in the evenings and mornings in case a patient forgot to use the eDiary. Change in the maximum number of attempts for Pulmonary Function Testing Extension of time window for reversibility testing. Use of a central laboratory for testing of safety parameters for study sites in the USA. Page I of9 Proprietary confidential information. © 2010 Boehringer lngelheim International GmbH or one or mot·e of its a ffiliated companies. All rights reserved. This document may not . in full or in part · be passed on, reproduced, published or otherwise used without prior wriuen permission. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 325 U12-2466-01 Boehringer Ingelbeim Bl Trial No.: 205.418 Protocol Local Amendment I USA Fi11af, 17 Nov 2010 Page 2 of9 SIGNATURE PAGE(S) This amendment D concerns administrative matters only so that the coordinating investigator's signature will not be obtained. 0 concerns matters dealing with design elements of the study, in-/exclusion criteria, observations, or safety or efficacy related study elements so that the coordinating investigator's signature needs to be obtained. Trial Clinical Monitor IB flov 2'010 ate Trial Statistician Boehringer lngelheim Pharma GmbH & Co. KG, Biberach/ C MED Clinical Operations + Team Member Medicine , -'' AI <.) /V-i]V 1D10 Date GmbH & Co. KG, Biberach/ Dep. Clinical Research, Trial Clinical Pharmacokineticist ~& N"v <,oto Date Boehringer lngelheim Phanna GmbH & Co. KG, Biberach/ Development Germany Pro1>rietary confidential info•·mation. © 2010 Boehringer lngclheim International GmbH or one or more of its affiliated companies. AU rights reserved. This docmnelllmay not - in full or in part - be passed on. reproduced. published or otherwise used Without pnor wriuen permission. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 326 U12-2466-01 Boehringer lngelheim BI Trial No.: 205.418 Protocol Local Amendment 1 USA Final, 17 Nov 2010 Page 3 of9 CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety oftiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 ~g once daily) compared with placebo and salmeterol HFA MDI (50 Jlg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.418 I herewith certify that I agree to adhere to the trial protocol amendment and to all documents referenced in the trial protocol amendment. Name: Affiliation: Date: 2 ~ ~ !) - It - Z 1 Proprietary confidential information. © 2010 Boehringer lngelbeim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not- in full or in part · be passed on, reproduced 1 published or othe1wise used without prior written pernlission. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 327 U12-2466-01 Boehringer lngelheim BI Trial No.: 205.418 Protocol Loca l Amendment I USA Filla/, 17 Nov 2010 Page 4 of9 SIGNATURES (PRINCIPAL INVESTIGATOR OF SITE AND CLINICAL MONITOR LOCAL) Clinical Monitor Local: Full name Clinical Research - Respiratory Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877, USA I herewith certify that I agree to adhere to the trial protocol amendment and to all documents referenced in the trial pr otocol amendment. Principal Investigator (site): Date Name Full name Organisation/Department Proprietary confidential informaticm. © 2010 Boehringer lngelhcim International GmbH or one or more of its affiliated companies. All rights reserved. This documenl may noc · in full or in pari - be passed on. reproduced, published or otherwise nscd wilhoul prior wriuen permission Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehringer lngelheim BI Trial No.: 205.418 Protocol Local Amendment 1 USA Change 1: Page 328 U12-2466-01 Filla/, 17 Nov 2010 Page 5 of9 Additional instructions regarding trial medication administration. Section 4.1.4 Drug assignment and administration of doses for each patient. Instructing the patient. Patients who miss a dose should be instructed to take the next dose at the next scheduled time. Was changed to: If the patient forgot to take the evening dose of patient's own ICS, LTRA (if applicable) and trial medication within the specified time window, the patient is allowed to administer the evening dose until 12.00 pm (midnight). After 12.00 pm the patient should skip the evening dose and take the next dose in the morning at the scheduled time. The evening dose on the day before the clinic visit should be taken at the specified time window to avoid influence on the data collected on the clinic visit day. If the patient took the evening dose after 8 pm on the day before the clinic visit, the clinic visit should be re-scheduled. If the patient forgot to take the morning dose of patient's own ICS, LTRA (if applicable) and trial medication (MDI only) within the specified time window, the patient is allowed to administer the morning dose until 12.00 am (noon). After 12.00 am the patient should skip the morning dose and take the next dose in the evening at the scheduled time. The morning dose on the day of the clinic visit should be taken at the specified time to avoid influence on the data collected on the clinic visit day. If the patient took the morning dose (at home) after 8 am on the day of the clinic visit, the clinic visit should be re-scheduled. Reason for Change I : Time windows for medication administration at home in case a patient missed a dose are changed to increase patient treatment compliance. Change 2: Change in time windows for eDiary use at home in the evenings and mornings in case the patient forgot to use the eDiary. Section 5.1.2 Electronic peak flow meter with electronic diary (Asthma Monitor"'' AM3) Morning and evening recordings and measurements should be performed at approximately the same time of the day(± 30 minutes) between 6:00 and 08:00am and 6:00 and 08.00 pm, respectively. Was changed to: Morning and evening recordings and measurements should be performed at approximately the same time of the day(± 30 minutes) between 6:00 and 08:00am and 6:00 and 08.00 pm, respectively. An alarm will sound at 8:00 and 8:30am and pm to remind the patient to use the Proprietary confidential information. © 2010 Boehringer lngclbeirn International GmbH or one or more of its affiliated companies. All rights reserved. This documcnl may nor -in full or in part - be pussed on. reproduced. published or otherwise used wilhoul prior \Willen permission. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boelu·inge•· lngelheim BI Trial No.: 205.418 P.-otocol Local Amendment I USA Page 329 U12-2466-01 Fi11al, 17 Nov 2010 Page 6 of9 AM3. When the patient forgot to use the AM3 between 06:00 and 08:00, the patient should be instructed to use the AM3 if it is still before II :59 (am or pm). Reason for Change 2: To add instructions in case a patient forgot to use the Asthma Monitor®AM3 within the specified time window. Change 3: Change in the maximum number of attempts for Pulmonary Function Testing Section 5.I.2 Pulmonary Function Testing (PFT) on study visits The best of three efforts will be defined as the highest FEV 1, the highest FV C and the highest PEF each obtained on any of three blows meeting the ATS criteria (with a maximum of five attempts). Was changed to: The best of three efforts will be defined as the highest FEV 1, the highest FVC and the highest PEF each obtained on any of three blows meeting the ATS criteria (with preferably a maximum of five manoeuvres: however, a maximum of eight manoeuvres would be acceptable). Reason for Change 3: To be consistent with the ATS/ERS criteria and with other studies within the same project (Tiotropium in Asthma). Change4: Extension of time window for reversibility testing. Change 4.1: Footnote #I 3 for Flow Chatt I 0 minutes pre- and 15 minutes post-bronchodilator PFT after inhalation of 4 puffs (I 00 pg/puff) salbutamol/albuterol. 1-Vas changed to: I 0 minutes pre- and I 5 to 30 minutes post-bronchodilator PFT after inhalation of 4 puffs (I 00 pg/puff) salbutamol/albuterol. Change 4.2: Section 3.3.2. Inclusion criterion 5 Proprietary confidentia l information. © 2010 Boeh ringer Jngelheim Internat ional GmbH or one or more of its a ffiliated compa nies. All rights r eserved. This document may not - in full or in pnrt • be passed on. reproduced. published or otherwise used without prior written pcnnission. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boehl"inger lngelheim Bl Trial No.: 205.418 Protocol Local Amendment 1 USA Page 330 U12-2466-01 Fi11nl, 17 Nov 2010 Page 7 of9 The diagnosis of asthma has to be confirmed at Visit I with a bronchodilator reversibility (IS minutes after 400 ).lg salbutamol (albuterol)) resulting in a FEV 1 increase of~ 12% and~ 200mL Was changed to: The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility ( 1S to 30 minutes after 400 ).lg salbutamol (albuterol)) resulting in a FEV 1 increase of:;: 12% and ~200mL Change4.3: Section 6.2.1 Observations and procedures at visit 1 Pulmonary function testing with the MasterScope® CT spirometer will be conducted in the evening between 06.00 and 08.00 pm immediately prior to (-10 min) and 1S minutes after the inhalation of 4 puffs of salbutamol (albutcrol). Was changed to: Pulmonary function testing with the MasterScope® CT spirometer will be conducted in the evening between 06.00 and 08.00 pm immediately prior to (-10 min) and 15 to 30 minutes after the inhalation of 4 puffs of salbutamol (albuterol). Change 4.4: Appendix 10.4 Additional information regarding in/ex criteria- Reversibility testing Three additional, acceptable post-bronchodilator forced expiratory manoeuvre tests are recorded~ I 0 min and up to IS min later after the last dose of salbutamol (albuterol) is inhaled. Was changed to: Three additional, acceptable post-bronchodilator forced expiratory manoeuvre tests are recorded ~ I 0 min and up to 30 min later after the last dose of salbutamol (albuterol) is inhaled. Reason for Change 4.1 to 4.4: To allow patients who reverse after 30 minutes to pa11icipate in the study. Change 5: the USA. Use of central laboratory for testing of safety parameters for study sites in Change 5.1 : Footnote #4 for Flow Chart Proprietary confidential information. © 2010 Boehringer lngelheim International GmbH or one or more of its nffillated companies. All rights reserved. This document may not ·in full or in part · be passed 011, reproduced, published or otherwise used without prior written permission. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boeh•·inger Jngelheim BI Trial No.: 205.418 Protocol Local Amendment 1 USA Page 331 U12-2466-01 Fi11al, 17 Nov 2010 PageS of9 Haematology and blood chemistry (local laboratory). Was changed to: Haematology and blood chemistry (local laboratory). Central laboratory will be used for study sites in the USA. Change 5.2: Section 3.1 Overall Trial Design and Plan Analysis of clinical laboratory samples will be performed by the local laboratory of each site. Was changed to: Analysis of clinical laboratory samples will be performed by the local laboratory (central laboratory for the study sites in the USA) of each site. Change5.3: Section 5.2.3 Assessment of safety laboratory parameters: Clinical laboratory testing Lab parameters will be analysed by the local laboratory of each participating site. Was changed to: Lab parameters will be analysed by the local laboratory of each participating site (study sites in the USA will use a central laboratory). Change 5.4: Section 6.2.1: Screening and run-in period(s), Observations and procedures at Visit 1 Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. Was changed to: Blood samples will be collected and submitted to the site's local laboratory (central laboratory for study sites in the USA) for haematology and serum chemistry. Change 5.5: Section 6.2.2: Treatment periods, Observations and Procedures at Visit 6 Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. Was changed to: Proprietary confidential informa tion. © 2010 Boehringer lngelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not · in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Boeh•·inge•· Ingclheim BI Trial No.: 205.418 Protocol Local Amendment 1 USA Page 332 U12-2466-01 Finfll, 17 Nov 2010 Page 9 of9 Blood samples will be collected and submitted to the site's local laboratory (central laboratory for study sites in the USA) for haematology and serum chemistry. Change5.6: Section 6.2.3: End of trial and follow-up period, Observations and Procedures in case of premature withdrawal Blood samples will be collected and submitted to the site' s local laboratory for haematology and serum chemistry. Was changed to: Blood samples will be collected and submitted to the site' s local laboratory (central laboratory for study sites in the USA) for haematology and serum chemistry. Change5.7: Section 10.11 CLINICAL LAB PARAMETERS Lab parameters will be analysed by the local laboratory of each participating site. Lab samples may be stored overnight. The local lab should be contacted to discuss the required overnight storage conditions (fridge or room temperature). Was changed to: Lab parameters will be analysed by the local laboratory (central laboratory for study sites in the USA) of each participating site. Lab samples may be stored overnight. The local lab (central lab for study sites in the USA) should be contacted to discuss the required overnight storage conditions (fridge or room temperature). Reason for Change 5.1 to 5.7: For logistical reasons, a central laboratory (located in the USA) is used to analyse safety laboratory parameters for study sites in the USA. Proprietary confi dential information. © 2010 Boehringer lngelheim lnternational Gmb l~ or one or more of its a ffiliated co111panies. All rights reserved. This document may not · in full or in part· be passed on. reproduced, puhlished or otherwise used without prior written permission Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Page 333 U12-2466-01 Page 16.1.1.3 List of participating Operative Units ................................................................. 333 List of participating Operative Units .......................................................................... 334 Boehringer Ingelheim BI Trial No.: 205.418 16.1.1 Protocol and amendments Operative Unit Boehringer Ingelheim RCV GmbH & Co KG Boehringer Ingelheim India Pvt. Ltd. Nippon Boehringer Ingelheim Co.,Ltd. Boehringer Ingelheim International Trading (Shanghai) Co., Ltd. Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim do Brasil 334 Page U12-2466-01 Address Division Medicine/Department of Clinical Development Dr. Boehringer Gasse 5-11 1121 Wien Austria 1102, Hallmark Business Plaza, Guru Nanak Hospital Road Mumbai Mumbai - 400 051 India Osaki 2-1-1 ThinkPark Tower Tokyo 141-6017 Japan Medical Department 29F, Park Place, No.1601, Nanjing Road (West) Shanghai 200040 China 900 Ridgebury Road Ridgefield 06877 United States of America Av. das Nações Unidas, 14.171 - 18º Andar Sao Paulo 04795-100 Brazil Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Page 3 U12-2467-02 Clinical Trial Protocol Doc. No.: U10-1635-01 EudraCT No.: 2009-018005-43 BI Trial No.: 205.419 BI Investigational Product(s): Tiotropium bromide Inhalation Solution Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Clinical Phase: III Trial Clinical Monitor: Boehringer Ingelheim bv, Medical department Comeniusstraat 6, 1817 MS Alkmaar, The Netherlands Phone: Fax: , MD Co-ordinating Investigator: The Netherlands Phone: Status, Version, and Date of Protocol: , Fax: Final Protocol, Version 1.0, 21 April 2010 Page 1 of 137 Proprietary confidential information. © 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. TITLE PAGE Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 4 U12-2467-02 21 Apr 2010 Page 2 of 137 Trial Protocol CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.419 I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Name: , MD Signature:__________________________ Signed signature page is located in the electronic Clinical Trial Master File Affiliation: Date: The Netherlands ___________________________ Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 5 Page U12-2467-02 21 Apr 2010 Page 3 of 137 Trial Protocol LOCAL SIGNATURES (PRINCIPAL INVESTIGATOR OF SITE AND LOCAL CLINICAL MONITOR (CML)) Local Clinical Monitor <optional, delete if not applicable>: Date Name Full name Organisation/Department <Add other signatories if applicable.> I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Principal Investigator (site): Date Name Full name Organisation/Department Signed signature page is located in the electronic Clinical Trial Master File Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Page 6 U12-2467-02 Boehringer Ingelheim BI Trial No.: 205.419 Trial Protocol 21 Apr 2010 Page 4 of 137 CLINICAL TRIAL PROTOCOL SYNOPSIS Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 21 April 2010 Title of trial: Trial number: 205.419 Revision date: A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma , MD, Co-ordinating Investigator : , The Netherlands Trial site(s) : Multi-centre, Multi-national Clinical phase: III Objective(s): Evaluate the long term efficacy and safety of tiotropium (2.5 and 5 µg once daily administered in the evening) inhalation solution delivered by the Respimat® inhaler compared to placebo and salmeterol (administered twice daily) in patients with moderate persistent asthma Methodology: Randomised, double-blind, placebo- and active-controlled, parallel-group design comparing tiotropium versus placebo and salmeterol over 24 weeks on top of maintenance therapy with an inhaled corticosteroid controller medication No. of patients: total entered: 1000 each treatment: 250 Diagnosis : Asthma Main criteria for inclusion: Outpatients of either sex, age 18 - 75 years, never-smokers or ex-smokers with < 10 pack years and smoking cessation at least one year prior to enrolment. Patients must have at least a 3-month history of asthma that was diagnosed before the age of 40, and a current diagnosis of moderate persistent asthma (according to GINA guideline). Patients need to be still symptomatic, i.e. not fully controlled with their current maintenance treatment (assessed by ACQ mean score and pulmonary lung function tests). Maintenance treatment with medium dose of inhaled corticosteroids (Appendix 10.4) is required. Test products : Tiotropium inhalation solution 2.5µg (2 actuations of 1.25 µg) and 5 µg (2 actuations of 2.5 µg) once daily in the evening mode of admin. : Oral inhalation via Respimat® inhaler dose: Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 7 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 5 of 137 Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 21 April 2010 Trial number: 205.419 Revision date: Comparator product 1: Salmeterol hydrofluoroalkane (HFA 134a) metered dose inhaler (MDI) dose: 50 µg (2 actuations of 25 µg per actuations) twice daily (morning and evening) mode of admin. : Oral inhalation from HFA MDI Comparator product 2: Placebo inhalation solution dose: Not applicable mode of admin. : Oral inhalation via Respimat® inhaler Comparator product 3: Placebo MDI dose: Not applicable mode of admin. : Oral inhalation via HFA MDI Duration of treatment: 24 weeks Criteria for efficacy: Co-primary endpoints: peak FEV1 response (within 3 hours post evening dosing) and trough FEV1 response after 24 weeks treatment Secondary endpoints: Peak FVC; trough FVC; FEV1 (AUC0-3h); FVC (AUC0-3h); individual in-clinic FEV1/FVC/PEF measurements; Asthma Quality of Life Questionnaire (AQLQ (S)); Home assessment: PEF am/pm (last weekly mean of treatment period), use of PRN rescue medication; daytime and nocturnal symptoms; asthma symptom free days. In a subset of patients: FEV1 (AUC0-12h), FEV1 (AUC1224h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h) Other endpoints: Home assessments during treatment period PEF am/pm; FEV1 am/pm; PEF variability Meta-analysis on combined data from the two twin trials 205.418 and 205.419. Primary endpoint: Control of asthma (Asthma Control Questionnaire) after 24 weeks treatment. Secondary endpoints: time to first exacerbation; time to first severe asthma exacerbation. ACQ at each visit. Criteria for pharmacokinetics: Plasma and urine samples for the quantification of tiotropium will be obtained in a subset of patients following the administration of the first dose and following administration of tiotropium for 4 weeks (i.e., at steady state). Additionally, a predose and 5 minute post-dose blood sample will be obtained on study days 7, 14 and 21 to confirm the achievement of steady-state. Enough patients will be included in this subset to ensure at least 80 patients will complete the PK sampling visits. Criteria for health economics: Health care resource utilisation (HCRU) and Quality of Life assessed by EQ-5D Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 8 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 6 of 137 Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 21 April 2010 Trial number: 205.419 Revision date: Criteria for pharmacogenomics: Unspecified pharmacogenetic testing Criteria for safety: Adverse events, vital signs, vital status information Statistical methods: For the two co-primary FEV1 endpoints: restricted maximum likelihood (REML)based mixed effects model with repeated measures (MMRM) with terms for treatment, investigative site, visit, and treatment by visit interaction as fixed categorical effects, and baseline and fixed covariates baseline by visit interaction. The comparisons with salmeterol are not part of the inferential analysis. Standard statistical parameters (number of non-missing values, mean, standard deviation (SD), median, quartiles, minimum, and maximum) or frequency tables will be calculated where appropriate for all parameters. Meta analysis: primary endpoint (ACQ): pooled analysis of the twin trials with trial numbers 205.418 and 205.419. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 9 Page U12-2467-02 21 Apr 2010 Page 7 of 137 Trial Protocol FLOW CHART Trial periods Treatment* Screening Visit 0 1 2 Week Day Time window** - -4 -28 ±4 0 1 Informed consent1 Instruct patient on washout/restrictions1 Demographics Medical History/Baseline conditions2 Physical examination (incl. vital signs) Review smoking status ECG, laboratory and pregnancy test4 Inclusion/exclusion criteria Dispense rescue medication Respimat® training Randomisation Dispense trial medication Administration of trial medication in clinic5 Collect trial medication Drug accountability Blood sample for pharmacogenetics6 Pharmacokinetic sampling7 Training eDiary with PEF-meter Issue eDiary with PEF-meter Download eDiary with PEF-meter Collect eDiary with PEF-meter Issue paper diary card Review/collect paper diary card ACQ9 AQLQ (S)9 EQ-5D9 Review exacerbation and HCRU Medication washout check11 Pulmonary function test12 Vital signs (seated) Adverse events Concomitant therapy Termination of trial medication Completion of trial X X X X X X X X X X X X * ** X1 X X X X X X10 X X13 X X 2A7 2B7 2C7 3 4 5 6 7 7 ±1 14 ±1 21 ±1 4 28 ±2 8 56 ±2 16 112 ±4 24 168 ±4 27 189 ± 4 X X X X X X X X3 X3 X3 X X X X X X 16 Follow up X X X X X X 16 X X X X X X X X X X X X X X X X X X X X X X X X3 X3 X3, 8 X3 X8 X8 X8 X X X10 X X X X X14 X15 X X X X X X X X X X14 X15 X X X X X X X X X X14 X15 X X X X X X X X X X14 X15 X X X X X X X X X X X16 X X8 X X X3 X X X X X X14 X15 X3 X3 X3 Visit 0 and 7 may be conducted during business hours. Visits 1 to 6 will allways start in the evening. Each Respimat® inhaler and MDI contains drug supply for 30 days which must be obeyed regarding visit flexibility after randomisation. X X X Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 10 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 8 of 137 All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions (see Section 4.2.2). A separate consent for pharmacokinetic sampling should be signed if patients are participating in the pharmacokinetic substudy. A separate consent for pharmacogenetic sampling should be signed if patients are participating in the pharmacogenetic substudy. The interval between Visit 0 and Visit 1 may be between 1 and 28 days depending on medication washout requirements and restrictions. A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid unnecessary washout procedures in non-eligible patients. Including asthma background characteristics. To be completed by all patients who took at least one dose of trial medication including those who discontinue early. Vital status information has to be collected on the originally planned follow up visit date (Visit 7). Haematology and blood chemistry (local laboratory). White bloodcell count, eosinophil count (absolute and relative), total serum IgE and creatinine levels will be documented in eCRF at Visit 1. Urine pregnancy test required for all women of child-bearing potential. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI, 3. trial medication from assigned Respimat®. Patient’s ICS should be administered without change in posology (bid/qd; am/pm), i.e. as prescribed by patient’s treating physician prior to trial entry. Blood sample for pharmacogenetics will be drawn from all randomised patients that received at least one dose of trial medication and that gave a separate informed consent. Participation in the pharmacogenetic subset is not a pre-requisite for participation in the trial. The blood sample will be drawn at preferably Visit 2 or at any other subsequent visit after randomisation. PK in a subset of patients at selected sites (separate informed consent should be obtained first). e-Diary compliance check (see Section 4.3 and Section 6.1). First ACQ, then AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. ACQ at screening will be used for assessment of degree of asthma control. If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). Refer to Section 4.2.2.1. Pre-bronchodilator FEV1 at Visit 1 and pre-dose FEV1 at Visit 2 must be within ± 30% variation prior to randomisation based on absolute FEV1 values. If the variation of FEV1 in the screening period exceeds ± 30%, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). 10 minutes pre- and 15 minutes post-bronchodilator PFT after inhalation of 4 puffs (100 µg/puff) salbutamol/albuterol. 10 minutes prior to trial drug administration (pre-dose) and until 3 hours post-dose. In a subgroup of patients at selected sites at Visit 6: 10 minutes prior to trial drug administration and until 24 hours post-dose. In conjunction with pulmonary function testing until 3 hours post-dose (measured immediately before PFT). Rescue medication only. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 11 Page U12-2467-02 21 Apr 2010 Page 9 of 137 Trial Protocol TIMING OF TRIAL PROCEDURES DURING THE TREATMENT PERIOD 3 hour pulmonary function test without pharmacokinetic sampling1 Timing related to evening inhalation of study drug -1h -30’ -15’ -10’ Administer patient’s usual ICS medication followed by trial medication2 0 30’ 1h 2h 3h X AM3 Å ------ Æ Patient self-administration of questionnaires3 Å -------------- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X 1 Order of procedures if performed at the same time point: - Vital signs followed by pulmonary function testing - Use of AM3 device followed by filling out questionnaires Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat®). ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. 2 3 Pharmacokinetic plasma sampling at Visits 2A (day 7), 2B (day 14), and 2C (day 21)1 Timing related to evening inhalation of study drug -1h -30’ -15’ 0 5’ Administer patient’s usual ICS medication followed by trial medication2 Å --------------------- Æ AM3 PK plasma sampling 1 2 X X X At selected sites only. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat®). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments 12 Page U12-2467-02 Boehringer Ingelheim BI Trial No.: 205.419 21 Apr 2010 Page 10 of 137 Trial Protocol 3 hour pulmonary function test with 24 hour pharmacokinetic sampling at Visit 2 and Visit 31, 2 Timing related to evening inhalation of study drug -1h Administer patient’s usual evening ICS medication followed by trial medication3 Administer patient’s usual morning ICS medication followed by trial medication4 AM3 Patient self-administration of questionnaires6 PK plasma sampling PK urine collection 1 2 3 4 5 6 7 8 9 7 -30' -15' -10' 0 2' 5' 7' 10' 15' 30' 1h 2h 3h 6h 12h 24h8,9 X X X5 Å ----- Æ Å -------------- Æ X X Å ----------------------- Æ X X X X X X Å ---------------------------------------------------- Æ X X Å --- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X X X Å --------------- Æ Order of procedures if performed at the same time point: - PK plasma sampling (as close to planned time point as possible!), vital signs and pulmonary function testing - Use of AM3 device followed by filling out questionnaires At selected sites only. Patients may stay overnight. Refer to Section 5.5.2 for more information. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat ®). Morning trial drug administration will occur between 06.00 and 08.00 am and 12 hours (± 5 minutes) after the time of the pm administration. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI. Patient should use AM3 device immediately upon arising and prior to inhalation of medication. ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. Patients must empty bladder at the end of each urine collection interval. All urine voided during the sampling intervals -1 to 0 pre-dose and 0 to 2, 2 to 6 and 6 to 24 hours post-dose will be collected in containers. Patients should continue urine collection at home. Urine fraction must be kept cold at all times. Patient should return 30 minutes prior to last PK sample. Refer to Section 5.5.2 and Investigator Site File (ISF) chapter 10 for instructions. PK blood sample should be collected 15 minutes prior to the administration of next dose ICS and trial medication, i.e., at time point 23:45. Patients must void urinary bladder into the 6-24 container up to 5 minutes prior to the inhalation of the next day ICS and tiotropium doses (i.e., up to 23:55 hours after last dosing). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments 13 Page U12-2467-02 Boehringer Ingelheim BI Trial No.: 205.419 21 Apr 2010 Page 11 of 137 Trial Protocol 24 hour pulmonary function test after 24 weeks (Visit 6)1, 2 Timing related to evening inhalation of study drug -1h -30' -15' -10' 0 30' 1h 2h 3h 4h 11h10' 11h50' 12h 12h30' 13h 14h 15h 16h 18h 20h 22h 23h 23h50' Administer patient’s usual evening ICS medication followed by trial medication3 Administer patient’s usual morning ICS medication followed by trial medication4 AM3 Patient self-administration of questionnaires6 1 2 3 4 5 6 X X X5 Å -Æ Å -------- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X X X X X X X X X X X X X Order of procedures if performed at the same time point: - Vital signs followed by pulmonary function testing - Use of AM3 device followed by filling out questionnaires At selected sites only. Requires overnight stay. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat ®). Morning trial drug administration will occur between 06.00 and 08.00 am and 12 hours (± 5 minutes) after the time of the pm administration. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI. Patient should be woken 40 minutes (± 10 minutes) prior to the start of the initial morning PFT (11h50’ time point). Patient should use AM3 device immediately upon arising and prior to inhalation of medication. ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 14 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 12 of 137 TABLE OF CONTENTS TITLE PAGE ...................................................................................................... 1 CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................ 4 FLOW CHART ................................................................................................... 7 TABLE OF CONTENTS ................................................................................. 12 ABBREVIATIONS ........................................................................................... 16 1. INTRODUCTION................................................................................ 20 1.1 MEDICAL BACKGROUND ............................................................................ 20 1.2 DRUG PROFILE ............................................................................................... 21 1.2.1 Inhalation solution and Respimat® Inhaler ................................................ 25 2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT ..................................................................................... 26 2.1 2.2 2.3 3. RATIONALE FOR PERFORMING THE TRIAL ........................................ 26 TRIAL OBJECTIVES ....................................................................................... 27 BENEFIT - RISK ASSESSMENT.................................................................... 27 DESCRIPTION OF DESIGN AND TRIAL POPULATION.......... 29 3.1 OVERALL TRIAL DESIGN AND PLAN ...................................................... 29 3.1.1 Administrative structure of the trial ........................................................... 30 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S) ..................................................................................... 31 3.3 SELECTION OF TRIAL POPULATION ...................................................... 31 3.3.1 Main diagnosis for study entry .................................................................... 32 3.3.2 Inclusion criteria............................................................................................ 32 3.3.3 Exclusion criteria ........................................................................................... 33 3.3.4 Removal of patients from therapy or assessments ..................................... 36 3.3.4.1 Removal of individual patients ................................................................... 36 3.3.4.2 Discontinuation of the trial by the sponsor ................................................. 37 4. TREATMENTS .................................................................................... 38 4.1 TREATMENTS TO BE ADMINISTERED .................................................... 38 4.1.1 Identity of BI investigational product and comparator product(s) .......... 38 4.1.2 Method of assigning patients to treatment groups ..................................... 39 4.1.3 Selection of doses in the trial ........................................................................ 40 4.1.4 Drug assignment and administration of doses for each patient ................ 40 4.1.5 Blinding and procedures for unblinding ..................................................... 43 4.1.5.1 Blinding ...................................................................................................... 43 4.1.5.2 Procedures for emergency unblinding ........................................................ 43 4.1.6 Packaging, labelling, and re-supply ............................................................. 43 4.1.7 Storage conditions ......................................................................................... 45 4.1.8 Drug accountability ....................................................................................... 46 4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT .................................................................................................... 47 4.2.1 Rescue medication, emergency procedures, and additional treatment(s) 47 4.2.1.1 Rescue medication ...................................................................................... 47 4.2.1.2 Emergency procedures ............................................................................... 48 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 15 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 13 of 137 4.2.1.3 Additional treatments ................................................................................. 48 4.2.2 Restrictions..................................................................................................... 49 4.2.2.1 Restrictions regarding concomitant treatment ............................................ 49 4.2.2.2 Restrictions on diet and life style ............................................................... 53 4.3 TREATMENT COMPLIANCE ....................................................................... 53 5. VARIABLES AND THEIR ASSESSMENT ..................................... 55 5.1 EFFICACY - CLINICAL PHARMACODYNAMICS ................................... 55 5.1.1 Endpoint(s) of efficacy .................................................................................. 55 5.1.1.1 Primary Endpoints ...................................................................................... 55 5.1.1.2 Secondary Endpoints .................................................................................. 55 5.1.1.3 Other Endpoints .......................................................................................... 57 5.1.2 Assessment of efficacy ................................................................................... 57 5.2 SAFETY .............................................................................................................. 62 5.2.1 Endpoint(s) of safety ..................................................................................... 62 5.2.2 Assessment of adverse events ....................................................................... 62 5.2.2.1 Definitions of adverse events ..................................................................... 62 5.2.2.2 Adverse event and serious adverse event reporting.................................... 63 5.2.3 Assessment of safety laboratory parameters .............................................. 65 5.2.4 Electrocardiogram......................................................................................... 65 5.2.5 Assessment of other safety parameters ....................................................... 65 5.3 OTHER ............................................................................................................... 66 5.3.1 Other endpoints ............................................................................................. 66 5.3.2 Other assessments.......................................................................................... 66 5.3.3 Pharmacogenetic evaluation......................................................................... 67 5.3.3.1 Methods of sample collection ..................................................................... 67 5.3.3.2 Analytical determinations ........................................................................... 68 5.4 APPROPRIATENESS OF MEASUREMENTS ............................................. 68 5.5 DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS .................................................................................. 68 5.5.1 Pharmacokinetic endpoint(s)........................................................................ 68 5.5.2 Methods of sample collection........................................................................ 70 5.5.3 Analytical determinations............................................................................. 72 5.6 BIOMARKER(S) ............................................................................................... 72 5.7 PHARMACODYNAMICS ................................................................................ 72 5.8 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP...... 72 6. INVESTIGATIONAL PLAN ............................................................. 73 6.1 VISIT SCHEDULE ............................................................................................ 73 6.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................ 75 6.2.1 Screening and run-in period(s) .................................................................... 75 6.2.2 Treatment period(s) ...................................................................................... 76 6.2.3 End of trial and follow-up period ................................................................ 80 7. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................................................................................... 82 7.1 7.2 7.3 STATISTICAL DESIGN - MODEL ................................................................ 82 NULL AND ALTERNATIVE HYPOTHESES .............................................. 83 PLANNED ANALYSES .................................................................................... 85 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 16 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 14 of 137 7.3.1 Primary analyses ........................................................................................... 85 7.3.2 Secondary analyses ........................................................................................ 86 7.3.3 Safety analyses ............................................................................................... 87 7.3.4 Interim analyses............................................................................................. 88 7.3.5 Pharmacokinetic analyses ............................................................................. 88 7.3.6 Pharmacodynamic analyses.......................................................................... 88 7.3.7 Pharmacogenetic analyses ............................................................................ 88 7.3.8 Health economic analyses ............................................................................. 88 7.4 HANDLING OF MISSING DATA .................................................................. 88 7.5 RANDOMISATION .......................................................................................... 89 7.6 DETERMINATION OF SAMPLE SIZE ........................................................ 89 8. INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS ............................................................................................ 92 8.1 8.2 8.3 8.3.1 8.3.2 8.3.3 8.4 8.4.1 8.4.2 8.5 8.6 8.7 8.8 9. STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT .......................................................................................................... 92 DATA QUALITY ASSURANCE ..................................................................... 94 RECORDS .......................................................................................................... 94 Source documents .......................................................................................... 94 Direct access to source data and documents ............................................... 94 Storage of records .......................................................................................... 95 LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS .............................................................................................................................. 95 Listedness ....................................................................................................... 95 Expedited reporting to health authorities and IECs/IRBs ........................ 95 STATEMENT OF CONFIDENTIALITY ....................................................... 95 COMPLETION OF TRIAL .............................................................................. 96 PROTOCOL VIOLATIONS ............................................................................ 96 COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL RELATED INJURY............................................................................. 96 REFERENCES ..................................................................................... 97 9.1 9.2 10. 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 10.12 PUBLISHED REFERENCES ........................................................................... 97 UNPUBLISHED REFERENCES ..................................................................... 99 APPENDICES .................................................................................... 101 INSTRUCTIONS FOR THE USE OF THE RESPIMAT INHALER ........ 102 INSTRUCTIONS FOR THE USE OF THE MDI ........................................ 108 INSTRUCTIONS FOR RETURN OF MALFUNCTIONING RESPIMAT INHALERS ....................................................................................................... 110 ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA ........ 111 ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S)) ............. 113 ASTHMA CONTROL QUESTIONNAIRE (ACQ) ..................................... 119 EQ-5D HEALTH QUESTIONNAIRE........................................................... 122 PAPER PATIENT DIARY CARD ................................................................. 125 AM3 PATIENT INSTRUCTION CARD ...................................................... 126 DEFINITION ASTHMA EXACERBATION ............................................... 130 CLINICAL LAB PARAMETERS ................................................................. 132 PHARMACOKINETIC METHODS ............................................................. 133 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 17 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 15 of 137 10.12.1 Planned analyses for pharmacokinetic evaluations ................................. 133 10.12.2 Handling of missing data ............................................................................ 133 10.12.3 Derivation of PK parameters ..................................................................... 134 11. SUMMARY OF CLINICAL TRIAL PROTOCOL MODIFICATIONS ............................................................................ 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 18 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 16 of 137 ABBREVIATIONS °C °F µg ACQ ACRN Ae AE Aet1-t2,ss Degree Celsius Ddegree Fahrenheit Microgram Asthma Control Questionnaire Asthma Clinical Research Network Amount of analyte that is eliminated in urine Adverse Event Amount of analyte that is eliminated in urine from the time point t1 to time point t2 (Ae0-2, Ae2-6 at steady state) am Ante meridiem AM3 Asthma Monitor® 3 ANCOVA Analysis of Variance AQLQ(S) Standardised Asthma Quality of Life Questionnaire ATS American Thoracic Society AUC Area under the curve Area under the plasma concentration-time curve at steady AUCτ,ss state over a uniform dosing interval τ at steady state AUCt1-t2,ss Area under the concentration time curve of analyte in plasma over the time interval t1 to t2 at steady state Area under the first moment curve at steady state AUMCss b.i.d. Bis in die (twice daily) BAC Benzalkonium chloride BARGE trial Beta-Adrenergic Response by Genotype trial BDI Baseline Dyspnoea Index BI Boehringer Ingelheim BLQ Below the limit of quantification CA Competent Authority CCDS Company Core Data Sheet CFC Chlorofluorocarbon CL/F,ss Apparent clearance of analyte in the plasma after extravascular administration CLR,t1-t1 Renal clearance of analyte in plasma from the time point t1 to time point t2 Cmax [pg/mL] Maximum measured concentration of the analyte in plasma Cmax,ss Maximum measured concentration of analyte in plasma at steady state Cmin,ss Minimum concentration of analyte in plasma at steady state CML Clinical Monitor Local COPD Chronic obstructive pulmonary disease Cpre,ss Predose concentration of analyte in plasma at steady state CRA Clinical Research Assistant/Associate CRO Contract Research Organisation CTMF Clinical Trial Master File CTP Clinical Trial Protocol Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 CTR CVA CZ DNA DPI DSMB ECG eCRF ECSC EDC EDTA EEC EQ-5D ERS EU FAS FDA fet1-t2 FEV1 [L] FVC [L] GCP gCV GINA gMean h HCRU HFA HPLC/MS/MS ICH ICS IEC IgE INN IRB ISF IVRS IWRS kg L LABA LARGE trial LDH LI LOCF 19 Page U12-2467-02 Trial Protocol Clinical Trial Report Cerebrovasculair accident Climate Zone Deoxyribonucleic acid Dry powder inhaler Drug safety monitoring board Electrocardiogram Electronic Case Report Form European Community for Steel and Coal Electronic Data Capture Ethylenediaminetetraacetic acid European Economic Community Quality of life questionnaire developed by EuroQol group European Respiratory Society European Union Full Analysis Set Food and Drug Administration Fraction of analyte eliminated in urine from time point t1 to time point t2 Forced expiratory volume in one second Forced vital capacity Good Clinical Practice Geometric coefficient of variation Global Initiative for Asthma Geometric mean Hour(s) Health Care Resource Utilization Hydrofluororalkane High Performance Liquid Chromatography/ Mass Spectrometry/Mass Spectrometry International Conference on Harmonisation Inhaled CorticoSteroids Independent Ethics Committee Immunoglobulin E International Non-proprietary Name Institutional review board Investigator Site File Interactive Voice Response System Interactive Web Response System Kilogram Litre(s) Long-acting beta-adrenergic Long-Acting Beta Agonist Response by Genotype trial Lactate dehydrogenase Lineary Index Last observation carried forward 21 Apr 2010 Page 17 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 LTRA max MCID MD MDI MedDRA mg min mL MMRM MRTih NA NC nnACh No. NOA NOP NOR NOS OPU PEF(R) [L/sec] PFT pg PK pm pMDI PRN q.d. RA REML ROW SABA SAE SD SGOT SGPT SNP SOMS SOP SPC SUSAR T, t [h or min] t.b.d. t½,ss t1/2 TCM 20 Page U12-2467-02 Trial Protocol Leukotriene Receptor Antagonist (leukotriene modifier) Maximal Minimum clinically important difference Multiple dose Metered dose inhaler Medical Dictionary for Regulatory Activities Milligram Minimal; minute Millilitre(s) Mixed effect model with repeated measures mean residence time of analyte in the body after inhalation Not applicable Not calculated Non-neuronal acetylcholine Number Not analysed No peak detectable No valid result No sample Operative Unit (of BI) Peak expiratory flow (rate) Pulmonary function test Picogram Pharmacokinetic(s) Post meridiem Pressurized Metered Dose Inhaler As occasion requires Quaque die (once daily) Accumulation ratio Restricted maximum likelihood Rest of World Short-acting beta-adrenergic Serious Adverse Event Standard deviation or single dose Serum glutamic oxaloacetic transaminase Serum glutamic pyruvic transaminase Single nucleotide polymorphisms Summary of Clinical Trial Protocol Modifications Sheet Standard Operating Procedure Summary of product characteristics Suspected Unexpected Serious Adverse Reaction Time To be determined Terminal half-life of analyte in plasma at steady state Terminal half-life of analyte in plasma Trial Clinical Monitor 21 Apr 2010 Page 18 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 TDMAP TinA tmax tmax,ss TNF TSAP USA USPI Vz/F γ-GT 21 Page U12-2467-02 Trial Protocol Trial data management and analysis plan Tiotropium in Asthma Time from dosing to the maximum concentration of the analyte in plasma Time from dosing to the maximum concentration of analyte in plasma at steady state Tumor Necrosis Factor Trial Statistical Analysis Plan United States of America US prescribing information Apparent volume of distribution of analyte during the terminal phase following an extravascular dose Gamma glutamyltransferase 21 Apr 2010 Page 19 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 22 Page U12-2467-02 Trial Protocol 1. INTRODUCTION 1.1 MEDICAL BACKGROUND 21 Apr 2010 Page 20 of 137 Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular products play a role. The overall worldwide prevalence of asthma is about 5%, affecting 300 million people worldwide with over 60 million affected in the United States and Europe and high variability from country to country. Researchers estimate that an additional 100 to 150 million persons are likely to have asthma by 2025 with the projected increase of world’s urban population from 45% to 59% [P10-03196]. Central to the various phenotypic patterns of asthma is the presence of chronic underlying airway inflammation. The inflammatory cell components involved are variable, but with overlapping patterns that reflect the different phenotypes of the disease, such as intermittent versus persistent or acute versus chronic manifestations.The inflammation causes airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment [P10-03196]. According to the worldwide accepted guidelines of GINA (Global Initiative for Asthma 2009) [P10-03196] asthma is categorised into different severity categories and three levels of asthma control. The severity assessment is based on level of symptoms, airflow limitation, and lung function variability. Asthma severity can be intermittent, or it can be persistently mild, moderate or severe. The classification of asthma by severity is useful for initial assessment of the patient and initial treatment decisions. Due to the variability of asthma severity over time and individual patient’s response to treatment, a periodic assessment of the achieved asthma control is more relevant for ongoing treatment decisions. Asthma control is categorized into three levels based on daytime and nocturnal symptoms, limitations of activities, need for reliever treatment, lung function and exacerbations. Asthma can be controlled, partly controlled or uncontrolled. The aim of any asthma treatment is to achieve and maintain control for prolonged periods, thereby considering the safety of treatment, potential for adverse effects, and the cost of treatment required to achieve this goal. Asthma severity can be classified into so called GINA steps 1 to 5. The severity of asthma determines the treatment to be required. For many patients, medication must be taken everyday to control symptoms, to improve lung function and to prevent exacerbations. Medications are optionally also required to relieve acute symptoms such as wheezing, chest tightness, and cough. The role of long-acting anticholinergics as controller medication remains still to be eludicated in the treatment of asthma but appears to be promising based on preclinical findings and a successful proof-of-concept trial with tiotropium in patients with severe persistent asthma who were not fully controlled despite adequate treatment with at least high-dose ICS and LABAs. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 23 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 21 of 137 In this present study we will investigate if patients with moderate persistent asthma who are not fully controlled despite treatment with medium doses inhaled corticosteroids would benefit from tiotropium. The effects on pulmonary function and patient-reported outcomes of two different doses of tiotropium will be compared to placebo and salmeterol. 1.2 DRUG PROFILE Please refer to the "Investigator’s Brochure" [U92-0551] for the detailed outline of the existing quality, non-clinical and clinical data of tiotropium. Tiotropium is a quaternary ammonium compound developed as a long-acting orally inhaled anticholinergic bronchodilator and approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Two product formulations have been investigated in clinical trials. The first formulation is a single-dose capsule containing 18 µg of tiotropium (equivalent to 22.5 µg of tiotropium bromide monohydrate) formulated in a powder blend with lactose monohydrate. The inhalation powder formulation has been registered in about 100 countries (Spiriva® Handihaler®) and is presently being used in Phase IV clinical studies. The second product is an aqueous solution of tiotropium formulated with the excipients benzalkonium chloride and EDTA (2.5 µg tiotropium per actuation, 2 actuations per dose), which is intended for oral inhalation only via the Respimat® inhaler. The Respimat® inhaler is a novel propellant-free inhaler, which may prove to be an alternative to metered-dose and dry powder inhalers (MDIs and DPIs). The Respimat®inhaler is designed to deliver a single dose of Spiriva® in two actuations. Tiotropium in the Respimat® inhaler has been tested in a set of Phase III clinical studies, has been registered in several countries of the European Union and filed for New Drug Application in the United States of America. The beneficial effect of tiotropium on bronchoconstriction is well established and clinically used for years in the treatment of chronic obstructive pulmonary disease (COPD). The following text describes the pharmacological properties of tiotropium on a molecular level. Investigations on mucus (hyper-) secretion, potential anti-inflammatory effects as well as on anti-remodelling properties of tiotropium are reviewed. Receptor binding In vitro studies with human and animal muscarinic receptor subtypes (M1, M2, and M3) and with human and animal isolated tracheal preparations established tiotropium as a potent, selective and reversible muscarinic receptor antagonist. No other receptor interactions were detected at relevant concentrations. Association and dissociation from muscarinic receptors (M1, M2, and M3) were slow compared to ipratropium. The dissociation half-life of tiotropium-M3-complexes at 23°C was 34.7 hours compared to 0.26 hours for ipratropiumM3-complexes. Tiotropium-M2-complexes and ipratropium-M2-complexes dissociate more rapidly than M3- or M1-receptor-complexes. This pattern suggests a “kinetic receptor subtype selectivity” of occupation and blockade of M3>M1>M2-receptors [U99-1004]. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 24 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 22 of 137 Mucus modifying effects In a model of ovalbumine-induced asthma in guinea pigs [P05-05129] tiotropium prevented goblet cell hyperplasia and reduced the histologically assessed mucus gland area. In particular, the ovalbumine-stimulated increase in mucus gland area was reduced to baseline by inhalative treatment with tiotropium. These effects may positively influence mucus hypersecretion and airway plugging, and may thus improve lung function in asthma patients. Anti-inflammatory properties First in vitro investigations on the inflammatory potential of acetylcholine, the endogenous ligand of muscarinic receptors, were performed by Sato et al. [R05-0813]. Acetylcholine induced the release of neutrophil and monocyte chemotactic activity in bovine airway epithelial cells. Furthermore, acetylcholine stimulated alveolar macrophages to release eosinophil chemotactic mediators [R05-2327]. In a similar trial [P07-12448] acetylcholine stimulated different primary airway cells and cell lines to release inflammatory chemotactic factors. The acetylcholine-induced release of neutrophil chemotactic factors was abolished by tiotropium bromide suggesting an effect mediated by M3 receptors. Anti-inflammatory effects have also been shown for oxitropium bromide, another antimuscarinic, by Profita et al. in sputum cells derived from COPD patients [P05-11064]. In vivo investigations in an asthma model in guinea pigs have shown that eosinophilic inflammation was in part prevented by tiotropium [P07-10315]. Anti-remodeling effects In the above mentioned guinea pig asthma model ovalbumine induced an increase in airway smooth muscle mass measured morphometrically as well as on the alpha smooth muscle myosin heavy chain expression level. This may reflect airway smooth muscle hyperplasia observed in asthma patients. This pathophysiological proliferative effect on airway smooth muscles in guinea pigs was significantly reduced by inhaled tiotropium [P05-05129]. The above mentioned non-bronchodilating effects may contribute to beneficial long-term effects of tiotropium in the treatment of chronic airway diseases, including asthma. Comprehensive information about the development program of tiotropium is provided in the "Investigator´s Brochure" [U92-0551]. Renal impairment Tiotropium is mainly excreted renally. Increased plasma concentrations were described in patients with moderate to severe renal impairment (creatinine clearance ≤ 50mL/min). A dose reduction based on renal dysfunction cannot be recommended. Tiotropium should only be used in patients with moderate to severe renal impairment if the expected benefit outweighs the potential risk. As with all predominantly renally excreted drugs, tiotropium use should be monitored closely in patients with moderate to severe renal impairment. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 25 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 23 of 137 Drug-Drug Interaction Drug interactions of tiotropium with other drugs are unlikely due to the small dose and very low steady state plasma levels of tiotropium and the lack of inhibition of cytochrome P 450 isoenzymes by tiotropium [U97-2651]. The Respimat® Inhaler The Respimat® is a multi-dose inhaler differing from currently marketed dry powder and pressurized metered dose inhalers (pMDIs) by several features, including: (1) relatively slow aerosol delivery (1.5 seconds spray duration) that facilitates a better inhalation coordination for the patient, (2) high fine particle fraction of the spray permitting increased efficiency of drug delivery to the target organ, (3) a delivered dose independent of patient’s inspiratory flow, (4) propellant-free environment-friendly formulation, (5) convenience of a multidose inhaler, and (6) technological advances that enhance the proper use by the patient (e.g. a dose indicator and a locking mechanism that prevent tail-off of dosing after the declared number of doses). Tiotropium inhalation powder/HandiHaler® in Patients with Asthma Four randomized clinical trials have been conducted in patients with asthma using the inhalation powder capsule formulation of tiotropium [U96-0240, U98-3174, U98-3274, U991019]. These trials in the general (and exercise-induced) asthma population have demonstrated that tiotropium provides some degree of bronchodilation in asthmatic patients. Dose-dependency and convincing pharmacodynamic duration of action were not shown. Tiotropium did provide dose-related protection against methacholine induced bronchoconstriction in patients with mild to moderate asthma. The incidence of adverse events was low in all four asthma trials using doses up to 36 µg inhalation powder/HandiHaler® over 21 to 28 days of treatment. The type and rate of events were not different from those seen in the trials with COPD patients, aside from “asthma exacerbation”. The most common events were asthma exacerbation, upper respiratory infection, headache and dry mouth. Tiotropium inhalation solution/Respimat® in Patients with Asthma Three trials have been conducted with Spiriva® Respimat® in patients with asthma: Trial 205.248 [U02-1222]: local tolerability of Spiriva® Respimat® placebo formulation in hypersensitive asthmatic patients Trial 205.248 was a Phase II, single-dose, randomised, double-blind (within-device), fourway crossover trial conducted to evaluate the local tolerability of an acidic solution (pH = 2.7) for inhalation with the Spiriva® Respimat® placebo solution. This trial was conducted in 34 hypersensitive asthmatic patients. No adverse effects were attributed to the acidic solution, which was well tolerated. Neither spirometric parameters nor vital signs were changed by study treatment. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 26 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 24 of 137 Trial 205.341 [U08-2081]: Phase II proof-of-concept, severe persistent asthma This trial was an 8-week randomised, placebo-controlled, double-blind, 3-way crossover comparison of 5 µg and 10 µg Spiriva® Respimat® and placebo Respimat® administered once daily in the morning as add-on therapy in 100 adult asthmatics with maximized controller medication, who were still symptomatic. The primary endpoint of peak FEV1 response showed statistically significant superiority for both doses of Spiriva® Respimat® compared to placebo, with these results supported by the analysis of secondary endpoints. Thus, clinical proof of concept has been demonstrated for the 5 and 10 µg doses of Spiriva® Respimat® as add-on therapy in a population of patients with symptomatic severe persistent asthma. The 5 µg Spiriva® Respimat® administered as once daily in the morning was shown to be well tolerated with a comparable safety profile to placebo. Treatment with 10 µg Spiriva® Respimat® was similarly effective, generally well tolerated with comparable safety profile to placebo too; however, the higher occurrence of dry mouth is interpreted as sensitive indicator of a systemic anticholinergic reaction. Trial 205.342 [U09-1701]: Phase II proof-of-concept, moderate persistent asthma This trial was a 16-week randomised, placebo- and active-controlled, double-blind, doubledummy, parallel-group study comparing the efficacy and safety of Spiriva® Respimat® (5 µg once daily) in the evening with that of salmeterol HFA MDI (2 puffs of 25 µg twice daily) both in addition to maintenance ICS in moderate persistent asthma patients homozygous for arginine at ADRB2. The primary endpoint of this study, the change in mean weekly morning PEF from baseline to the last week of treatment,demonstrated the statistical non-inferiority of 5 µg Spiriva® Respimat® versus salmeterol and its superiority versus placebo. Thus, 5 µg Spiriva® Respimat® was as effective as salmeterol in the treatment of patients homozygous for arginine at the 16th amino acid position of the β2-adrenergic receptor (B16-Arg/Arg) with moderate persistent asthma. Spiriva® Respimat® showed an acceptable safety profile with no marked differences compared to salmeterol or placebo. Relevance of the B16-Arg/Arg genotype for the adrenergic or anticholinergic response The implications of selecting this subgroup of patients by receptor genotype are discussed extensively in the Investigator's Brochure [U92-0551]. Trial 205.342 [U09-1701] investigated the effect of Spiriva® Respimat® in B16-Arg/Arg patients with moderate persistent asthma for whom previously published studies suggested that they might not benefit from a LABA such as salmeterol therapy [P04-11193 and P0907838]. There is currently no evidence or mechanistic rationale to assume that the anticholinergic response is different in asthma patients homozygous for arginine at ADRB2. For this reason, the efficacy profile shown in patients homozygous for B16-arginine is most likely relevant for the general population with moderate persistent asthma. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 27 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 25 of 137 In conclusion: Two BI trials 205.341 [U08-2081] and 205.342 [U09-1701] showed a significant efficacy signal and a favourable safety profile for tiotropium administered via the Respimat® inhaler in moderate or severe persistent asthma in patients adequately treated with ICS according to current treatment guidelines. All trials for tiotropium Respimat® in asthma were and will be conducted only with an appropriate maintenance treatment with an ICS. 1.2.1 Inhalation solution and Respimat® Inhaler Active ingredient solution The tiotropium inhalation solution is aqueous based. The pH value is adjusted to pH 2.9 ± 0.2, near the stability optimum of the active substance. Administration of tiotropium inhalation solution is achieved with the Respimat® inhaler in combination with a drug reservoir/cartridge. The drug is delivered from the Respimat® inhaler as two actuations per dose. As a multi-dose device and solution, the drug formulation contains ethylenediaminetetraacetic acid, disodium salt (EDTA) and the bacteriostatic agent benzalkonium chloride (BAC), which have been reported to induce bronchospasm in some patients inhaling such solutions from a nebulizer. However, the doses of EDTA and BAC administered with two actuations of the Respimat® are well below the amounts for which bronchospasm has been reported with nebulized solutions. Additionally, clinical data for the Respimat® inhaler with a variety of drug substances (including tiotropium) indicates that it is unlikely that patients using the Respimat® inhaler will experience an EDTA or preservativerelated bronchospasm (see Section 6.4.4.4 of the tiotropium Investigator's brochure for further information) [U92-0551]. Details of the Respimat® device and the cartridge for active ingredient solution and the instructions for use are found in Appendix 8.2 of the tiotropium Investigator's Brochure [U92-0551] and in this protocol (Section 10.1). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 28 Page U12-2467-02 Trial Protocol 2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT 2.1 RATIONALE FOR PERFORMING THE TRIAL 21 Apr 2010 Page 26 of 137 Airway smooth muscle tone is controlled by sympathetic and parasympathetic influences as well as a range of other mediators. The predominant neural constrictor pathway is cholinergic but its impact depends on the influence of a range of other involved mediators. As consequence, anticholinergics have been explored as anti-obstructive therapies with variable responses in the different obstructive airway diseases. Neuronally released acetylcholine stimulates M3 muscarinic receptors on the airway smooth muscle and mucus glands causing bronchoconstriction and mucus (hyper-) secretion. Classically regarded as a neurotransmitter of the parasympathetic nervous system, acetylcholine is suggested to be also synthesized in many other cell types found in the airways as concluded from the expression of choline acetyl transferase, the enzyme responsible for the acetylcholine synthesis. Acetylcholine produced by these non-neuronal cells is commonly referred to as non-neuronal acetylcholine (nnACh). Additional components of the cholinergic system, in particular muscarinic receptors have been detected in nearly all cell types present in the lungs. Consequently, increasing evidence suggests that non-neuronal acetylcholine may play a role in various pathophysiological processes relevant in the course of chronic airway diseases. Taken together, these effects suggest that tiotropium, an anticholinergic, might have (beside its well characterized bronchodilatory mode of action) additional important characteristics which could be of potential therapeutic benefit for the patient. Preclinical in vivo studies in a guinea pig asthma model revealed that tiotropium attenuates airway inflammation as well as remodelling processes in these models [P05-05129 and P07-10315]. A published Cochrane Database review concluded that “the role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma” [P05-01207]. Anticholinergics are considered as a first-line therapy in COPD and there is a large body of evidence demonstrating its efficacy and safety, whereas, the place of anticholinergics in the treatment of asthma is less well-defined, particularly in patients with not optimally controlled or uncontrolled asthma. Patients with severe persistent asthma who are inadequately controlled despite treatment with a combination of inhaled steroids/long- acting ß2-agonists therapy are a therapeutic challenge with significant unmet medical need. An additional anticholinergic bronchodilator may provide added benefits for these patients. For some patients still symptomatic on maintenance therapy with an ICS alone, treatment with a longacting anticholinergic could be an alternative bronchodilator controller medication instead of a long-acting ß2-agonist. Short-acting anticholinergic agents such as ipratropium bromide, alone or in combination with ß2-agonists, are used in the management of chronic asthma in many countries. They are recognized particularly as alternative bronchodilators for patients who experience adverse effects such as tachycardia, arrhythmia and tremor from rapid-acting ß2-agonists (Global Initiative for Asthma (GINA) (2009) [P10-03196]). A meta-analysis of trials in which nebulized ipratropium bromide was added to a nebulized ß2-agonist [P99-02952] showed that Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 29 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 27 of 137 ipratropium bromide has an additional effect when nebulized together with a rapid-acting ß2agonist for exacerbations of asthma.The anticholinergic not only produced a statistically significant improvement in pulmonary function, but also significantly reduced the risk of hospital admission. According to the results of Beck R, et al. [P86-0614] a beneficial effect of ipratropium inhalation added to the standard care could be shown. Therefore clinical efficacy of inhaled tiotropium as a long acting anticholinergic can be expected. As tiotropium offers a superior time-response profile as a bronchodilator to ipratropium in COPD, tiotropium also likely will be more effective and have sustained antiobstructive effects for 24 hours in asthma. The 24-hour duration of action profile may be of special value in a population suffering from nocturnal events of, e.g., shortness of breath, which is the case in moderate and severe but still not optimally controlled asthma. Two completed phase II proof-of-concept trials (205.341 and 205.342) confirmed clinically relevant effectiveness of the 5 µg dose of tiotropium inhalation solution in patients with severe and moderate persistent asthma. Two identical 1-year phase III trials (205.416 and 205.417) are currently in conduct to confirm the safety and efficacy of 5 µg tiotropium inhalation solution (on top of at least ICS and LABA) in patients with severe persistent asthma. Trials 205.418 and 205.419 will be performed to evaluate the safety and efficacy of 2.5 and 5 µg tiotropium inhalation solution (on top of ICS) in patients with moderate asthma. Comprehensive information about the development program of tiotropium is provided in the "Investigator’s Brochure" [U92-0551]. Refer to Section 4.1.3 for the selection of doses in the trial. Please refer to Section 3.2 for a discussion on the trial design, including the choice of control groups, and to Section 4.1.3 for information on the selection of doses in the trial. 2.2 TRIAL OBJECTIVES This is one of two confirmatory phase III trials with identical protocols (twin trials with BI trial numbers 205.418 and 205.419). The primary objective of each trial is to evaluate the long term (24 weeks) efficacy and safety of two doses (2.5 µg and 5 µg) of tiotropium inhalation solution (administered once daily) compared to placebo and to salmeterol (50 µg; administered twice daily) on top of maintenance therapy with inhaled corticosteroid controller medication in patients with moderate persistent asthma. The comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. A 24 hour PK profile of tiotropium is only available for COPD patients. In this trial PK samples will be collected from 80 patients to confirm this 24 hour profile in asthma patients. Refer to Section 5 for the endpoints. 2.3 BENEFIT - RISK ASSESSMENT The favourable benefit-risk ratio based on the so far acquired knowledge about inhaled tiotropium is the rationale to conduct further studies with tiotropium in asthma. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 30 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 28 of 137 The incidence of adverse events was low in all four asthma trials using doses up to 36 µg inhalation powder/HandiHaler® over 21 to 28 days of treatment. The type and rate of events were not different from those seen in the trials with COPD patients, aside from “asthma exacerbation”. The most common events were asthma exacerbation, upper respiratory infection, headache and dry mouth. Single doses of placebo inhalation solution/Respimat® were well tolerated, as evaluated in 32 mild asthmatic patients. During a crossover efficacy and safety evaluation trial (205.341) of 8-week treatment periods of two doses (5 and 10 µg ) tiotropium inhalation solution delivered by the Respimat® inhaler as add-on therapy in patients with severe persistent asthma the overall occurrence of adverse events was similar between the placebo and 5 µg tiotropium groups (39.8% and 42.3% of patients, respectively, reported at least one adverse event), but slightly higher in the 10 µg tiotropium group (49.5% of patients reported at least one adverse event). The most common treatment-emergent adverse events were nasopharyngitis and asthma (MedDRA preferred term classification including aggravated asthma and exacerbation of asthma), with both being reported overall by 28 patients (26.2%). The only treatment-emergent adverse event reported in more than one patient was dry mouth, which was considered drug-related in 4 patients (3.9%) only in the 10 µg tiotropium group [U08-2081]. During the double-blind treatment and follow-up period of trial 205.342, mean (standard deviation) duration of double-blind exposure to trial medication was 109.6 (21.3) days (placebo), 110.9 (16.2) days (tiotropium), and 111.8 (16.8) days (salmeterol). During the double-blind treatment and follow-up periods, the overall incidence of AEs was similar in the active treatment and placebo groups: 52 (41.3%) placebo patients; 51 (39.8%) tiotropium patients; 56 (41.8%) salmeterol patients. Few AEs were considered drug-related and the incidences of such AEs were also similar across groups: 4 (3.2%) placebo patients, 6 (4.7%) tiotropium patients, and 3 (2.2%) salmeterol patients. The most common AEs by preferred term were asthma exacerbation (including preferred term asthma) and nasopharyngitis [U091701]. In conclusion, the studies conducted in asthmatic patients provided no evidence of serious adverse effects with suspected causal relationship to tiotropium treatment. The administration of tiotropium can be considered as safe for patients. For detailed information regarding the safety of tiotropium in COPD, please refer to the "Investigator’s Brochure" [U92-0551]. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 31 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 29 of 137 3. DESCRIPTION OF DESIGN AND TRIAL POPULATION 3.1 OVERALL TRIAL DESIGN AND PLAN This is a randomised, double-blind, double-dummy, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of 2.5 and 5 µg of tiotropium inhalation solution delivered by the Respimat® inhaler (once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in moderate persistent asthma patients treated with medium doses of inhaled corticosteroids. After signing informed consent and an initial screening visit, patients will enter a 28-day screening period. Patients who meet all inclusion and none of the exclusion criteria will be randomised into the 24-week treatment period in which they will receive either 2.5 µg tiotropium (2 puffs of 1.25 µg) once daily, 5 µg tiotropium (2 puffs of 2.5 µg) once daily, 50 µg salmeterol (2 puffs of 25 µg) twice daily or placebo in a double-dummy fashion. Patients will be evaluated for an additional 21 days following completion of the randomised treatment period. Visit 0 and Visit 7 may be conducted during business hours. Visit 1 to Visit 6 will always start in the evening. Patients who withdraw prematurely from the randomised treatment period will be followed up regarding their vital status. They will be contacted at their predicted normal exit date from the trial, i.e. completion of the 24 week treatment period plus 21 days follow-up period. Pulmonary function testing will be conducted at the screening visit (Visit 1) and vital signs will be measured in conjunction with pulmonary function tests until three hours post-dosing at all visits (except at Visits 2A, 2B and 2C) during the randomised treatment period. Asthma exacerbations according to protocol-specific definition (see Appendix 10.10) will be documented together with additional observations including utilisation of healthcare resources, adverse events and concomitant therapies. Three paper-based questionnaires (ACQ, AQLQ (S) and EQ-5D) will be patient self-administered during the treatment period. The ACQ will also be self-administered at Visit 1. The ACQ mean score at Visit 1 and Visit 2 will be used to determine the patient's eligibility. The patient will record morning and evening PEF and FEV1 and use an electronic diary throughout the screening and treatment period. Physical examination will be performed together with an evaluation of the patient's smoking status and asthma background characteristics at Visit 1. Blood samples for clinical laboratory testing will be obtained and a 12-lead ECG will be recorded at Visit 1 to evaluate the patient's eligibility. Urine pregnancy testing will be done at Visit 1 in females of childbearing potential. The physical examination, laboratory testing, pregnancy testing, ECG and evaluation of the patient's smoking status will be repeated on completion of patient's participation in the randomised treatment period of the trial. Analysis of clinical laboratory samples will be performed by the local laboratory of each site. Depending on patient's informed consent, a blood sample for pharmacogenetics will be drawn at Visit 2 (or any subsequent visit) from all randomised patients that received at least one dose of trial medication. If a patient signed an informed consent for participation in the PK substudy, blood samples for pharmacokinetic evaluation will be drawn over 24 hours at Visits 2 and 3 and pre- and post-dose at Visit 2A, 2B and 2C (in a subset of patients at selected Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 32 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 30 of 137 sites). Pulmonary function testing over 24 hours will be performed at Visit 6 in a subset of patients at sites capable of performing 24 hour measurements. Adverse events will be documented throughout the trial, i.e. starting with informed consent and ending 21 days after last administration of trial medication. All trial relevant documentation will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). Trial relevant documentation for the trial sites will be filed in the Investigator Site File (ISF) at the investigator sites. 3.1.1 Administrative structure of the trial Sponsor: Clinical trial drug supplies including trial, training and rescue medication will be provided by the sponsor. Co-ordinating Investigator: The co-ordinating investigator was selected by the sponsor. He will review the trial protocol, any subsequent amendments to the protocol and the (draft) Clinical Trial Report (CTR). He will provide his signature on the final protocol signature page and amendments and will provide his signature on the (draft) Clinical Trial Report (CTR) indicating that, to the best of Co-ordinator’s knowledge, the final CTR accurately describes the conduct and results of the Trial. Targeted group of Investigators: Pulmonologists/qualified sites with access to the requested patient population. The following local facilities/equipment are required at the investigational site: clinical laboratory, ECG, scale and sphygmomanometer. The sites have to be able to perform the 3 hour PFT measurements in the evening. Selected sites have to be able to perform the (24 hour) PK and/or 24 hour PFT measurements. DSMB: A DSMB will not be implemented on trial level, but might be implemented on project level. If so, safety review meetings will be held as per separate DSMB charter Central laboratory: The sample transport logistics (from site to sponsor) for PK and pharmacogenetic samples will be the responsibility of the central lab. The central lab will provide sampling and shipment materials. IVRS: : An interactive voice response system (IVRS) will be used for randomisation to a treatment group in this trial and for appropriate re-supply of medication to patients. The ability to unblind will be available to the investigator via the IVRS. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 33 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 31 of 137 CROs: A CRO will provide MasterScope® CT and AM3® devices for the complete duration of the trial. All contracts and relevant meeting minutes will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S) The trial design has been selected to allow comparison of the effects on pulmonary function and patient-reported outcomes of different doses of tiotropium to placebo and salmeterol in patients with moderate persistent asthma that is not fully controlled although the patients are treated with medium doses inhaled corticosteroids. The selection of evening administration in this patient subgroup was mainly to consider nocturnal control of airway patency. In trials 205.341 and 205.342 no untoward events happened to patients treated with placebo and the overall incidence of AEs and the incidence of asthma exacerbations were similar in active treatment and placebo arms. Based on these data, a 'placebo' (i.e. no second controller medication) treatment group in this trial could be considered safe, because all patients are at least on a maintenance treatment with a stable dose of an anti-inflammatory medication (inhaled corticosteroid). Moreover, all patients will be provided with so-called rescue medication (open-label salbutamol (albuterol) HFA MDI). Boehringer Ingelheim intends to conduct a Phase 3 program that will fulfil global registration requirements. According to EU regulations, inclusion of an active comparator treatment arm is required. BI decided to use Serevent® HFA MDI as approved and commercially available in the EU as the active comparator. Washout requirements prior to pulmonary function testing and other medication restrictions (see Section 4.2.2) are given to reduce possible influences on pulmonary function testing and ensure patient's safety during the trial. The permitted concomitant asthma medication (see Section 4.2) should be kept stable during the complete trial period with the exception of acute treatment of asthma exacerbations. The data collected in a controlled, double-blind, randomised and placebo-controlled trial will provide useful information to health care providers and patients regarding the efficacy and safety of 2 doses of tiotropium inhalation solution delivered by the Respimat® inhaler added to inhaled corticosteroids in the treatment of not fully controlled moderate asthma in comparison to placebo and salmeterol. 3.3 SELECTION OF TRIAL POPULATION A sufficient number of patients of either sex with a diagnosis of moderate persistent asthma will be enrolled in the study to ensure approximately 1000 adult patients are entered (randomised) in the trial. Additional sites may be initiated and 'non-productive' sites may be closed to ensure sponsor's timelines. Randomisation will end when the trial clinical monitor has determined that enough patients are evaluable. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 34 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 32 of 137 Participation in the PK part of the trial is optional and not a prerequisite for patients to participate in the trial. Several sites capable of performing 24 hour PK sampling will be selected to participate in the PK part of the trial. All participating patients at these sites will be asked to consent to the PK visits until at least 80 patients have completed the PK substudy. Participation in the 24 hour PFT visit (at Visit 6) is optional and not a prerequisite for patients to participate in the trial. All sites capable of performing 24 hour PFT measurements will be selected to perform the 24 hour PFT visit. All participating patients at these sites will be asked to consent to the 24 hour PFT visit. The number of patients participating in the 24 hour PFT measurements is not limited. Every effort should be made to keep patients in the trial until they complete all trial procedures. Patients who discontinue after randomisation may not be re-enrolled at a later date. A record will be kept of all patients who fail to complete all trial visits and their reason for discontinuation. A log of all patients included into the study (i.e. having given informed consent) will be maintained in the ISF at the investigational site irrespective of whether they have been treated with investigational drug or not. 3.3.1 Main diagnosis for study entry Outpatients with a history of asthma and a current diagnosis of moderate persistent asthma (according to GINA guideline) and who are symptomatic (partly controlled) despite their current maintenance treatment with at least a medium dose of inhaled corticosteroids are eligible for inclusion if they fulfil all the inclusion criteria (Section 3.3.2) and none of the exclusion criteria (Section 3.3.3). 3.3.2 Inclusion criteria 1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1). 2. Male or female patients aged at least 18 years but not more than 75 years. 3. All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5. 4. The initial diagnosis of asthma must have been made before the patient's age of 40. 5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 minutes after 400 µg salbutamol (albuterol)) resulting in a FEV1 increase of ≥ 12% and ≥ 200mL (see Appendix 10.4). 6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (see Appendix 10.4) (alone or in a fixed combination with a LABA or SABA) for at least for 4 weeks prior to Visit 1. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 35 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 33 of 137 7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ (see Appendix 10.6) mean score of ≥ 1.5. NOTE: If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). 8. All patients must have a pre-bronchodilator FEV1 ≥ 60% and ≤ 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to ECSC [R94-1408] (see Appendix 10.4). 9. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30% (see Appendix 10.4 for calculation). 10. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years (see Appendix 10.4 for calculation). 11. Patients must be able to use the Respimat® inhaler (Appendix 10.1) and metered dose inhaler (Appendix 10.2) correctly. 12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter (diary compliance of at least 80% is required; refer to Section 6.1 for instructions). 3.3.3 Exclusion criteria 1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial. 2. Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion 1. 3. Patients with a recent history (i.e. six months or less) of myocardial infarction. 4. Patients who have been hospitalised for cardiac failure during the past year. 5. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. 6. Patients with lung diseases other than asthma (e.g. COPD). 7. Patients with known active tuberculosis. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 36 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 34 of 137 8. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed. 9. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1. 10. Patients with significant alcohol or drug abuse within the past two years. 11. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening). 12. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA, salmeterol xinafoate or any other components of the study medication delivery systems. 13. Pregnant or nursing woman. 14. Women of childbearing potential not using a highly effective method of birth control. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner. Barrier methods of contraception are accepted if condom or occlusive cap are used together with spermicides (e.g. foam, gel). Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years. 15. Patients who have taken an investigational drug within four weeks prior to Visit 1. 16. Patients who have been treated with beta-blocker medication - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). Topical cardio-selective beta-blocker eye medications for non-arrow angle glaucoma are allowed. 17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 18. Patients who have been treated with oral or patch beta-adrenergics - within four weeks prior to Visit 1 and/or - during the Screening period (period between Visit 1 and Visit 2) 19. Patients who have been treated with oral corticosteroids - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 37 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 35 of 137 20. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), - within 6 months prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 21. Patients who have been treated with cromone - within two weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors - within two weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 23. Patients who have been treated with other non-approved and according to international guidelines not recommended ’experimental’ drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) - within four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 and Visit 2). 24. Patients with any asthma exacerbation or any respiratory tract infection - in the four weeks prior to Visit 1 and/or - during the screening period (period between Visit 1 to Visit 2). Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection. Refer to Section 6.1 for information on re-scheduling of visits. 25. Patients who have previously been randomised in this trial or in the respective twin trial (205.418) or are currently participating in another trial. Precautionary statement Tiotropium As an anticholinergic drug, tiotropium may potentially worsen symptoms and signs associated with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction and should be used with caution in patients with any of these conditions. As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min) treated with tiotropium should be monitored closely. Salmeterol Salmeterol should be administered with caution in patients predisposed to low levels of serum potassium, patients with thyrotoxicosis or pre-existing cardiovascular disease, or patients with a history of diabetes mellitus. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A4 inhibitors (e.g. ketoconazole, atazanavir, ritonavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir) is not recommended. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 38 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 36 of 137 Both non-selective and selective beta-blockers should be avoided, unless there are compelling reasons for their use. 3.3.4 Removal of patients from therapy or assessments 3.3.4.1 Removal of individual patients An individual patient is to be withdrawn from the trial if any of the following criteria apply: • • • • The patient withdraws consent, without the need to justify the decision. The patient is no longer able to participate for medical reasons (e.g. pregnancy, surgery, adverse events, or other diseases). Administrative reasons (protocol violations, persistent non-compliance). Decision by Boehringer Ingelheim to discontinue a specific patient (e.g. in case of SAEs). No patient should be discontinued from the trial for a protocol violation before discussion with the clinical monitor. Withdrawal from the trial of an individual patient may be considered if any of the following criteria apply: • • • • • Intercurrent illness or an adverse event, which requires discontinuation of treatment per protocol. Investigators should check carefully if this applies for patients who experience any of the following criteria: More than 3 courses of systemic corticosteroids are required to treat asthma exacerbations. Twelve or more puffs of rescue medication (salbutamol/albuterol MDI) per day are used for more than 2 consecutive days (use of 12 or more puffs of rescue medication for at least 2 consecutive days will be alerted by the AM3®) A drop of patient’s pre-bronchodilator FEV1 (clinic assessment) below 40% predicted. A decrease of patient's best morning PEF of ≥ 40% from the patient's mean morning PEF for more than 2 consecutive days (a decrease of ≥30% for at least 2 consecutive days will be alerted by the AM3®). During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. Data of patients who discontinue or withdraw prior to randomisation will be entered in the trial database and will be listed. Data of patients who discontinue or withdraw after randomisation must be documented and the reason for withdrawal must be recorded in the eCRF. The data must be included in the trial database and must be reported. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 39 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 37 of 137 Refer to Section 6.2.3 for procedures to be followed for patients prematurely terminating the trial. Pregnancy If a patient becomes pregnant during the trial the investigational product needs to be stopped and the patient should be followed up until birth or otherwise termination of the pregnancy. The data of the patient will be collected and reported in the clinical trial report until patients last visit and any events thereafter will be reported in the BI drug safety database. Refer to Section 5.2.2.2 for detailed information on event reporting in case of pregnancy. 3.3.4.2 Discontinuation of the trial by the sponsor Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial site at any time for the following reasons: • • • Failure to meet expected enrolment goals overall or at a particular trial site. Emergence of any efficacy/safety information that could significantly affect continuation of the trial. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the appropriate conduct of the trial. The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of trial termination (except in case of the third reason). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 40 Page U12-2467-02 Trial Protocol 4. TREATMENTS 4.1 TREATMENTS TO BE ADMINISTERED 21 Apr 2010 Page 38 of 137 Patients will be randomized 1:1:1:1 to 2.5 µg tiotropium inhalation solution, or 5 µg tiotropium inhalation solution, or salmeterol HFA-MDI, or placebo over the 24-week treatment period. The double-blind, double-dummy design of the study is realized by the use of matching placebos. During the treatment period the patients inhale two puffs from the MDI (salmeterol or placebo) every morning and every evening. In addition, the patients inhale two puffs from the Respimat® inhaler (tiotropium or placebo) every evening. Patients randomised to 2.5 µg tiotropium (treatment A) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations of tiotropium from the 1.25 µg Respimat® inhaler. Patients randomised to 5 µg tiotropium (treatment B) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations of tiotropium from the 2.5 µg Respimat® inhaler. Patients randomised to salmeterol (treatment C) inhale the following medication In the morning: two actuations of 25 µg salmeterol from the salmeterol MDI, In the evening: two actuations of 25 µg salmeterol from the salmeterol MDI followed by two actuations from the placebo Respimat® inhaler. Patients randomised to placebo (treatment D) inhale the following medication In the morning: two actuations from the placebo MDI, In the evening: two actuations from the placebo MDI followed by two actuations from the placebo Respimat® inhaler. Boehringer Ingelheim Pharma GmbH & Co. KG will supply the investigational product. 4.1.1 Identity of BI investigational product and comparator product(s) Investigational product - 2.5 µg tiotropium bromide Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Tiotropium bromide Inhalation solution 2.5 µg (1.25 µg per actuation) delivered dose ex mouthpiece Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 41 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 39 of 137 Investigational product - 5 µg tiotropium bromide Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Tiotropium bromide Inhalation solution 5 µg (2.5 µg per actuation) delivered dose ex mouthpiece Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Comparator - 50 µg salmeterol xinafoate Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Salmeterol xinafoate Hydrofluoroalkane (HFA 134a) metered dose inhaler 50 µg (25 µg per actuation) Pressurised metered dose inhaler 2 actuations of 25 µg twice daily (in the morning and the evening) Oral inhalation Placebo - inhalation solution Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Placebo Inhalation solution NA Respimat® inhaler 2 actuations once daily (in the evening) Oral inhalation Placebo - metered dose inhaler Substance (INN): Pharmaceutical form: Unit strength: Device: Posology: Route of administration: Placebo Metered dose inhaler NA Pressurised meter dose inhaler 2 actuations twice daily (in the morning and the evening) Oral inhalation Instructions for use of the Respimat® and metered dose inhaler are provided in Appendix 10.1 and Appendix 10.2 respectively. 4.1.2 Method of assigning patients to treatment groups When a patient is qualified for entry into the randomised treatment period, treatment assignment will be by means of a third-party phone/web-based randomisation on Visit 2. This Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 42 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 40 of 137 will involve the use of an Interactive Voice Response System (IVRS/Interactive Web Response system, IWRS). To facilitate the use of IVRS, the investigator will receive an IVRS/IWRS worksheet for each patient with the complete IVRS/IWRS dialogue and all necessary instructions for using the IVRS/IWRS. Upon signing informed consent, patients will be assigned a unique patient number. At each visit (Visit 2 - 5), the IVRS/IWRS will assign medication numbers to each patient. Refer to Section 4.1.6 for details on packaging and labelling, Details on the IVRS/IWRS system are provided in the ISF. 4.1.3 Selection of doses in the trial Two completed Phase 2 proof-of-concept trials (205.341 and 205.342) provide evidence that the 5 µg dose of Spiriva® Respimat® is effective in severe persistent asthma on top of ICSLABA and provide clinically effective bronchodilation in patients with severe and moderate persistent asthma. Trial 205.341 also evaluated the 10 µg dose and established the therapeutic plateau for the higher dosing level. The lower dose of 2.5 µg has been added to the Phase III trials in moderate persistent asthma (205.418 and 205.419) to assess whether a lower dose may still offer sufficient response. The selection of evening administration in this patient subgroup was mainly to consider nocturnal control of airway patency. 4.1.4 Drug assignment and administration of doses for each patient Dispensing of trial medication Patients will be randomised at Visit 2 to one of the four treatment groups. Trial medication will be dispensed to the patient by the investigator/pharmacist at Visits 2 to 5. The amount of trial medication dispensed will be recorded on the drug accountability forms. Priming of the Respimat® inhaler Each newly assembled Respimat® inhaler has to be primed. The inhaler should be primed by actuating it until an aerosol is visible plus three additional actuations. All priming actuations should be directed to the ground. Priming should NOT take place in the same room where the patient is inhaling trial medication nor where samples for PK analyses are drawn or processed (to avoid undue contamination of the environment). Once assembled, the shelf-life of the Respimat® is 3 months (study medication and training devices). Therefore it is important to ALWAYS enter the date of first priming on the medication label of the Respimat® immediately after first priming. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 43 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 41 of 137 Testing of the MDI Before using for the first time, one actuation should be released into the air to make sure the device is working. This testing should NOT take place in the same room where the patient is inhaling trial medication (to avoid undue contamination of the environment). Instructing the patient Detailed instructions and training for the use of the Respimat® inhaler and MDI will be given to the patient at Visits 1 and 2 (see Appendix 10.1 and 10.2). Patients should NOT inhale from a training device on Visit 2. At all subsequent visits (Visit 3, 4, 5 and 6) the investigator or qualified study personnel will observe the inhalation procedure and will reinforce a correct inhalation technique. Patients will be instructed to contact the site should they need to use their reserve inhaler and the site will document this. Patients will be instructed at each visit to retain and return all used and unused medication and devices at the subsequent visit. Patients who miss a dose should be instructed to take the next dose at the next scheduled time. Trial medication administration at clinic visits Patients will be instructed to withhold their evening dose of study medication and the evening dose of their usual ICS (if regular posology) and their leukotriene modifier (LTRA) (if applicable) on the day of clinic visits. The administration of the evening doses of ICS, LTRA (if applicable) and trial medication should be done in the clinic only after the pre-dose procedures (which include AM3 PEF/FEV1 measurement and eDiary, questionnaires, vital signs and pulmonary function test, and PK if applicable). At each clinic visit during the treatment period medication administration will be conducted in a fixed sequence (1. ICS (if regular posology) and LTRA (if applicable), 2. from MDI, 3. from Respimat®). Patient’s ICS should be administered without change in posology (bid/qd; am/pm), i.e. as previously prescribed by patient’s treating physician. Study medication must be inhaled within 5 minutes after the inhalation of the patient's own ICS medication and the patient should inhale from the Respimat® immediately after inhaling from the MDI. The patient should be in a seated position under the direct supervision of the investigator or his/her delegate. Trial medication will be administered in the evening between 06.00 - 08.00 pm and within ± 30 minutes of time of administration at Visit 2 at all visits during the treatment period: 1. Patient will inhale own ICS (if patient usually administrates in the evening) and take their LTRA (if applicable) 2. Patient will inhale 2 actuations of the trial medication from the assigned MDI 3. Patient will inhale 2 actuations of the trial medication from the assigned Respimat® inhaler Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 44 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 42 of 137 On the 24 hour visits (PK and PFT), trial medication (MDI only) will also be adminstered on the following morning between 06.00 - 08.00 am and this should be 12 hours (± 5 minutes) after the time of pm administration the previous evening: 1. Patient will inhale own ICS (if patient usually administrates in the morning) and take their LTRA (if applicable) 2. Patient will inhale 2 actuations of the trial medication from the assigned MDI On all clinic visits the start time of the first inhalation and end time of the second inhalation from the Respimat® will be captured with the MasterScope® CT spirometer provided by Boehringer Ingelheim, except on PK Visits 2A, 2B and 2C where no pulmonary function testing is planned. On Visits 2A, 2B and 2C both, the start and end time of the inhalation from the Respimat® will be recorded on the eCRF. For patients participating in the PK measurements, on Visits 2, 2A, 2B, 2C and 3, the end time of the evening administration from the Respimat® device on the evening preceeding the visit will be recorded on the eCRF. A PK Visit Card will be provided to the patients to record the end time of inhalation at home. On 24 hour PFT visit days the start and end time of the second (in-clinic) inhalation from the MDI in the morning of the visit will also be captured with the MasterScope® CT spirometer. Trial medication administration at home Patients will self-administer the morning and evening doses of trial medication between clinic visits and will record the administration of each dose of trial medication in the electronic diary. The evening dose of patient's own ICS, LTRA (if applicable) and trial medication should be administered within ± 30 minutes of the time of evening administration at Visit 2 and between 06.00 and 08.00 pm. The morning dose of patient's own ICS, LTRA (if applicable) and trial medication (MDI only) should be administered 12 hours (± 30 minutes) after the time of pm administration and between 06.00 - 08.00 am. Medication must be taken immediately after the eDiary questions have been answered and the PEF measurements have been performed. Respimat® and MDI Inhaler Return Patients should return all dispensed trial medication (including reserve and rescue medication) to the clinic at all visits. Study medication dispensed at Visit 2, will be used for the trial medication administration at Visit 2 and will be returned at Visit 3. Study medication dispensed at Visit 3, will be used for the trial medication administration at Visit 3 and will be returned at Visit 4. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 45 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 43 of 137 Study medication dispensed at Visit 4, will be used for the trial medication administration at Visit 4 and will be returned at Visit 5. Study medication dispensed at Visit 5, will be used for the trial medication administration at Visit 5 and at Visit 6 and will be returned at Visit 6. No study medication will be dispensed at Visit 6. Any Respimat® inhaler that has been reported as malfunctioning by a patient or investigator will be returned to the Department of Drug Delivery, Boehringer Ingelheim Pharma GmbH & Co. KG (Germany), for investigation. A detail of the procedure for the return of used inhalers is provided in Appendix 10.3. See Section 4.1.8 for details regarding drug accountability requirements. 4.1.5 Blinding and procedures for unblinding 4.1.5.1 Blinding Patients, investigators and everyone involved in analysing or with an interest in this doubleblind study will remain blinded with regard to the randomised treatment assignments until after database lock. Boehringer Ingelheim will generate the randomisation schedule, and prepare and code the medication in a blinded fashion. Trial supplies will be assigned to the patients via IVRS. The randomisation codes will be provided to bioanalytics prior to database lock to allow them to exclude PK samples taken from placebo and salmeterol patients from the bioanalytical analyses. Bioanalytics will not disclose the randomisation code or the results of their measurements until the study is officially unblinded. Refer to Section 4.1.5.2 for rules of breaking the code for an individual or for all patients in emergency situations. 4.1.5.2 Procedures for emergency unblinding The ability to unblind will be available to the investigator via the IVRS. Unblinding must only be used in emergency situations when the identity of the study drug must be known by the investigator to provide appropriate medical treatment. Each site receives a manual from the IVRS provider that contains instructions on how to unblind the treatment of a patient via the IVRS (via 24-hour Emergency helpline). If possible, the Clinical Monitor Local (CML) and Trial Clinical Monitor (TCM) must be contacted prior to the site unblinding a patient's treatment. Patients unblinded to treatment will be withdrawn from the trial. 4.1.6 Packaging, labelling, and re-supply All study medication will be contained in individual patient treatment boxes identified with the trial number and a medication number. The boxes will have a two-part tear-off label. One Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 46 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 44 of 137 part of each tear-off label will remain on the box, and the other part will be attached to a special drug dispensing log which will be part of the ISF. Examples of the labels are provided in the ISF. The investigator or designee should fill out the following information on the medication label prior to dispensing the medication to the patient: • • investigator's name (should be entered at time of dispense) date of first priming (Respimat® only; should be entered at time of first priming) For details of packaging and the description of the label, refer to the ISF. Respimat® treatment box The 1-month Respimat® treatment box will contain one Respimat® inhaler plus one drugfilled cartridge. The 1-month treatment box will contain sufficient medication for 30 days of treatment. The 2-month Respimat® treatment box will contain two Respimat® inhalers plus two drugfilled cartridges. The 2-month treatment box will contain sufficient medication for 60 days of treatment. The Respimat® inhaler will lock after 60 actuations have been administered and will no longer actuate any medication. Each Respimat® device and treatment box label will be identified by a moon indicating evening administration. MDI treatment box The 1-month MDI treatment box will contain one MDI. The 1-month treatment box will contain sufficient medication for 30 days of treatment. The 2-month MDI treatment box will contain two MDIs. The 2-month treatment box will contain sufficient medication for 60 days of treatment. Each MDI device and treatment box label will be identified by a sun and a moon indicating morning and evening administration. Medication dispensing The allocation of treatment boxes dispensed at each visit will be handled by an IVRS/IWRS system. At Visit 2, patients will be dispensed a 2-month Respimat® treatment box and a 2-month MDI treatment box. One Respimat® and one MDI (labeled with R1 and M1 respectively) will contain a sufficient amount of study medication to last the patient until Visit 3. The second Respimat® and the second MDI (labeled with R2 and M2 respectively) are reserve medication. This is to allow the patient the flexibility of not having to return to the clinic immediately to replace a lost Respimat® inhaler or MDI. The reserve Respimat® and drug- Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 47 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 45 of 137 filled cartridge should NOT be assembled prior to leaving the clinic. The patient must assemble and prime the reserve device at home if needed. At Visits 3, patients will be dispensed a 1-month Respimat® treatment box and a 1-month MDI treatment box which will contain a sufficient amount of study medication to last the patient until the next clinic visit. At Visits 4 and 5, patients will be dispensed a 2-month Respimat® treatment box and a 2month MDI treatment box which will contain a sufficient amount of study medication to last the patient until the next clinic visit. The second Respimat® and drug-filled cartridge in the Respimat® treatment box should NOT be assembled prior to leaving the clinic. The patient must assemble and prime this device at home after the first cartridge is emptied. Additional 1-month Respimat® and additional 1-month MDI treatment boxes are available at the investigational site for issuing on an as needed basis. Patients should always have a reserve Respimat® (plus drug-filled cartridge) and a reserve MDI in their possession. At each visit, site staff should assess whether the reserve medication can be re-dispensed to the patient (considering remaining puffs and shelf-life) or if dispense of a new (replacement) reserve Respimat® inhaler plus drug-filled cartridge and/or MDI is needed. New reserve Respimats® and drug-filled cartridges should NOT be assembled prior to leaving the clinic. The patient must assemble and prime the reserve device at home if needed. Allocation of new reserve medication boxes will be handled by the IVRS/IWRS system. Re-supply One or more re-supplies are currently planned for this trial. Open-label supplies Boehringer Ingelheim will provide the following open-label supplies: • • 4.1.7 Respimat® inhalers, placebo cartridges and disposable mouthpieces for training purposes. A training device may be used for more than one training session. The training Respimat® can be used until 3 months after priming or until the device is empty. The date of first priming should be entered on the medication label of the Respimat®. A new mouthpiece should be used for each patient. Salbutamol (albuterol) HFA MDI inhalation aerosol (100 µg per actuation) for use as rescue medication during screening, treatment and follow-up periods (Visit 0 to V7). It will also be used for reversibility testing at Visit 1. Salbutamol (albuterol) will be dispensed to the patient at clinic visits as needed. Storage conditions All clinical trial supplies must be stored in a locked, secure cabinet and must be kept in their original packaging under the recommended storage conditions and may only be dispensed to trial subjects according to protocol. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 48 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 46 of 137 A temperature log must be maintained at the site. If the storage conditions are found to be outside the specified range, immediately contact the local clinical monitor. Further details are provided in the IB and on the country-specific labels, a sample of which will be part of the ISF. 4.1.8 Drug accountability Drug supplies, which will be provided by the sponsor, must be kept in a secure, limited access storage area under the storage conditions defined by the sponsor. A temperature log must be maintained to make certain that the drug supplies are stored at the correct temperature. The investigator / pharmacist / investigational drug storage manager will receive the investigational drugs delivered by the sponsor when the following requirements are fulfilled: • approval of the study protocol by the IRB / ethics committee, • availability of a signed and dated clinical trial contract between the sponsor and the Head of Trial Centre, • approval/notification of the regulatory authority, e.g. competent authority, • availability of the curriculum vitae of the principal investigator, • availability of a signed and dated clinical trial protocol or immediately imminent signing of the clinical trial protocol, • if applicable, availability of the proof of a medical licence for the principal investigator, • for USA only: availability of the Form 1572. The investigator / pharmacist / investigational drug storage manager must maintain records of the product’s delivery to the trial site, the inventory at the site, the use by each patient, and the return to the sponsor or alternative disposition of unused product(s). Any discrepancies in drug supplies will be noted and explained. These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and the unique code numbers assigned to the investigational product(s) and trial patients. The investigator / pharmacist / investigational drug storage manager will maintain records that document adequately that the patients were provided the doses specified by the CTP and reconcile all investigational product(s) received from the sponsor. At the time of return to the sponsor, the investigator / pharmacist / investigational drug storage manager must verify that all unused or partially used drug supplies have been returned by the clinical trial patient and that no remaining supplies are in the investigator’s possession. For non-investigational medicinal products (salbutamol/albuterol) specific drug accountability requirements need to be fulfilled. Refer to Section 4.2.1.1 for details. ADDITIONAL INFORMATION FOR JAPAN ONLY The investigator / pharmacist / investigational drug storage manager should return the unused and collected investigational drugs (including empty boxes) to the sponsor (OPU) after unblinding the trial. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 49 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 47 of 137 In case investigational drugs are returned before unblinding of the trial, the investigator / pharmacist / investigational drug storage manager should seal the opened box (excluding empty boxes) for the patient, and before returning the unused and collected investigational drugs (including empty boxes) to the sponsor. When returning the investigational drugs, the investigator / pharmacist / investigational drug storage manager should exercise utmost caution to assure that the sponsor and other relevant trial staff members remain blinded to the patient's name on the package (box or label) of the investigational drugs. Upon completion of the trial, the investigator / pharmacist / investigational drug storage manager submits to the sponsor a copy of the investigational drug dispensing and return log. When submitting the copy, the investigator / pharmacist / investigational drug storage manager should exercise caution to assure that the sponsor and other relevant trial staff members remain blinded to the patient's name. 4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT The investigator must record all medication used by the patient in the three months prior to Visit 0 and throughout the trial on the Concomitant Therapy electronic case report form (eCRF). 4.2.1 Rescue medication, emergency procedures, and additional treatment(s) 4.2.1.1 Rescue medication Administration of rescue medication is allowed at any point during the trial. Open-label salbutamol (albuterol) HFA MDI (100 µg per puff) will be provided as rescue medication (non-investigational medicinal product). During the complete trial period including screening, treatment and follow-up period, only salbutamol (albuterol) MDI provided by BI is allowed for PRN rescue medication use. Formoterol, alone or in fixed combinations with an ICS such as Symbicort® (budesonide and formoterol), is not allowed as rescue medication in this trial. During the screening and treatment period, patients must record the number of inhalations (puffs) of rescue medication used during the daytime and the nighttime in their electronic diary. If rescue medication is administered during a 3 or 24h PFT visit day, the visit will be discontinued and the patient will not complete the remainder of the pulmonary function testing. If rescue medication is administered during a PK visit, pulmonary function tests may be discontinued, but blood and urine collection for PK evaluation should be completed. Discontinued visits due to rescue medication intake will not be rescheduled. The medication used, dosage, route, date and 24-hour clock time of administration will be recorded on the Rescue Medication eCRF page. If rescue medication is administered on a visit day within 8 hours prior to the pre-dose PFT, the visit will be re-scheduled once. Further rescheduling should be discussed with the local clinical monitor. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 50 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 48 of 137 Salbutamol (albuterol) is considered a non-investigational medicinal product. Source data documentation and full drug accountability in regard to dispensed and returned medication to investigational site and to patients are required. 4.2.1.2 Emergency procedures There are no special emergency procedures to be followed. 4.2.1.3 Additional treatments Medications allowed to control acute asthma exacerbations as medically necessary during the screening, treatment and follow-up period: 1. PRN salbutamol (albuterol) HFA inhalation aerosol (MDI) provided by BI and to be recorded in the patient’s electronic diary. 2. Temporary addition of systemic corticosteroids is allowed during the study period. Pulmonary function testing should not occur within four weeks of the last administered dose of the addition (see Section 6.1 for visit schedule). 3. Temporary increases in the dose of inhaled corticosteroids are allowed during the study period. Pulmonary function testing should not occur within three weeks of the last administered dose of an increase (see Section 6.1 for visit schedule). 4. Temporary addition of theophylline preparations is allowed during the study period. Pulmonary function testing should not occur within seven days of the last administered dose of an increase or addition (see Section 6.1 for visit schedule). 5. The use of antibiotics is not restricted and may be used as medically necessary for asthma exacerbations and/or other infections. Pulmonary function testing should not occur within four days of the last administered dose of an increase or addition of antibiotics if given for an asthma exacerbation or respiratory tract infection (see Section 6.1 for visit schedule). The treatment of asthma exacerbations including initiation of systemic corticosteroids should be done according to the investigator´s or treating physician´s medical judgement and should be in line with national and international recommendations. In the case of life-threatening exacerbations, any and all therapies deemed medically necessary may be prescribed. Medications allowed prior to and throughout the trial: 1. Maintenance treatment with medium doses inhaled corticosteroids (required for study entry; refer to inclusion criterion no. 6). 2. Leukotriene modifiers (if stabilised for at least 4 weeks prior to the trial and remains stable throughout the trial). 3. Mucolytic agents not containing bronchodilators. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 51 Page U12-2467-02 21 Apr 2010 Page 49 of 137 Trial Protocol 4. Any orally inhaled rapid-acting beta-adrenergic agent is allowed prior to Visit 0. During the screening and randomised treatment periods and during the follow-up period, only salbutamol (albuterol) MDI provided by BI is allowed for PRN rescue medication use. The washout requirements before clinic visits need to be followed. 5. Antihistamines. Oral beta-adrenergics and beta blockers may be re-introduced during the follow-up period. However, it is not allowed to start with oral beta-adrenergics and beta blockers if not already prescribed prior to study entry. Treatment with pulmonary medications should remain stabilised as far as possible throughout the trial period. Refer to Section 4.2.2.1 for washout periods prior to pulmonary function testing during the study (including Visit 1). 4.2.2 Restrictions 4.2.2.1 Restrictions regarding concomitant treatment The following table provides an overview of required, permitted and restricted medication. Table 4.2.2.1: 1 Overview of required, permitted and restricted medication Medications prescribed for asthma may be washed out after Visit 0 (after signing informed consent) and prior to Visit 1 to comply with the criteria in the table below. Study Period Drug Class Sub-class Prior to study Screening Period Treatment Period Follow up Period Corticosteroids Inhaled corticosteroids1 REQUIRED Patients must have been on maintenance treatment with a medium, stable dose for at least 4 weeks prior to Visit 1 Maintenance treatment with a medium, stable dose REQUIRED Maintenance treatment with a medium, stable dose REQUIRED Maintenance treatment with a medium, stable dose REQUIRED Oral corticosteroids NOT permitted for at least four weeks prior to Visit 1 NOT permitted Temporary addition to treat exacerbations is allowed.1 NOT permitted Temporary addition to treat exacerbations is allowed. 1 Permitted Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 52 Page U12-2467-02 21 Apr 2010 Page 50 of 137 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class Sub-class Betaadrenergics / Beta-blockers Anticholinergics Prior to study Screening Period Treatment Period Follow up Period Inhaled shortacting betaadrenergics Permitted Rescue (prior to all visits at least 8-hour washout) Rescue (prior to all visits at least 8-hour washout) Rescue Inhaled longacting betaadrenergics Permitted NOT permitted from 24 hours prior to Visit 1 Study medication Permitted Oral and patch beta-adrenergics NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted Permitted Beta blockers NOT permitted for at least four weeks prior to Visit 1 Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. NOT permitted Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. NOT permitted Topical cardioselective betablocker eye medications for treatment of non-narrow angle glaucoma are allowed. Short-acting anticholinergics (inhalation aerosol and nasal spray) Permitted NOT permitted from 8 hours prior to Visit 1 Not permitted Permitted Long-acting anticholinergics NOT permitted for at least four weeks prior to Visit 1 NOT permitted Study medication NOT permitted (only reintroduction is allowed. NOT allowed to start if not used prior to trial entry) Permitted (only reintroduction is allowed. NOT allowed to start if not used prior to trial entry) Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 53 Page U12-2467-02 21 Apr 2010 Page 51 of 137 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class Sub-class Prior to study Screening Period Treatment Period Follow up Period Miscellaneous Other investigational drugs NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted Combination ICS/LABA (e.g. Advair®/ Seretide®; Symbicort®; Foster ®) Permitted NOT permitted Permitted Combination ICS/SABA (e.g. Butasol®) Permitted NOT permitted Permitted Combination short-acting anticholinergic/ SABA (e.g. Berodual®, Combivent®, Duovent®) Permitted NOT permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 24 hours prior to Visit 1 NOT permitted Patient should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 8 hours prior to visit 1 NOT permitted from 8 hours prior to Visit 1 NOT permitted Permitted NOT permitted for at least two weeks prior to Visit 1 NOT permitted NOT permitted Permitted Permitted Permitted Permitted Permitted Cromone Antihistamines Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 54 Page U12-2467-02 21 Apr 2010 Page 52 of 137 Trial Protocol Table 4.2.2.1: 1 Overview of required, permitted and restricted medication (continued) Study Period Drug Class Sub-class Prior to study Screening Period Treatment Period Follow up Period NOT permitted for at least two weeks prior to Visit 1 NOT permitted Temporary addition of theophylline to treat exacerbations is allowed1 NOT permitted Temporary addition of theophylline to treat exacerbations is allowed1 Permitted Mucolytics Permitted Permitted Permitted Permitted Leukotriene modifiers Permitted To be stabilised for four weeks prior to Visit 1 and throughout the trial. Permitted Permitted Permitted Anti-IgE treatment (e.g. Omalizumab) NOT permitted for at least 6 months prior to Visit 1 NOT permitted NOT permitted Permitted ´Experimental´, non-approved asthma medications (e.g TNF-alpha blockers) NOT permitted for at least four weeks prior to Visit 1 NOT permitted NOT permitted NOT permitted Methylxanthines /phosphodiesterase 4 inhibitors 1 Refer to Section 4.2.1.3 for washout period prior to PFTs in case of treatment of an asthma exacerbation. Medication restrictions for pulmonary function testing (including Visit 1): 1. At least a 24-hour washout of long-acting beta-adrenergic bronchodilators prior to Visit 1 (not allowed between Visit 1 and 6). 2. At least a 24-hour washout of combination products, long-acting beta-adrenergic bronchodilators/corticosteroid prior to Visit 1 (not allowed between Visit 1 and 6). Patients should be switched to the inhaled steroid mono-product without changing the steroid dose at least 24 hours prior to Visit 1. 3. At least an 8-hour washout of short-acting beta-adrenergic bronchodilators prior to PFTs. 4. At least an 8-hour washout of short-acting anticholinergic bronchodilators prior to Visit 1 (not allowed between Visit 1 and 6). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 55 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 53 of 137 5. At least an 8-hour washout of combination short-acting anticholinergic/SABA prior to Visit 1 (not allowed between Visit 1 and 6) 6. At least an 8-hour washout of combination products ICS/SABA prior to Visit 1 (not allowed between Visit 1 and 6). Patients should be switched to the inhaled steroid monoproduct without changing the steroid dose at least 8 hours prior to Visit 1 7. On a visit day, the evening doses of the patient's regular ICS therapy, LTRA (if applicable) and trial medication should be taken after the visit day pre-dose PFT (i.e. at the clinic and not at home). 4.2.2.2 Restrictions on diet and life style Restrictions prior to PFT visits 1. Medication washout restrictions should be adhered to as described in Section 4.2.2.1. 2. The patient must remain in the building where the pulmonary function testing is performed and must return to the laboratory at least ten minutes prior to the start of each test. 3. On pulmonary function test days (including the Screening Visit), patients must refrain from strenuous activity for at least 12 hours prior to pulmonary function testing and throughout the testing period. Patients should also avoid cold temperatures, environmental smoke, dust or areas with strong odours (e.g. perfumes). 4. Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and icecold beverages are not allowed at least 2 hours prior to and during the pulmonary function testing period at clinic visits. Decaffeinated beverages are acceptable. 5. If a patient (re-)starts smoking during the trial, smoking should be discouraged for the 12 hours prior to pulmonary function testing and throughout the test day and will not be permitted in the 30-minute period prior to spirometry. Additional restrictions for patients participating in PK subset Patients who participate in pharmacokinetic sampling are not allowed to take any fruit juices (e.g. oranges, grapefruits), as well as products containing St. John´s wort (Hypericum perforatum) 72 hours before the pharmacokinetic sampling at Visits 2, 2A, 2B, 2C and 3. 4.3 TREATMENT COMPLIANCE The patient will complete an eDiary confirming that trial medication has been taken and indicating the number of puffs of salbutamol (albuterol) MDI use. The investigator will review these records with the patient at each visit (Visits 2 to 6) to assess treatment compliance. Compliance should be emphasised with a goal of at least 80% compliance rate. However, randomised patients will not be discontinued for lack of compliance without prior discussion with the local clinical monitor. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 56 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 54 of 137 On visit days, compliance will be guaranteed by administration of the trial drug under supervision of the investigating physician or designee. Each patient will be trained in the correct use of the Respimat® inhaler at Visit 1 and Visit 2. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 57 Page U12-2467-02 Trial Protocol 5. VARIABLES AND THEIR ASSESSMENT 5.1 EFFICACY - CLINICAL PHARMACODYNAMICS 5.1.1 Endpoint(s) of efficacy 21 Apr 2010 Page 55 of 137 Combined data of the two twin trials 205.418 and 205.419 will be used to ensure an adequate number of patients for the endpoints ACQ, time to first severe asthma exacerbation and time to first asthma exacerbation. These endpoints will be comprehensively analysed in a metaanalysis, the individual reports will only provide basic descriptive displays regarding these endpoints. 5.1.1.1 Primary Endpoints The co-primary endpoints are 1. Peak forced expiratory volume in one second (FEV1) response (within 3 hours post dosing) determined at the end of the 24-week treatment period. 2. Trough FEV1 response determined at the end of the 24-week treatment period. Peak FEV1 is defined as the highest FEV1 reading observed within 3 hours after administration of the evening dose of each randomised treatment. Peak FEV1 response is defined as the change from baseline in peak FEV1. Trough FEV1 is defined as the FEV1 measured (in the evening) at the -10 minute time point at the end of the dosing interval (24 hours post drug administration). Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline is the pre-treatment FEV1 measured at Visit 2 in the evening 10 minutes prior to the evening dose of patient’s usual inhaled corticosteroid controller medication (if regular posology) and first dose of trial medication (inhalation via MDI followed by inhalation via Respimat® inhaler). Meta-Analysis: The primary endpoint is the responder as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period on combined data from the two twin trials 205.418 and 205.419. The following definition for responder will be used. A patient is said to be a responder if for that patient an improvement of at least 0.5 for the ACQ was observed. The minimum clinical important deifference (MCID) for the ACQ is 0.5. 5.1.1.2 Secondary Endpoints 1. Peak (within 3 hours post dosing) and trough forced vital capacity (FVC) determined at the end of the 24-week treatment period (as defined above for FEV1). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 58 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 56 of 137 2. FEV1 (AUC0-3h) and FVC (AUC0-3h) at the end of the 24-week treatment period. The AUC0-3h will be calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough values will be assigned to zero time. FEV1 AUC 0−3h = 1 4 1 ( FEV1 (t i −1 ) + FEV1 (t i )) * (t i − t i −1 ) ∑ i =1 3h 2 (Trapezoid rule) where FEV1(ti) = FEV1 reading at planned time ti t0 = pre-dosing (= 0 min), t1 = 0.5h, …t4 = 3h FVC (AUC0-3h) is defined in the same way as FEV1 (AUC0-3h). 3. Individual in-clinic FEV1, FVC and PEF measurements at all time-points including peak, trough and AUC0-3h during the 24-week treatment period. 4. Quality of Life as assessed by standardised Asthma Quality of Life Questionnaire (AQLQ (S)) at all clinic visits during the 24-week treatment period. 5. PEF am/pm: change from baseline in mean weekly pre-dose morning and evening PEF measured by patients at home in the last week of the 24-week treatment period. Baseline is defined as the last week prior to randomization. 6. Use of PRN salbutamol (albuterol) rescue medication during the 24-week treatment period: number of puffs of rescue therapy used per day (i.e. the full 24 hour period, the daytime and the nighttime; weekly means will be compared). 7. Asthma symptoms as assessed by the patient’s electronic diary during the 24-week treatment period. Analysis with regard to daytime and nocturnal symptoms will be done. 8. Asthma symptom free days during the 24-week treatment period: asthma symptom free day is defined as a day with no reported symptoms and no use of rescue medication. Additionally in a subset of patients: 9. FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC1224h), FVC (AUC0-24h) after 24-week treatment FEV1 AUC n − mh = 1 k 1 ∑ ( FEV1 (t i −1 ) + FEV1 (t i )) * (t i − t i −1 ) mh i = j 2 where FEV1(ti) = FEV1 reading at planned time ti t0 = pre-dosing (= 0 min), t1 = 0.5h, …t16 = 23.5h and tj-1=nh, tk=mh FVC (AUCn-mh) is defined in the same way as FEV1 (AUCn-mh). (Trapezoid rule) Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 59 U12-2467-02 Trial Protocol 21 Apr 2010 Page 57 of 137 The FEV1 (AUC0-12h), FEV1 (AUC12-24h), and FEV1 (AUC0-24h) will be calculated as described above for FEV1 (AUC0-3h). The same method applies to the different areas under the curve for FVC. 10. The responder as assessed by the ACQ determined at the end of the 24-week treatment period for each trial separately. Meta-Analysis: The secondary endpoints on combined data from the two twin trials 205.418 and 205.419 are: 1. Time to first severe asthma exacerbation during the 24-week treatment period. 2. Time to first asthma exacerbation during the 24-week treatment period. 3. The ACQ value at each visit during the 24 week treatment period 5.1.1.3 Other Endpoints Three additional pulmonary function endpoints will be analysed: 1. PEF am/pm: weekly mean pre-dose morning and evening PEF measured by patients at home (weekly means will be compared) from baseline to the last week of the 24-week treatment period. Baseline is defined as the last week prior to randomization. 2. FEV1 am/pm: mean pre-dose morning and evening FEV1 measured by patients at home (weekly means will be compared) from baseline to the last week of treatment. Baseline is defined as the last week prior to randomization. 3. PEF variability: PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values (weekly means will be compared) during the 24-week treatment period. 5.1.2 Assessment of efficacy Pulmonary Function Testing (PFT) on study visits Germany) will be provided to sites MasterScope® CT spirometers ( for the in-clinic spirometry measurements. The spirometers and their use, including daily calibration, must meet ATS/ERS criteria [P05-12782]. Spirometry will be conducted with the patient in a seated position having abstained from medications as specified in Section 4.2.2.1, and it is preferable that the same trained individual performs the PFTs for a given patient. The best of three efforts will be defined as the highest FEV1, the highest FVC and the highest PEF each obtained on any of three blows meeting the ATS criteria (with a maximum of five attempts). The highest FEV1, FVC and PEF will be selected regardless of whether they come from different spirometric manoeuvres or from the same manoeuvre. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 60 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 58 of 137 At the 24-hour PFT test-day (Visit 6), patients participating in this subset should be woken 40 minutes (± 10 minutes) prior to the start of the initial morning PFT (11h50’ time point). For each patient, pulmonary function testing will always start at approximately the same time of the day and depending on the time of dosing. At Visit 1 pulmonary function testing will be performed between 06.00 and 08.00 pm. At Visits 2 to Visit 6, visits and PFTs will be scheduled to enable dosing between 6:00 pm and 8:00 pm. At Visits 3 to Visit 6 pulmonary function testing should start with ± 30 minutes maximum difference between the start of the tests on Visit 2 and the tests conducted on subsequent test days . The end of the 2nd inhalation of evening dose of study medication from the Respimat® will be regarded as time point zero for pulmonary function testing. At Visits 2 to 6, the 10 minute pre-dose measurement will be obtained in the period from 25 minutes to 5 minutes prior to the evening dose of ICS and study medication. The 30 and 60 minute measurements will be obtained within ± 5 minutes of the specified time point; and measurements made from 2-24 hours post-dose will be performed within ± 10 minutes of the scheduled time point. If a patient is unable to complete the PFTs during a visit, the local clinical monitor should be notified as soon as possible. The eCRF will be completed indicating the reason for stopping testing. Refer to Section 4.2.1.1 for more details on conduction of trial procedures if rescue medication was administered during a visit day. Patients who are unable to complete the trial visit may leave the clinic only upon instruction from the supervising physician. Refer to Section 4.1.4 (Trial medication at clinic visits) for more information on medication intake times that will be captured with the Masterscope® CT spirometer. Refer to Section 4.2.2.1 for restrictions regarding concomitant therapy prior to PFTs. Refer to Section 4.2.2.2 for restrictions on diet and life style prior to PFTs. Refer to the Flow Chart for the time schedule. Asthma Control Questionnaire (ACQ) The Asthma Control Questionnaire (ACQ) developed by Elizabeth Juniper [R00-1157] has 6 patient self-administered questions for the time period of the last week prior to the visit and one question concerning pre-bronchodilator FEV1 to be completed by a member of the clinic staff. Each question has a 7-point scale. The ACQ will be completed from Visit 1 to Visit 6 and should be the first questionnaire completed during Visit 2 to 6 and should precede any discussion with a health professional (physician, nurse or study co-ordinator). Question 7 will be completed after pulmonary function testing. The questions in the questionnaire are weighted equally, the score is the mean of the responses to all 7 questions. The ACQ is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Please refer to Appendix 10.6 for an example of the questionnaire. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 61 U12-2467-02 Trial Protocol 21 Apr 2010 Page 59 of 137 Electronic peak flow meter with electronic diary (Asthma Monitor® AM3) Germany) The patients will receive an Asthma Monitor® AM3 ( which combines the features of an electronic peak flow meter (measurement of both PEF and FEV1) and an electronic diary in one device. Patients will receive the AM3 at Visit 1 and instructions for the use of the device at Visit 1 and Visit 2. They will use the device during the screening and treatment period (Visit 1 to Visit 6). The device will be used twice daily to first record questions related to asthma symptoms and quality of life, use of rescue salbutamol (albuterol), use of trial medication (during the treatment period only), and then to measure PEF and FEV1. Morning and evening recordings and measurements should be performed at approximately the same time of the day (± 30 minutes) between 6:00 and 08:00 am and 6:00 and 08.00 pm, respectively. The patient will be alerted by the AM3 to contact the investigator in case of one of the following situations: • A decrease of patient's best morning PEF of ≥ 30% from the patient's mean morning PEF for at least two consecutive days During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. • The patient used 12 or more puffs of rescue medication for at least two consecutive days All PEF/FEV1 and eDiary data saved in the AM3 will be downloaded at each visit after Visit 1 (except at Visits 2A, 2B and 2C) and transmitted via the MasterScope® CT to central data management of the vendor. At each trial visit the investigator receives a print-out of all downloaded AM3 data for review. Details and instructions for use are given in the Appendix 10.9 and the ISF. Electronic diary (eDiary) at home The diary part of the AM3 will be used to record the answers to the questions raised in the daily diary. The eDiary includes questions on asthma symptoms, quality of life and number of puffs of rescue medication. The diary must be answered in the morning immediately upon arising (after the patient has cleared out mucus) and in the evening both prior to administration of maintenance ICS (if regular posology) and trial medication (and rescue medication if needed). Trial medication taken during the treatment period (morning and evening) will also be recorded in the AM3. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 62 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 60 of 137 Peak flow measurements at home The patient will record twice-daily PEF and FEV1 during the screening and treatment period (Visit 1 to Visit 6) with the AM3 immediately after answering the eDiary questions. The morning measurement should be performed upon arising after the patient has cleared out mucus and prior to administration of maintenance ICS (if regular posology) and trial medication (and rescue medication if needed). The evening measurement will be performed prior to administration of maintenance ICS (if regular posology) and trial medication (and rescue medication if needed). The patient should perform three peak expiratory flow manoeuvres in the standing position with the AM3. All acceptable PEF and FEV1 values are stored in the AM3 with date and time of the reading. The highest PEF and the highest FEV1 out of up to three acceptable blows, but not necessarily from the same blow, will be used for evaluation. Peak flow measurements and eDiary at Visit days 2 to 6 The morning recordings at home should be done as usual. In the afternoon/evening, patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic between -1:00 and -0:30h and prior to administration of maintenance ICS (if regular posology) and trial medication. The medication should be administered at the clinic after the pre-dose pulmonary function testing with the MasterScope® CT. Peak flow measurements and eDiary at 24 hour visits (Visit 2, 3 and/or 6 at selected sites) The morning recordings at home and on the following morning in the clinic should be done as usual. Also see the Flow Chart. The afternoon/evening recordings should be done in the clinic as described above. On the following afternoon/evening (at the end of the visit), patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic prior to administration of maintenance ICS (if regular posology) and trial medication and prior to leaving the clinic. Peak flow measurements and eDiary at Visits 2A, 2B and 2C at selected sites The morning recordings at home should be done as usual. In the afternoon/evening, patients should answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic between -1:00 and -0:30h and prior to administration of maintenance ICS (if regular posology) and trial medication.The medication administration should be performed at the clinic after the pre-dose PK sample has been drawn. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 63 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 61 of 137 Asthma Exacerbations The patient will document any worsening of asthma symptoms during the screening and treatment period in the electronic diary of the AM3 and measure the PEF twice daily (see Appendix 10.9). In addition, the patient will receive a paper patient diary card to document specific asthma symptoms, required medical treatment (e.g. change in asthma medication, need for medical care) or lost working days due to the asthma worsening (see Appendix 10.8). The investigator will review the patient’s entries and enter the relevant information from the paper patient diary card in the eCRF. The paper patient diary card will remain at the site. A new patient diary card should be dispensed at every visit as needed. The investigator should collect all information regarding asthma exacerbations including review of the electronic and paper diary. Specific questions should be raised to capture any asthma worsening, any changes in concomitant asthma medication including the introduction of systemic corticosteroids or any unplanned need for medical care due to asthma or lost working days that have not been documented in the patient’s diaries. It is the investigator’s responsibility to report any deterioration of asthma as an AE regardless if the sponsor’s definition of asthma exacerbations is fulfilled or not. The treatment of asthma exacerbations including initiation of systemic corticosteroids should be done according to the investigator´s or treating physician´s medical judgement and should be in line with national and international recommendations. If systemic corticosteroids are required, the GINA guidelines recommend to initially dose oral glucocorticosteroids between 0.5 to 1 mg of prednisolone or equivalent /kg body weight during 24-hours [P10-03196]. Whenever feasible, the following scheme is recommended for the trial: 30 mg/day prednisolone or prednisolone equivalent for 7 days. The onset of an asthma exacerbation should be defined by the onset of the first worsened symptom respectively PEF deterioration. The end of an asthma exacerbation should be recorded as defined by the investigator. Courses of systemic corticosteroids that are separated by one week or more should be treated as separate exacerbations. Refer to Appendix 10.10 for the BI definition of an asthma exacerbation in general and a severe asthma exacerbation. Asthma Quality of Life Questionnaire (AQLQ (S)) The standardised Asthma Quality of Life Questionnaire (AQLQ (S)) developed by Elizabeth Juniper [R08-0092] is administered on every visit from Visit 2 to 6. The AQLQ (S) is patient self-administered. The AQLQ (S) has 32 questions for the time period of the last two weeks prior to the visit and each question has a 7-point scale. Eleven questions refer to activity limitations, twelve questions refer to symptoms, five questions to emotional function and another four questions to environmental stimuli. The AQLQ (S) should be the second questionnaire completed (ACQ is completed first) and should precede any discussion with a health professional (physician, nurse or trial co-ordinator). The AQLQ (S) is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. The investigator (or designated site personnel) should check Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 64 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 62 of 137 that all items have been completed by the patient, but the response to each item should not be questioned. Challenges to inconsistent responses (pronounced outliers) should only be done very infrequently and with very careful consideration. Please refer to Appendix 10.5 for an example of the questionnaire. 5.2 SAFETY 5.2.1 Endpoint(s) of safety 1. All adverse events. 2. Vital signs: pulse rate and blood pressure (seated) recorded in conjunction with spirometry until 3 hours post-dose. 3. Vital status information of prematurely discontinued patients to be collected for all randomised patients on the originally planned follow up visit date (Visit 7). 5.2.2 Assessment of adverse events 5.2.2.1 Definitions of adverse events Adverse event An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. The event does not necessarily have to have a causal relationship with this treatment. Serious adverse event A serious adverse event (SAE) is defined as any AE which results in death, is immediately life-threatening, results in persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an important medical event when based upon appropriate medical judgement which may jeopardise the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above definitions. Additional information for Japan: An AE which possibly leads to disability will be reported as an SAE. Every new occurrence of cancer will be reported as a SAE regardless of the duration between discontinuation of the drug and the occurrence of the cancer. Significant Adverse Events No events have been classified as "significant" for this trial. Intensity of adverse event The intensity of the AE should be judged based on the following: • • Mild: Moderate: Awareness of sign(s) or symptom(s) which is/are easily tolerated Enough discomfort to cause interference with usual activity Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 • Severe: 65 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 63 of 137 Incapacitating or causing inability to work or to perform usual activities Causal relationship of adverse event Medical judgment should be used to determine the relationship, considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant medication, concomitant diseases and relevant history. Assessment of causal relationship should be recorded in the case report forms. Additional information for Japan: The reason for the decision on causal relationship needs to be provided in the eCRF. • • Yes: There is a reasonable causal relationship between the investigational product administered and the AE. No: There is no reasonable causal relationship between the investigational product administered and the AE. If a SAE is reported from a still blinded trial, the causal relationship must be provided by the investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. any active comparator or placebo according to the trial design). Worsening of underlying disease or other pre-existing conditions Expected fluctuations or expected deterioration of the underlying disease and other preexisting conditions should not be recorded as an AE unless at least one of the following criteria is met: − the worsening of the disease constitutes an SAE, − the investigational drug is discontinued or the dose is reduced or increased, − additional treatment is required, i.e. concomitant medication is added or changed. − an unexpected deterioration from baseline has occurred in the opinion of the investigator. Changes in vital signs, ECG, physical examination, and laboratory test results Changes in vital signs including blood pressure, pulse rate, ECG, physical examination, and laboratory tests will be only then recorded as AEs if they are not associated with an already reported AE, symptom or diagnosis, and the investigational drug is either discontinued, reduced or increased, or additional treatment is required, i.e. concomitant medication is added or changed. Listed Adverse Events Please refer to Section 8.4.1 for more information. 5.2.2.2 Adverse event and serious adverse event reporting All adverse events, serious and non-serious, occurring during the course of the clinical trial (i.e., from signing the informed consent onwards through the observational phase and until 21 days after the last dose of trial medication) will be collected, documented and reported to the sponsor by the investigator on the appropriate CRF(s) / eCRFs / SAE reporting forms. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 66 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 64 of 137 Reporting will be done according to the specific definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File. All AEs, including those persisting after trial completion must be followed up until they have resolved or have been sufficiently characterised. For each adverse event, the investigator will provide the onset date, end date, intensity, treatment required, outcome, seriousness, and action taken with the investigational drug. The investigator will determine the relationship of the investigational drug to all AEs as defined in Section 5.2.2.1. If not stipulated differently in the ISF, the investigator must report the following events via telephone/fax using the SAE form immediately (within 24 hours or the next business day whichever is shorter) to the sponsor: SAEs and non-serious AEs occurring at the same time as an SAE and/or which are medically related to the SAE(s). Additional information for Japan: This information must be also reported immediately to the head of the trial site. With receipt of any further information to these events, a follow-up SAE report has to be provided. SAEs and non-serious AEs must include a causal relationship assessment made by the investigator. The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU (country-specific contact details will be provided in the Investigator Site File). This immediate report is required irrespective of whether the investigational product has been administered or not and irrespective of causal relationship. It also applies if new information to existing SAEs becomes available. Vital status information After any premature withdrawal of patients that took at least one dose of trial medication, the vital status information (dead or alive) will be collected on the originally planned visit date of the follow up visit (Visit 7). Any death during the vital status observation period needs to be reported as SAE by the investigator according to the Boehringer Ingelheim SAE procedures. Pregnancy In rare cases, pregnancy might occur in clinical trials. Once a female subject has been enrolled into the clinical trial, after having taken study medication, the investigator must report immediately any drug exposure during pregnancy to the sponsor. Drug exposure during pregnancy has to be reported immediately (within 24 hours or next business day whichever is shorter) to the defined unique entry point for SAE forms of the respective BI OPU (country-specific contact details will be provided in the Investigator Site File). The outcome of the pregnancy associated with the drug exposure during pregnancy must be followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 5.2.3 67 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 65 of 137 Assessment of safety laboratory parameters Clinical laboratory testing Clinical laboratory testing will be conducted on all patients at Visit 1 (to determine patient's eligibility) and Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. Lab parameters will be analysed by the local laboratory of each participating site. Please refer to Appendix 10.11 for methodological details. At Visit 1, the white blood cell count, eosinophil count (absolute and relative), total serum IgE and creatinine levels will be recorded on the eCRF. Pregnancy testing A pregnancy test will be conducted at Visit 1 and Visit 6 (or at the withdrawal visit if the patient does not complete all trial visits) in all women of childbearing potential. It will be sufficient to use a urine test kit (provided by BI or by the investigator/hospital). 5.2.4 Electrocardiogram A standard 12-lead electrocardiogram (ECG) will be performed on all patients at Visit 1 (to obtain information about the patient's baseline condition and to determine patient's eligibility) and at Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. All clinically significant findings at screening (Visit 1) will be recorded on the Medical History/Baseline Condition page in the eCRF. New clinically significant findings or worsening of screening conditions detected at Visit 6 (or at a withdrawal visit) will be recorded as adverse events on the appropriate eCRF page. An explanation of the aetiology of clinically significant abnormal findings must be made on the eCRF. All relevant abnormal findings have to be followed up until they have normalised or have been sufficiently characterised. 5.2.5 Assessment of other safety parameters Vital signs Pulse rate, systolic and diastolic blood pressure will be measured and recorded in conjunction with pulmonary function testing at Visit 2 to Visit 6 and prior to inhalation of medication and until 3 hours post-dose. Measurements will always be obtained immediately before pulmonary function testing with the patient seated and rested for a minimum of five minutes. The same person using the same blood pressure instrument on the same arm should perform all recordings. Physical examination A complete, head-to-toe physical examination will be completed on all patients at the screening visit (Visit 1) and at Visit 6 or at the withdrawal visit if the patient does not complete all trial visits. The physical examination will also include measurements of systolic Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 68 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 66 of 137 and diastolic blood pressure and pulse rate, which will be measured with the patient seated after having rested for at least 5 minutes. All clinically significant findings at screening (Visit 1) will be recorded on the Medical History/Baseline Condition page in the eCRF. New clinically significant findings or worsening of screening conditions detected at Visit 6 (or at a withdrawal visit) will be recorded as adverse events on the appropriate eCRF page. An explanation of the aetiology of clinically significant abnormal physical findings must be made on the eCRF. All relevant abnormal physical findings have to be followed up until they have normalised or have been sufficiently characterised. Vital status Vital status information (dead or alive) will be collected at the originally planned visit date of the follow up visit (Visit 7) for discontinued patients following randomisation. The vital status eCRF will be completed. Collection of vital status information does not require a patient visit. If no information can be collected despite at least 3 (documented) phone calls and at least one registered letter have remained unanswered, the patient will be regarded as lost to follow-up. 5.3 OTHER 5.3.1 Other endpoints For the purpose of a separate health economic analysis (for example cost-effectiveness analysis including the clinical endpoint as effectiveness parameter), health care resource utilisation (HCRU) data will be collected and Quality of Life will be assessed at all time points during the 24-week treatment period. The economic evaluation of the HCRU and EQ-5D data will not be part of the clinical trial report. 5.3.2 Other assessments Additional pulmonary function endpoints Refer to Section 5.1.2 for assessments of additional pulmonary function endpoints. HCRU data Resource use related to asthma will be captured within the trial in order to estimate and compare cost of treatment across treatment arms. HCRU data will be collected from Visit 2 to 6. Resource use data collected for calculating direct costs will include, e.g. number of days in hospital, number of unscheduled health care provider visits, number of visits in emergency room, number of days in intensive care unit, concomitant medications, and lost working days due to asthma. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 69 U12-2467-02 Trial Protocol 21 Apr 2010 Page 67 of 137 EQ-5D The EQ-5D self-report questionnaire was developed by the ( and is a standardised instrument for use as a measure of health outcome [R96-2382]. The EQ-5D is patient self-administered and will be completed from Visit 2 to 6. The questionnaire essentially consists of 2 pages. The first page is the descriptive system with 5 questions to the patient’s health state today. Each question captures one dimension of health (e.g. mobility, self-care) and has three levels to answer. The second page records the patient’s self-rated health status of today on a vertical graduated (0-100) visual analogue scale. The EQ-5D should be the third questionnaire completed and should precede any discussion with a health professional (physician, nurse or study co-ordinator). The EQ-5D is provided on paper. Patients should be by themselves in a quiet place when they complete the questionnaire. In instances where a patient cannot give or decide upon a response, no response should be recorded. The investigator (or designated site personnel) should check that all items have been completed by the patient, but the response to each item should not be questioned. Please refer to Appendix 10.7 for an example of the questionnaire. 5.3.3 Pharmacogenetic evaluation Exploratory genetic investigations in respiratory diseases might be done after complete anonymisation of the patient’s blood sample. 5.3.3.1 Methods of sample collection To allow pharmacogenetic analyses, all patients (who signed a separate informed consent) will be asked for one blood sample after successful randomisation at Visit 2 (or at any other subsequent Visit after randomisation). The samples will be taken and stored in accordance with local ethical and regulatory requirements. Participation in the pharmacogenetics part is voluntary and not a prerequisite for participation in the trial. The blood sample will be completely anonymised. The anonymisation procedure will guarantee a very high level of data protection for the donor. Once the anonymisation has been carried out, there will be no legal way to trace back to the identity of the donor. The anonymised DNA may be analysed at a later time to identify whether there are genetic factors that could contribute to a better therapeutic outcome or a higher risk of developing treatment related adverse drug reactions. Genetic investigations will be limited to the investigation of the effects of genetic variations on respiratory diseases, and on efficacy, safety and pharmacokinetics of the trial drug. After anonymisation, the blood sample (or the DNA derived thereof) will be stored at Boehringer Ingelheim for 15 years after the end of the clinical trial or until there is no more material available for tests. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 5.3.3.2 Page 70 U12-2467-02 Trial Protocol 21 Apr 2010 Page 68 of 137 Analytical determinations Genomic DNA will be extracted from blood samples according to standard molecular genetics methods. 5.4 APPROPRIATENESS OF MEASUREMENTS Pulmonary function tests are a validated and well established measurement tool for lung function testing. Pulmonary function tests will be conducted at clinic visits using the MasterScope® CT Spirometer ( , Germany). FEV1 is a standard measurement for the assessment of lung function. The AM3 device ( , , Germany) will be used for measurement of PEF and FEV1 and to record the data of the eDiary. The AM3 complies with the regulations of European Medical Device Directive and the FDA guidelines in the United States. The EQ-5D, AQLQ(S) and ACQ are well established and validated questionnaires. 5.5 DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS A subset of 80 patients will participate in the PK part of the trial. Plasma and urine concentration monitoring of tiotropium will be performed in order to assess drug exposure and to characterise the pharmacokinetics of tiotropium bromide in this patient population. A separate informed consent will be signed by the patients in accordance with local ethical and regulatory requirements. 5.5.1 Pharmacokinetic endpoint(s) The following pharmacokinetic parameters will be determined at Visit 2 (day 1) in relation to the administration of the first dose of tiotropium, when feasible: 1. Cmax (maximum concentration of tiotropium in plasma) 2. tmax (time from dosing to maximum tiotropium plasma concentration) 3. AUC0-tz (area under the concentration-time curve of tiotropium in plasma over the time interval from 0 to the last quantifiable data point within the first dosing interval) 4. Aet1-t2 (amount of tiotropium that is eliminated unchanged in urine from the time point t1 to time point t2) 5. fet1-t2 (fraction of tiotropium dose excreted in urine from time point t1 to t2) 6. AUCt1-t2 (area under the concentration-time curve of tiotropium in plasma over the time interval t1 to t2) Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 71 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 69 of 137 7. AUC0-∞ (area under the concentration-time curve of tiotropium in plasma over the time interval from 0 extrapolated to infinity) 8. %AUCtz-∞ (the percentage of the AUC0-∞ that is obtained by extrapolation) 9. λz (terminal rate constant of tiotropium in plasma) 10. t½ (terminal half-life of tiotropium in plasma) 11. MRTih (mean residence time of tiotropium in the body after inhalation) 12. CL/F (apparent clearance of tiotropium in the plasma after extravascular administration) 13. Vz/F (apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose) 14. CLR,t1-t1 (renal clearance of tiotropium in plasma from the time point t1 to time point t2) A pre-dose blood sample will be obtained at Visits 2A, 2B and 2C and will be reported as Cpre,N (pre-dose concentration of tiotropium in plasma). Similarly, a blood sample will be obtained 5 minutes post-dosing at Visits 2A, 2B and 2C and will be reported as C0.083,N (tiotropium plasma concentration 5 minutes post-dosing). At Visit 3 (week 4) tiotropium steady state will be assumed and the following parameters will be determined, when feasible: 1. AUCt1-t2,ss (area under the concentration time curve of tiotropium in plasma over the time interval t1 to t2 at steady state) 2. AUCτ,ss (area under the plasma concentration-time curve at steady state over a uniform dosing interval τ at steady state) 3. Cmax,ss (maximum measured concentration of tiotropium in plasma at steady state) 4. tmax,ss (time from dosing to the maximum concentration of tiotropium in plasma at steady state) 5. λz,ss (terminal rate constant in plasma at steady state) 6. t½,ss (terminal half-life of tiotropium in plasma at steady state) 7. MRTih,ss (mean residence time of tiotropium in the body after inhalational administration to steady state) 8. CL/F,ss (apparent clearance of tiotropium from plasma after extravascular administration to steady state) Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 72 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 70 of 137 9. Vz/F,ss (apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose) 10. Aet1-t2,ss (amount of tiotropium that is eliminated in urine from the time point t1 to time point t2 (Ae0-2, Ae2-6 at steady state) 11. fet1-t2, ss (fraction of tiotropium eliminated in urine from time point t1 to time point t2 (fe02, fe2-6 at steady state) 12. CLR,t1-t2,ss (renal clearance of tiotropium from the time point t1 until the time point t2) (CLR,0-2, CLR, 2-6 at steady state) 13. Cpre,ss (predose concentration of tiotropium in plasma at steady state) 14. Cmin,ss (minimum concentration of tiotropium in plasma at steady state) In addition, the linearity index (LI) and the following accumulation ratios of the analyte in plasma following 28 doses over a uniform dosing interval τ will be calculated: 15. RA,Cmax,28 based on Cmax 16. RA,AUC based on AUC Further pharmacokinetic parameters may be calculated as appropriate. Details on the pharmacokinetic methods can be found in Appendix 10.12. The pharmacokinetic parameters will be included in the clinical trial report. 5.5.2 Methods of sample collection Date and exact clock time of pharmacokinetic sampling have to be recorded and documented in the eCRFs by the site personnel. Clocktime of the MasterScope® CT should be used at Visit 2 and Visit 3. The time point zero for pharmacokinetic sampling is defined as end of last inhalation from the Respimat®. For handling of medication administration at clinic visits and collection of medication administration time points, please refer to Section 4.1.4. The pre-dose PK blood sample will be obtained 15 minutes before trial drug administration. A planned time of -0:15 will be used for data base set-up. The pre-dose urine sample collection interval will be the hour prior to trial drug administration. A planned start time of -1:00 and a stop time of 0:00 will be used for data base set-up. At Visit 2 and 3, the patient may leave the clinic after the morning inhalation of trial medication (or, if preferred by the patient, after the 6 hour post-dose sample has been drawn) and should return 30 minutes prior to the planned time for the last PK sample. Patients should continue urine collection at home and take the container with them from and to the clinic. All urine fractions must be kept cold at all times, i.e., during collection and transport. This includes the 6-24 hour urinefraction which will be taken home by the patient. A cold box will be provided to the patients for this purpose. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 73 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 71 of 137 Blood sampling For quantification of tiotropium plasma concentrations, at each sampling time point about 4 mL of blood will be taken from a forearm vein using a Monovette or Vacutainer collection tube containing EDTA (ethylenediaminetetraacetic acid) as anticoagulant. Blood samples shall be drawn as close to the planned time as possible. Two aliquots of plasma will be prepared from each blood sample. The sampling/collection tubes will be labeled with at least patient number, visit number and planned sampling time. A total amount of approximately 120 mL blood will be taken per patient during the trial for pharmacokinetic purposes. Refer to the Flow Chart for the time schedule. Detailed instructions for pharmacokinetic sampling, handling and shipment of plasma samples are provided in the ISF/labmanual. Urine sampling All urine voided during the collection intervals will be collected in containers. The urine bladder will be voided within 5 minutes before the beginning of each collection interval. In order to enable a sufficient urine flow patients might be asked to drink at least 150-200 mL of a non-caffeinated beverage 15 minutes prior to the end of each urine fraction in order to support a miction in time. The collection containers and tubes will be labeled with at least patient number, visit number and planned sampling time. Urine container weights (i.e. tare and gross) and times of collection will be documented in the eCRFs (weight will be set equal to volume without correction for specific gravity of urine when calculating the urine weight for analysis). Refer to the Flow Chart for the time schedule. Detailed instructions for pharmacokinetic sampling, handling and shipment of urine samples are provided in the ISF/labmanual. Prevention of contamination In order to avoid contamination of plasma and urine samples, the PK blood sampling, urine collection and plasma and urine preparation procedures must NOT take place in the same room where priming of the Respimat® inhaler or drug inhalation takes place. Study personnel should handle the Respimat® inhaler with gloves on, and these gloves should be changed and discarded immediately after a patient has completed inhalation and before any container for PK samples is touched. Prior to collecting and handling of blood, plasma or urine samples study personnel should wash their hands with soap. The urine containers, plasma vials and transfer pipettes shall not be touched with the same gloves already used for blood sampling. Plasma and urine vials/containers should be stored closed and should only be opened if necessary for the procedure. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 5.5.3 Page 74 U12-2467-02 Trial Protocol 21 Apr 2010 Page 72 of 137 Analytical determinations Plasma and urine concentrations of tiotropium will be determined by validated HPLC/MS/MS assays (high performance liquid chromatography) [U98-2028, U98-2029, U06-2246, U07-1752]. It should be noted that the bioanalytical method used for the analysis of tiotropium in plasma is being revalidated at the time of preparation of this protocol. The analysis will be performed by ( , Germany) and will be described in an Appendix in the clinical trial report. Plasma concentration measurement of samples from the salmeterol and placebo treatment will be restricted to the blood samples taken before treatment and taken at Cmax (i.e. plasma sample taken at 5 minutes after inhalation). Similarly, urinary concentrations of samples from salmeterol and placebo treatment will be restricted to pre-dose and 0-2 hour intervals (Visits 2 and 3). Only if one of these samples reveals tiotropium, the remaining samples of that particular patient will be analysed as well. 5.6 BIOMARKER(S) Not applicable to this trial. 5.7 PHARMACODYNAMICS Not applicable to this trial. 5.8 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP Not applicable to this trial. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 75 Page U12-2467-02 Trial Protocol 6. INVESTIGATIONAL PLAN 6.1 VISIT SCHEDULE 21 Apr 2010 Page 73 of 137 This trial consists of a screening period, a treatment period and a follow-up period. Following the screening visit (Visit 1) and the four-week screening period, patients will be randomised into the double-blind portion of the study (Visit 2). Additional visits will be scheduled after 4, 8, 16 and 24 weeks of therapy (Visits 3, 4, 5 and 6) and once 21 days post-treatment (Visit 7). For patients participating in the pharmacokinetic evaluations, additional visits will be scheduled after 1, 2 and 3 weeks of therapy (Visit 2A, 2B, and 2C). Patients should make every attempt to complete the study as specified. Investigators should encourage patient treatment compliance and adherence to other protocol specific activities. All deviations from the planned visit schedule will be documented. Rescheduling in general • A patient may be rescheduled twice (within two weeks of the scheduled visit date) due to lack of medication washout compliance. Rescheduling prior to randomization • The screening period (between Visit 1 and Visit 2) may be extended by an additional 4 weeks for administrative reasons. • If a patient experiences an asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1, the visit will be postponed until 4 weeks following recovery from the infection or exacerbation. • If a patient experiences an asthma exacerbation or respiratory tract infection during the screening period (between Visit 1 and 2), randomisation will be postponed until 4 weeks following recovery from the infection or exacerbation. • If the screening period is extended by more than an additional 4 weeks, but not more than an additional 8 weeks, the screening examination has to be repeated prior to randomisation. The repeat screening examination will include a physical examination, vital signs (blood pressure and pulse rate), 12-lead ECG and clinical laboratory evaluation (haematology, serum chemistry, and pregnancy test). The patient should return for these evaluations 2 weeks prior to the re-scheduled randomisation visit (Visit 2). All adverse events and concomitant therapies will be recorded. If the screening period is to be extended more than an additional 8 weeks, the clinical monitor should be contacted. • If on Visit 2, the eDiary completion compliance is below 80%, rescheduling of Visit 2 is required. Patients may continue the trial if they show an eDiary completion Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 76 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 74 of 137 compliance of at least 80% at the randomisation visit (Visit 2). Rescheduling of Visit 2 (for two weeks) is allowed twice. eDiary Completion Compliance is derived from the number of acceptable sessions. A session is either a set of morning data entries, or evening data entries. An acceptable session during the screening period is one in which at least two acceptable PEFs at the morning and evening session were stored and all diary data were entered. The calculation of the compliance during the screening period will be based on the last 10 days prior to Visit 2. • If on Visit 2, the inclusion criteria of an ACQ mean score of ≥ 1.5 or of the FEV1 variation within ± 30% between the pre-bronchodilator value of Visit 1 as compared to the pre-dose FEV1 of Visit 2 (absolute values of FEV1) are NOT met, Visit 2 can be repeated once within two weeks. If a respiratory tract infection or asthma exacerbation in the screening period was the reason for the FEV1 deterioration resulting in a FEV1 variation from Visit 1 of below 30%, Visit 2 may be repeated four weeks following recovery from the infection or exacerbation. At the repeated Visit 2, both criteria must be met; otherwise the patient is considered as non-eligible. Refer to Section 4.2.1.3 for details on medications allowed to control acute asthma exacerbations and restrictions for these medications prior to PFTs. Rescheduling after randomization • If rescheduling of visits after randomisation is necessary, the total daily doses of the Respimat® inhaler and MDI (i.e. 30 days) need to be obeyed and the need to take reserve medication should be avoided. If possible an additional intermediate visit to dispense the new drug supply should be planned in order to avoid use of the reserve trial medication. Refer to the Flow Chart for the rescheduling time windows. • If rescue medication is administered during a visit day within 8 hours prior to the pre-dose PFT, the visit will be rescheduled once. Further rescheduling should be discussed with the local clinical monitor. • Subsequent visits should always be planned to take place at the originally scheduled dates to assure a 24 week treatment period. Refer to Section 4.2.1.3 for details on medications allowed to control acute asthma exacerbations and restrictions for these medications prior to PFTs. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 77 Page U12-2467-02 Trial Protocol 6.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS 6.2.1 Screening and run-in period(s) 21 Apr 2010 Page 75 of 137 Informed Consent Visit (Visit 0) • • • • • • Informed Consent will be obtained prior to patient participation in the trial, which includes any medication washout procedures or restrictions. Upon obtaining Informed Consent, the patient will be instructed on the medication washout and other restrictions needed for the screening pulmonary function test at Visit 1. At sites capable of performing 24h PFT: patients will be asked to give Informed Consent for the 24-h PFT at visit 6. At selected sites: patients will be asked to give Informed Consent for the PK analyses. Patients will be asked to give Informed Consent to the pharmacogenomic analyses. The patient will receive directions on the as needed use of the salbutamol (albuterol) MDI (as rescue medication) that will be dispensed at this visit. A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid unnecessary washout procedures in non-eligible patients. Observations and procedures at Visit 1 • • • • • • • • • • Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms prior to any discussion with a health professional and prior to pulmonary function testing. Medication washout compliance will be verified. Demographic data (sex, race, date of birth, height, weight, duration of asthma, asthma background characteristics, pack years, smoking and employment status) will be recorded. Medical history regarding cardiovascular disorders, CVAs, urinary/renal disorders/diseases, cancer and narrow-angle glaucoma will be recorded. Current conditions and conditions for which therapy is given in the last 3 months prior to Visit 1 as well as any chronic disease (excluding asthma) will be recorded (baseline conditions). Physical examination including vital signs (blood pressure and pulse rate) will be conducted and a 12-lead ECG will be recorded. The vital signs (seated) and ECG should be conducted following five minutes of rest and prior to the PFT measurements. All adverse events experienced since signed Informed Consent will be reviewed and recorded. Concomitant therapy for the previous three months will be recorded. Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. Blood samples need to be taken prior to the salbutamol (albuterol) dosing. A urine pregnancy test will be conducted (if applicable). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 • • • • • • 78 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 76 of 137 Pulmonary function testing with the MasterScope® CT spirometer will be conducted in the evening between 06.00 and 08.00 pm immediately prior to (-10 min) and 15 minutes after the inhalation of 4 puffs of salbutamol (albuterol). Question 7 of the ACQ questionaire (regarding pre-bronchodilator FEV1 predicted) will be completed by qualified site staff. Inclusion and exclusion criteria will be reviewed. Patients will be trained in the use of the Respimat® inhaler. The patient's ability to perform technically acceptable pulmonary function tests and their ability to use the Respimat® inhaler will be assessed. Patients qualified to enter the 4-week screening period of the trial will be issued - an electronic peak flow meter with integrated electronic diary (AM3) - a paper patient diary card (and a PK Visit Card, if applicable) - additional rescue medication if needed Patients will receive training and instructions on - the use of the AM3 (including performance of PEFs and completing the eDiary) - the use of rescue medication - medication restrictions and washout requirements for the screening period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Screening Period Patients who qualify on Visit 1 will measure twice-daily PEF and record their asthma symptoms and the number of puffs of rescue medication (daytime and nighttime) in the eDiary during the 4-week screening period. If there is any indication during the screening period that the patient is not stable enough to complete the trial or that the patient is non-compliant with the trial medication or restrictions, the patient should not be randomised. This evaluation should take place by the investigator after PEF and eDiary data saved in the AM3 have been downloaded and reviewed. Details of any patient who is screened for the trial but is found to be ineligble must be entered in the Enrolment log and documented in the eCRF. 6.2.2 Treatment period(s) Observations and procedures at Visit 2 • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic. AM3 data will be downloaded and reviewed by the investigator. eDiary compliance should be reviewed (see inclusion criterion 12 and Section 6.1). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 • • • • • • • • • • • 79 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 77 of 137 Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional. Medication washout compliance will be verified. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. Patients will be trained in the use of the Respimat® inhaler. Note: the patient should NOT inhale from a placebo inhaler at this visit. Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. The variation from the pre-bronchodilator FEV1 at Visit 1 will be determined (must not exceed ± 30%). Question 7 of the ACQ questionnaire (regarding pre-bronchodilator FEV1 predicted) will be completed by qualified site staff. Vital signs will be conducted in conjunction with the pre-dose PFT measurement. Inclusion and exclusion criteria will be reviewed to determine eligibility. Patients who meet all inclusion criteria and violate none of the exclusion criteria will be assigned to treatment according to the following procedure: 1. Randomise patient using IVRS. 2. Allocate the appropriate medication kits using IVRS. • • • • • • Blood samples will be drawn from patients who consented to participate in the genotyping investigation. If blood sampling is not possible at this visit, it is also allowed at any subsequent visit. For a subset of patients at selected sites: blood and urine samples will be collected for evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). Refer to the Flow Chart for the time schedule. Patients will be issued - study medication including reserve medication - additional rescue medication if needed - a new paper patient diary card if needed (and a PK Visit Card, if applicable) Patients will receive training and instructions on - the use of the AM3 (including performance of PEFs and completing the eDiary) Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 80 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 78 of 137 - the use of rescue medication - medication restrictions and washout requirements for the treatment period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Observations and procedures at Visits 2A, 2B and 2C. • • • For a subset of patients at selected sites: blood samples will be collected for the evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic prior to inhalation of medication. eDiary data will NOT be downloaded. Observations and Procedures at Visits 3, 4 and 5 • • • • • • • • • • • • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter at the clinic. AM3 data will be downloaded and reviewed by the investigator. Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered questionnaire. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional. Medication washout compliance will be verified. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. Study medication from the previous visit will be collected prior to study medication administration and new study medication will be dispensed. Allocate the appropriate medication kits (including new reserve medication if needed) using IVRS. Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. Question 7 of the ACQ questionnaire (regarding prebronchodilator FEV1 predicted) will be completed by qualified site staff. For a subset of patients at selected sites at Visit 3: blood and urine samples will be collected for evaluation of the pharmacokinetics of tiotropium. Refer to the Flow Chart for the time schedule. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 • • • 81 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 79 of 137 Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). Refer to the Flow Chart for the time schedule. Patients will be issued - new study medication (including reserve medication if needed). - additional rescue medication if needed - a new paper patient diary card if needed Patients will receive instructions on - medication restrictions and washout requirements for the treatment period and subsequent visits - returning all issued medication, the AM3 device and the paper patient diary card to the clinic on all subsequent visits. Observations and Procedures at Visit 6 • • • • • • • • • • • • • • • • • • At home, prior to the visit, the patient should answer the morning questions of the electronic diary and use the electronic peak flow meter (AM3) as usual. Patients will answer the evening questions of the eDiary and use the electronic peak flow meter in the clinic. AM3 data will be downloaded and reviewed by the investigator. Question 1 to 6 of the ACQ questionnaire will be patient self-administered for assessment of degree of symptoms as first questionnaire prior to any discussion with a health professional and prior to pulmonary function testing. AQLQ(S) will be patient self-administered. The AQLQ(S) should be the second questionnaire completed during a clinic visit and should precede any discussion with a health professional. EQ-5D will be patient self-administered questionnaire. The EQ-5D should be the third questionnaire completed during a clinic visit and should precede any discussion with a health professional (physician, nurse or study coordinator). Medication washout compliance will be verified. The AM3 will be collected. Patient's paper diary card will be collected and reviewed. Adverse events and changes in concomitant therapies will be recorded. Information regarding asthma exacerbations and HCRU will be recorded. The patient's smoking status will be assessed. A 12-lead ECG will be recorded Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. A urine pregnancy test will be conducted (if applicable). Study medication from the previous visit will be collected after study medication administration and no new study medication will be dispensed. Pre-dosing PFT with the MasterScope® CT spirometer will be performed prior to inhalation of any medication. Question 7 of the ACQ questionnaire (regarding prebronchodilator FEV1 predicted) will be completed by qualified site staff. Patients will inhale medication in a fixed sequence as described in Section 4.1.4. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 • • • • 6.2.3 82 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 80 of 137 Post-dose PFTs will be performed. Vital signs will be conducted in conjunction with the PFT measurements (first 3 hours post-dosing). PFTs will be performed until 24 hours post-dosing in patients who consented to this. Refer to the Flow Chart for the time schedule. Physical examination including vital signs (blood pressure and pulse rate) will be conducted at the end of the visit after all PFT measurements. Patients will be issued additional rescue medication if needed. Patients will receive instructions for the follow-up period. End of trial and follow-up period Observations and Procedures at Visit 7 The patient will visit the clinic 21 days after the last dose of trial medication. Any adverse events or changes in concomitant therapies that have occurred will be recorded in addition to the trial completion information. Any ongoing (serious) adverse events should be followed until the event is resolved or there is a mutual agreement between the investigator and CML that follow-up is sufficient. Rescue medication will be collected. Observations and Procedures in case of premature withdrawal The following procedures should be performed after any premature withdrawal of patients that took at least one dose of trial medication • • • • • • • • • • Physical examination including vital signs (blood pressure and pulse rate) will be conducted A 12-lead ECG will be recorded Blood samples will be collected and submitted to the site's local laboratory for haematology and serum chemistry. A urine pregnancy test will be conducted (if applicable). Adverse events and changes in concomitant therapies will be recorded. Any ongoing (serious) adverse events should be followed until the event is resolved or there is a mutual agreement between the investigator and CML that follow-up is sufficient. All SAEs that occur within 21 days after a patient terminates trial medication must be reported according to Boehringer Ingelheim SAE procedures. Smoking status will be assessed. Study medication (used and unused) will be collected. AM3 data will be downloaded and reviewed by the investigator. The AM3 will be collected. Patient's paper diary card will be collected and reviewed. The investigator should make every effort to perform the follow-up visit 21 days after the last dose of study medication on patients that withdrew prematurely. Vital status information After any premature withdrawal of patients that took at least one dose of trial medication, the vital status information (dead or alive) will be collected on the originally planned visit date of Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 83 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 81 of 137 the follow up visit (Visit 7). The vital status eCRFs will be completed. Collection of vital status information does not require a patient visit. Patients will be asked to consent to telephone follow-up at their normal exit date from the trial. If death occurs, the investigator will review the circumstances, including the relevant medical records to ascertain the most likely primary and secondary causes. Any death during the vital status observation period needs to be reported as SAE by the investigator according to the Boehringer Ingelheim SAE procedures. Collection of vital status information will be performed in accordance with national ethical and regulatory guidelines. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 7. 84 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 82 of 137 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE This trial is one of two twin trials with identical protocols (BI trial numbers 205.418 and 205.419). The analysis described below will be performed for this trial and detailed in the Clinical Trial Report. In addition, a meta-analysis will comprise the analyses on combined data from the twin studies. This comprehensive meta-analysis, specifically indicated below, will be performed on the combined data in order to take advantage of the larger sample size. Separate documentation will be produced for each of the above. 7.1 STATISTICAL DESIGN - MODEL Design This is a randomised double-blind, placebo- and active-controlled, multinational, parallelgroup trial to evaluate the efficacy to evaluate the efficacy and safety of 2.5 and 5 µg of tiotropium inhalation solution delivered by the Respimat® inhaler (once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in moderate persistent asthma patients treated with at least medium doses of inhaled corticosteroids. The comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. Primary objective The primary objective of the trial is to demonstrate superiority of tiotropium (2.5 µg and 5 µg) with regard to primary pulmonary function endpoints after 24 weeks of treatment as compared to placebo. Meta-analysis: the primary objective of the meta-analysis is to demonstrate superiority in terms of asthma control (primary ACQ endpoint) of tiotropium (2.5 µg and 5 µg) over placebo after 24 weeks of treatment, on pooled data from the twin trials 205.418 and 205.419. Any comparison of tiotropium versus salmeterol and placebo versus salmeterol will only provide basic descriptive displays and will be used for descriptive purposes only. Primary Endpoints There are two co-primary variables in this trial (Peak FEV1 and trough FEV1) as lung function endpoints measured in relation to the evening dose. The first co-primary efficacy endpoint is the peak FEV1 response (within 3 hours post dosing) determined at the end of the 24-weeks treatment period. Peak FEV1 is defined as the maximum value of the FEV1 measurements within 3 hours post evening dosing. Peak FEV1 response is defined as the change from baseline in peak FEV1. Baseline is the pre-treatment FEV1 measured at Visit 2 in the evening just prior to the evening dose of patient’s usual asthma medication and first dose of trial medication. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 85 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 83 of 137 The second co-primary endpoint is the trough FEV1 response determined at the end of the 24week treatment period. Trough FEV1 is defined as the pre-evening-dose FEV1 measured in the clinic just prior to the inhalation of the evening doses. Trough FEV1 response is defined as the change from baseline in trough FEV1. Meta-analysis The primary endpoint is the responder as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period on combined data from the two twin trials 205.418 and 205.419. The two trials will be combined to get an adequate number of patients for this endpoint. The two trials will run concurrently. Responder is defined as an improvement with at least the minimum clinically important difference (MCID) in the ACQ which is defined as 0.5. Please refer to Section 5 for the list of secondary and safety endpoints. Baseline For all clinical spirometry endpoints, the pulmonary function test in the evening of the randomisation visit (Visit 2), measured just prior to the evening dose of patient’s usual ICS medication and first administration of the randomised treatment, is defined as baseline. For AQLQ (S) and ACQ, baseline is defined as the value obtained at the randomisation visit (Visit 2). For all endpoints measured with the AM3, the average of the data obtained in the week immediately preceding Visit 2 will be used as baseline. Response Response is defined as the change from baseline. Centre Centres might be pooled for analysis if necessary. The detailed strategy for pooling will be specified in the statistical analysis plan prior to database lock and unblinding. 7.2 NULL AND ALTERNATIVE HYPOTHESES The hypothesis will be tested in a stepwise manner to control the probability of Type I error: firstly, to establish the efficacy of tiotropium 5 µg over placebo, and secondly, to establish the efficacy of tiotropium 2.5 µg over placebo. The following hypotheses (α = 0.025 onesided) will be tested for the first co-primary endpoint: H01: H11: Peak FEV1(response) (tiotropium 5 µg) ≤ Peak FEV1(response) (placebo) versus Peak FEV1 (response) (tiotropium 5 µg) > Peak FEV1 (response) (placebo) If the null hypothesis H01 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 H02: H12: 86 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 84 of 137 Trough FEV1 (response) (tiotropium 5 µg) ≤ Trough FEV1 (response) (placebo) versus Trough FEV1 (response) (tiotropium 5 µg) > Trough FEV1 (response) (placebo) If the null hypothesis H02 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: H03: H13: Peak FEV1(response) (tiotropium 2.5 µg) ≤ Peak FEV1(response) (placebo) versus Peak FEV1 (response) (tiotropium 2.5 µg) > Peak FEV1 (response) (placebo) If the null hypothesis H03 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested: H04: H14: Trough FEV1 (response) (tiotropium 2.5 µg) ≤ Trough FEV1 (response) (placebo) versus Trough FEV1 (response) (tiotropium 2.5 µg) > Trough FEV1 (response) (placebo) Each step will only be considered confirmatory providing all the previous steps were successful. If any of the previous steps were not successful the analysis of the current step will be considered descriptive. Comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. Meta-analysis The primary endpoint (ACQ) will be tested on pooled data from the two twin-trials 205.418 and 205.419 only. The hypothesis will be tested in a stepwise manner to control the probability of Type I error: firstly, to establish the efficacy of tiotropium 5 µg over placebo, and secondly, to establish the efficacy of tiotropium 2.5 µg over placebo. It will not be used in the sequential testing for US registration. The following hypotheses (α = 0.025 one-sided) will be tested for this endpoint: H0M1: H1M1: Number of ACQ responders (tiotropium 5 µg) ≤ Number of ACQ responders (placebo) versus Number of ACQ responders (tiotropium 5 µg) > Number of ACQ responders (placebo) If the null hypothesis H0M1 is rejected then the following hypothesis (α = 0.025 one-sided) will be tested on pooled data from both twin trials: H0M2: H1M2: Number of ACQ responders (tiotropium 2.5 µg) ≤ Number of ACQ responders (placebo) versus Number of ACQ responders (tiotropium 2.5 µg) > Number of ACQ responders (placebo) Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 87 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 85 of 137 Comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. 7.3 PLANNED ANALYSES The efficacy analyses and the summary of safety data will be based on all randomised patients that received at least one dose of trial medication; this set of patients will be the Treated Set. The efficacy analyses and the summary of safety data will be based on all randomised patients that received at least one dose of trial medication; this set of patients will be the Treated Set (TS), the Full Analysis Set (FAS) includes all patients of the TS for which at least one post-baseline efficacy measurement is available.Full and clear definitions of each analysis set will be provided in the Trial Statistical Analysis Plan (TSAP). All individual data will be listed. Adherence to the protocol (e.g., inclusion/exclusion criteria, times of measurement, completeness and consistency of data, etc.) will be checked using the data recorded. Standard statistical parameters (number of non-missing values, mean, standard deviation (SD), median, quartiles, minimum, and maximum) or frequency tables will be calculated where appropriate. In general, these parameters or frequencies will be calculated separately for each treatment. Data from subjects who are screened but not treated will be listed, but not included in summary statistics. 7.3.1 Primary analyses The primary analysis will be performed on the FAS. The primary FEV1 endpoints (change from baseline) will be analyzed using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM). Analyses will include the fixed, categorical effects of treatment, centre, visit, and treatmentby-visit interaction, as well as the continuous, fixed covariates of baseline value and baseline value-by-visit-interaction. An unstructured (co)variance structure will be used to model the within-patient errors. If this analysis fails to converge, the following structures will be tested Compound Symmetry, Autoregressive Model (AR (1)) or Spatial Covariance. The (co)variance structure converging to the best fit, as determined by Akaike’s information criterion, will be used as the primary analysis. The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. Significance tests will be based on leastsquares means using a two-sided alpha=0.05 (two-sided 95% confidence intervals). The primary comparison will be the contrast between treatments at week 24. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. For sensitivity analysis of the primary endpoint an Analysis of Covariance Model (ANCOVA) of the 24-week response data will be performed with baseline, centre and Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 88 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 86 of 137 treatment as main effects. Centre will be included as random main effect. Missing data wil be imputed according the rules in Section 7.4. Meta-analysis The analysis on the primary ACQ endpoint will be conducted after combining the data from the two twin trials 205.418 and 205.419. Treatment groups will be compared using the same analysing method as used for the primary endpoints of the individual trials and will be comprehensive described in the Meta-Analysis-Plan. 7.3.2 Secondary analyses PFT Parameters The PFT parameters Peak FVC, trough FVC and AUC0-3h FEV1/FVC (change from baseline) and PEF variability will be analysed as detailed above for the co-primary FEV1 endpoint (24 weeks after treatment). In addition individual FEV1, FVC and PEF measurements at all time-points (4, 8, 16 and 24 weeks after treatment) including peak, trough and AUC0-3h will be analysed as mentioned above. The mean pre-dose morning and evening PEF and FEV1 measured with the AM3 device by the patients at home (weekly mean and overall mean) will be compared using the same method as mentioned above. For a subset of patients the endpoints FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h) will be analysed as detailed above for the co-primary FEV1 endpoint (after 24-week treatment). In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. AQLQ These parameters (change from baseline) will be analysed as detailed above for the coprimary FEV1 endpoint at all clinic visits during the 24 week treatment period. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. Use of PRN salbutamol The number of puffs rescue therapy used per day (i.e. daytime, night-time and the full 24 hour period) will be analysed using Poisson regression with log exposure as offset and adjusting for overdispersion. In case Poisson regression gives a bad fit due to large amount of zeros, negative binomial regression will be used for the analysis. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 89 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 87 of 137 Asthma symptoms Nocturnal and daytime asthma symptoms as well as the number of asthma free days will be analysed in the same way as detailed above for the co-primary FEV1 endpoint. Meta-analysis Time to first (severe) asthma exacerbation The analysis of (severe) asthma exacerbations will be conducted after combining the data from the two twin trials 205.418 and 205.419. Treatment groups will be compared with respect to the time to first (severe) asthma exacerbation during the 24 week randomised treatment period. Only (severe) asthma exacerbations with an onset during randomised treatment will be included in the analysis. The analysis will be performed using Cox's proportional hazards regression model with only treatment fitted as an effect. The hazard ration and corresponding 95% confidence interval will be presented along with the p-value. Kaplan-Meier estimates of the probability of not experiencing a (severe) asthma exacerbation over the treatment period will be plotted by treatment group. ACQ These parameters (change from baseline) will be analysed as detailed above for the coprimary FEV1 endpoint at all clinic visits during the 24 week treatment period, for each trial separately and on pooled data from the two twin trials 205.418 and 205.419. In case there is evidence, that the data are not normally distributed, the Wilcoxon-MannWitney test will be used to compare the treatment groups. 7.3.3 Safety analyses All treated patients will be included in the safety analysis. In general, safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis testing is planned prospectively. Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary. Standard BI summary tables and listings will be produced to compare the incidence of adverse events across the treatment groups. All events with an onset after the first dose of trial medication up to a period of 30 days after the last dose of trial medication will be assigned to the treatment period for evaluation. Other adverse events will be assigned either to the screening or post study period as appropriate. Changes from baseline in vital signs will be summarized by treatment group and compared descriptively. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 7.3.4 90 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 88 of 137 Interim analyses No interim analysis is planned. 7.3.5 Pharmacokinetic analyses Tiotropium will be analysed in blood and urine samples collected from a subset of patients in this trial with the objective of determining the pharmacokinetics of tiotropium in patients with moderate persistent asthma. Pharmacokinetics of tiotropium will be determined following the administration of a single dose and multiple doses of 2.5 and 5 µg tiotropium via Spiriva® Respimat®. Also, pre- and 5 minutes post-dose blood samples will be obtained at visits 2A, 2B and 2C to determine time needed to reach steady-state. It is not planned to test any statistical hypothesis with respect to the pharmacokinetic parameters. Instead, they will be presented in their entirety and evaluated by descriptive statistical methods 7.3.6 Pharmacodynamic analyses Not applicable. 7.3.7 Pharmacogenetic analyses Not applicable. 7.3.8 Health economic analyses The details of HCRU and EQ-5D analysis will be determined in a separate analysis plan. This HCRU and EQ-5D analysis will not be part of the clinical trial report. 7.4 HANDLING OF MISSING DATA Every effort will be made to collect FEV1 data at the specified time points, except if the patient has used rescue medication. Post-baseline missing FEV1 values will be replaced with the least favourable FEV1 value if a patient withdraws due to worsening of asthma. Randomly missing data after inhalation of study medication for which there are data from that visit both before and after inhalation will be linearly interpolated. Randomly missing data with no subsequent non-missing values for that visit will be imputed using the last observation carried forward (LOCF) technique to calculate peak and AUC. Data missing due to worsening of asthma or need of rescue medication will be replaced with the least favourable data for that visit (including pre-dose values). Completely missing data at a post-baseline visit, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used. Completely missing data at the baseline visit, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 91 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 89 of 137 No post baseline data available at all, for MMRM no imputation will be used, for the sensitivity analysis LOCF imputation will be used from previous visit. For Patient Daily Record data, when the number of salbutamol (albuterol) doses is missing but other data are filled out on any given day then these data will be imputed by zero (because the presence of other data is interpreted as meaning that the patient was not having a problem). Before calculating the baseline and treatment means, the following data will be excluded: • • • • • data with a missing Patient Daily Record date, PEF data which is less than 50 L/min, duplicate data for the same date Daily Record data for days after drug was discontinued, Patient Daily Record data for the period during which oral steroids or theophylline doses were increased because of an exacerbation of asthma. Missing AQLQ (S) and ACQ data will be imputed according the methods used in the validation of the respective questionnaire and will be described in detail in the TSAP. Methods to handle any other exceptional cases will be considered only before unblinding the data and will be applied in a manner consistent with other trials of this type. Full details on the handling of missing data will be provided in the TSAP. 7.5 RANDOMISATION Patients will be randomized 1:1:1:1 to 2.5 µg tiotropium inhalation solution, or 5 µg tiotropium inhalation solution, or salmeterol HFA-MDI, or placebo over the 24-week treatment period. The sponsor will arrange for the randomisation as well as packaging and labelling of trial medication. Each patient will have a single randomisation number indicating the allocated treatment. Medication numbers will be assigned at a visit level. The randomisation list will be generated using a validated system involving a pseudo-random number generator and a supplied seed number, thereby ensuring that the resulting allocation to a treatment is both reproducible and nonpredictable. The seed numbers will be documented in the report. An Interactive Voice Response System (IVRS) and/or an Interactive Web Response System (IWRS) will be used. BI will provide the randomisation and medication number lists to the IVRS/IWRS provider and the sites will contact the IVRS/IWRS to obtain the next medication numbers to be dispensed to the patient. 7.6 DETERMINATION OF SAMPLE SIZE For the first two co-primary variables sample size estimation is performed under the following assumptions. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 92 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 90 of 137 For the first co-primary variable peak FEV1 a SD between 310mL and 370mL was observed as worst case SD in period 1 of trial 205.341 for change from baseline. For the second coprimary variable trough FEV1 a SD between 290mL and 350mL was observed in trial 205.342 and between 266mL and 277mL in period 1 of trial 205.341 for change from baseline. Sample size is calculated using a two-group t-test with a power of 90% and a type I error probability of 2.5% (one-sided). The following Table 7.6.: 1 provides several sample size considerations based on a two group t-test with a power of 95% and a type I error of 2.5% (one-sided), to get on overall power for the first co-primary endpoints of about 90% (0.95 x 0.95 = 0.9025) considerations depending on number of patients per group using different scenarios. Table 7.6: 1 Number of patients necessary for the first two co-primary endpoints (Nquery, version 6.01) Endpoint peak FEV1 Delta 150 135 120 SD 310 340 370 310 340 370 310 340 370 N per group 112 135 160 139 166 197 175 210 249 trough FEV1 Delta SD 270 140 310 350 270 120 310 350 270 100 310 350 N per group 98 129 164 133 175 223 191 251 320 With a sample size of 250 patients per group one is able to detect a delta of 120mL and 100mL for peak FEV1 and trough FEV1, respectively under the expectation to have a SD for change from baseline of 370mL in peak FEV1 and 310mL in trough FEV1. Sample size consideration for the third co-primary variable ACQ are based on the endpoint of the relative frequency of patients who reached the minimum clinically important difference (MCID) in the ACQ which is defined as 0.5(i.e. MCDI>0.5 then responder)[R09-1589]. Assuming a delta of 10% in responder rate in comparison to placebo, the following number of patients per group based on a pooling the data of the two trials would be necessary depending on the expected placebo rate. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Table 7.6: 2 93 Page U12-2467-02 21 Apr 2010 Page 91 of 137 Trial Protocol Number of patients necessary for the third co-primary endpoint ACQ (Nquery, version 6.01) under the assumption of a power of 90% Expected placebo response rate Sample Size per group 20% 392 30% 477 40% 519 With 500 patients per treatment group, the power is 91.34% for the pooled analysis assuming a placebo response rate of 30%. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 8. 94 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 92 of 137 INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS The trial will be carried out in compliance with the protocol, the principles laid down in the Declaration of Helsinki, version as of October 1996 (as long as local laws do not require to follow other versions), in accordance with the ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the treating physician of the patient. The investigator should inform the sponsor immediately of any urgent safety measures taken to protect the study subjects against any immediate hazard, and also of any serious breaches of the protocol/ICH GCP and, for Japan, the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997). The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract. As a general rule, no trial results should be published prior to finalisation of the Clinical Trial Report. Insurance Cover: The terms and conditions of the insurance cover are made available to the investigator and the patients via documentation in the ISF (Investigator Site File). 8.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT This trial will be initiated only after all required legal documentation has been reviewed and approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and competent authority (CA) according to national and international regulations. The same applies for the implementation of changes introduced by amendments. Prior to patient participation in the trial, written informed consent must be obtained from each patient (or the patient’s legally accepted representative) according to ICH GCP and to the regulatory and legal requirements of the participating country. Each signature must be personally dated by each signatory and the informed consent and any additional patientinformation form retained by the investigator as part of the trial records. A signed copy of the informed consent and any additional patient information must be given to each patient or the patient’s legally accepted representative. The patient must be informed that his/her personal trial-related data will be used by Boehringer Ingelheim in accordance with the local data protection law. The level of disclosure must also be explained to the patient. The patient must be informed that his / her medical records may be examined by authorised monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities. ADDITIONAL INFORMATION FOR JAPAN The investigator must give a full explanation to trial patients including the items listed below in association with the use of the patient information form, which is prepared avoiding the Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 95 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 93 of 137 use of technical terms and expressions. The patient is given sufficient time to consider participation in the trial. The investigator obtains written consent of the patient's own free will with the informed consent form after confirming that the patient understands the contents. The investigator must sign (or place a seal on) and date the informed consent form. If a trial collaborator has given supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the informed consent. The following items need to be included: 1. That the clinical trial involves research, i.e. testing of drugs. 2. The objectives of the clinical trial. 3. The clinical trial procedures (including those aspects of the clinical trial that are experimental, patient inclusion criteria, specific fasting requirements for laboratory, and the probability for random assignment to each treatment. 4. Anticipated benefits of the investigational product and anticipated risks to the patient. 5. The expected duration of the patient's participation in the clinical trial. 6. The approximate number of patients involved in the clinical trial. 7. The reasonably foreseeable risks or inconveniences to the patient. If there is no intended clinical benefit to the patient, the patient should be made aware of this. 8. The alternative procedure(s) or course(s) of treatment that may be available to the patient, and their important potential benefits and risks. 9. The patient's primary physician will be informed by the investigator about participation in the trial. 10. The compensation and/or treatment available to the patient in the event of trial-related injury. 11. That the patient's participation in the clinical trial is voluntary and that the patient may refuse to participate in or withdraw from the clinical trial at any time, without penalty or loss of benefits to which the patient is otherwise entitled. 12. That the patient or the patient's proxy consenter will be informed in a timely manner if information becomes available that may be relevant to the patient's willingness to continue participation in the clinical trial. 13. The foreseesable circumstances and/or reasons under which the patient's participation in the clinical trial may be terminated. 14. That the monitor(s), the auditor(s), the IRB, and the regulatory authority(ies) may be provided direct access to the patient's original medical records. In such cases, the confidentiality of the patient should be protected, and by signing and sealing an informed consent form, the patient or the patient's proxy consenter is authorising such access. 15. The type of the IRB which is used for the reviews and deliberations in regard to the appropriate conduct of the clinical trial. The information to be reviewed by each IRB and any other topics concerning the IRBs involved in the clinical trial. 16. If the results of the clinical trial are published, the patient's identity will remain confidential. 17. The anticipated expenses, if any, to the patient for participating in the clinical trial. 18. The anticipated prorated payment, if any, to the patient for participating in the clinical trial. 19. The name, title, and address of the investigator or the sub-investigator to contact. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 96 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 94 of 137 20. The person(s) to contact for further information regarding the clinical trial and the rights of patient, and whom to contact in the event of a trial-related injury. 21. That necessary treatment is available to the patient in the event of trial-related injury and all other issues in regards to compensation in the event of any trial-related injury. 22. The patient's responsibilities. 8.2 DATA QUALITY ASSURANCE A quality assurance audit/inspection of this trial may be conducted by the sponsor or sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance auditor will have access to all medical records, the investigator’s trial-related files and correspondence, and the informed consent documentation of this clinical trial. The data management procedures to ensure the quality of the data are described in detail in the trial data management and analysis plan (TDMAP) available in the CTMF. 8.3 RECORDS Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on paper or via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to Section 4.1.8. 8.3.1 Source documents Source documents provide evidence for the existence of the patient and substantiate the integrity of the data collected. Source documents are filed at the investigator’s site and could for example be physician's notes in patient files, ECG results (original or copies of printouts), lung function test results, worksheets or patient diaries. Data entered in the eCRFs must be derived from source documents and must be consistent with the source documents or the discrepancies must be explained. The investigator may need to request previous medical records or transfer records, depending on the trial; also current medical records must be available. 8.3.2 Direct access to source data and documents The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review and regulatory inspection, providing direct access to all related source data / documents. CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and medical test results must be available at all times for review by the sponsor’s clinical trial monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by reviewing the documents described in Section 8.3.1. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 8.3.3 97 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 95 of 137 Storage of records ADDITIONAL INFORMATION FOR JAPAN ONLY Storage period of records Trial site(s): The trial site(s) must retain the source documents and essential documents for a period defined by the Japanese GCP regulation and the sponsor's SOP. Sponsor: The sponsor must retain the essential documents according to the sponsor's SOPs. When it is no longer necessary for the trial site to retain the source documents and essential documents, the sponsor must notify the head of trial site. 8.4 LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS 8.4.1 Listedness To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. Therefore a unique reference document for the evaluation of listedness needs to be provided. For the 2.5 and 5 µg tiotropium bromide inhalation solution this is the current version of the Investigator’s Brochure (U92-0551). For the salmeterol xinafoate metered dose inhaler this is the EU SP (Serevent Evohaler). For the non-investigational medicinal product salbutamol/albuterol, the reference document is the US-PI (Proair HFA). The current versions of these reference documents are to be provided in the ISF. No AEs are classified as listed for matching placebo, study design, or invasive procedures. 8.4.2 Expedited reporting to health authorities and IECs/IRBs Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local regulatory requirements. Further details regarding this reporting procedure are provided in the Investigator Site File. 8.5 STATEMENT OF CONFIDENTIALITY Individual patient medical information obtained as a result of this trial is considered confidential and disclosure to third parties is prohibited with the exceptions noted below. Patient confidentiality will be ensured by using patient identification code numbers. Treatment data may be given to the patient’s personal physician or to other appropriate medical personnel responsible for the patient’s welfare. Data generated as a result of the trial need to be available for inspection on request by the participating physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities, i.e. the CA. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 8.6 98 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 96 of 137 COMPLETION OF TRIAL ADDITIONAL INFORMATION FOR JAPAN ONLY When the trial is completed, the investigator should inform the head of the trial site of the completion in writing, and the head of the trial site should promptly inform the IRB and sponsor of the completion in writing. ADDITIONAL INFORMATION FOR EU MEMBER STATES The EC/competent authority in each participating EU member state needs to be notified about the end of the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the CTP) or early termination of the trial. 8.7 PROTOCOL VIOLATIONS ADDITIONAL INFORMATION FOR JAPAN ONLY The investigator or sub-investigator should record all CTP violations. The investigator should provide and submit the sponsor and the head of the trial site the records of violations infringing the Japanese GCP or violations to eliminate an immediate hazard to trial subjects and for other medically inevitable reasons. 8.8 COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL RELATED INJURY ADDITIONAL INFORMATION FOR JAPAN ONLY In the event of health injury associated with this trial, the sponsor is responsible for compensation based on the contract signed by the trial site. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 99 Page U12-2467-02 Trial Protocol 9. REFERENCES 9.1 PUBLISHED REFERENCES 21 Apr 2010 Page 97 of 137 P86-0614 Beck R, Robertson C, Galdes-Sebaldt M, Levison H Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma. J Pediatr 107, 605 - 608 (1985) P97-9482 Beakes DE The use of anticholinergics in asthma. J Asthma 34 (5) 1997: 357368 P98-7763 Lanes SF, Garrett JE, Wentworth CE, Fitzgerald JM, Karpel JP. The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma: a pooled analysis of three trials. Chest 114 (2) 1998: 365-372 P98-9345 Plotnick LH, Ducharme FM. Should inhaled anticholinergics be added to beta2 agonists for treating acute childhood and adolescent asthma? A systematic review. Br Med J 317 (7164) 1998: 971-977 P99-02952 Rodrigo G, Rodrigo C, Burschtin O. A meta-analysis of the effect of ipratropium bromide in adults with acute asthma. Am J Med 107 (4) 1999: 363-370 P04-11193 Israel E, et al. Use of regulary scheduled albuterol treatment in asthma: genotype statified, randomised, placebo-controlled cross-over trial. Lancet 364 (9444) 2004: 1505-1512 P05-01207 Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev (3) 2004 P05-05129 Gosens R, Bos IS, Zaagsma J, Meurs H: Protective effects of tiotropium bromide in the progression of airway smooth muscle remodelling, Am J Respir Crit Care Med 2005; 71:1096-1102 P05-08960 Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systemic review with metaanalysis. Thorax 2005; 60 (9): 740-746 P05-11064 Profita M,Di Giorgi R, Sala A, Bonanno A, Riccobono L, Mirabella F, Gjomarkaj M, Bonsignore G, Bousquet J, Vignola: Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients; Allergy 2005; 60:1361-1369 P05-12782 Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J Standardisation of spirometry. Eur Respir J 26 (2) , 319-338 (2005) Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 100 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 98 of 137 P06-03400 Wechsler ME, Lehman E, Lazarus SC, Lemanske RF, Boushey HA, Deykin A, et al. Beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173 (5):519-526. P07-10315 Bos IST, Gosens R, Zuidhof AB, Schaafsma D, Halayko AJ, Meurs H, Zaagsma . Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison. Eur Respir J 2007, 30 (4), 653-661 P07-12448 Buehling F, Lieder N, Kuehlmann UC, Waldburg N, Welte T. Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro. Respir Med 2007, 101 (11), 2386-2397 P08-00177 Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 370 (9605), 2118 - 2125 (2007) P09-07838 Asthma Clinical Research Network (ACRN) Long Acting beta agonist Response by GEnotype (LARGE). See website: acrn.org/large.html (access date: 15.06.2009) (2009) P10-03196 Global strategy for asthma management and prevention, Global Initiative For Asthma (GINA) 2009. Available from website: ginasthma.org. R94-1408 Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows.Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J 1993 ;6 (Suppl 16) :5 -40. R96-2382 EuroQol - a new facility for the measurement of health-related quality of life. Health Policy 1990; 16: 199-208 R00-1157 Juniper EF, O´Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999; 14: 902-907 R05-0813 Sato E, Koyama S, Okubo Y, Kubo K, Sekiguchi M Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am J Physiol (Lung Cell Mol Physiol 18) 1998; 274: L970-L979 R05-2327 Koyama S, Sato E, Nomura H, Kubo K, Nagai S, Izumi T: Acetylcholine and substance P stimulate bronchial epithelial cells to release eosinophil chemotactic activity. J Appl Physiol. 1998; 84(5):1528-34 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 101 U12-2467-02 Trial Protocol 21 Apr 2010 Page 99 of 137 R06-0573 Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, et al. Systematic review and meta-analysis of the association between beta2adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol 2005 ;162 (3) :201 -211. R06-0585 Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JPA. Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol 2005 ;115 (5) :963 -972. R08-0092 Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999, 115: 1265-1270. R08-5197 Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P Relationship of the type of tobacco and inhalation pattern to pulmonary and total mortality. Eur Respir J 5, 1111 - 1117 (1992) R09-1589 Juniper E. Asthma Control Questionnaire: background, administration and analysis. See website: qoltech.co.uk; Bosham: QOL Technologies 2005 9.2 UNPUBLISHED REFERENCES U92-0551 Investigator´s Brochure - Tiotropium Bromide, Ba 679 BR (tiotropium bromide inhalation powder and tiotropium bromide inhalation solution). BPO5601. Version 01 March 2008 U96-0240 . A double-blind, placebo-controlled, crossover study to determine the effect of inhaled Ba 679 BR (tiotropium) on methacholine responsiveness in patients with mild asthma. 205.121. 03 June 1996. U97-2651 . Ba 679 BR: in vitro inhibition studies on cytochrome P450 dependent metabolic reactions. B820. 09 October 1997 U98-2028 Validation report: determination of Tiotropium bromide in human plasma samples by LC-MS/MS. B884, GA375/1. 19 January 1998 U98-2029 Validation report: determination of Tiotropium bromide in human urine samples by LC-MS/MS. B885, GA375/2. 21 January 1998. U98-3174 The effect of twenty-one day dosing of tiotropium on bronchomotor tone in patients with moderate to severe asthma (a randomized, double-blind, placebo-controlled, parallel study). 205.201. 17 August 1998 U98-3274 The effect of tiotropium in patients with nocturnal asthma (a randomized, double-blind, double- Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 102 U12-2467-02 Trial Protocol 21 Apr 2010 Page 100 of 137 dummy, placebo and active-controlled, parallel study). 205.202. 09 November 1998 U99-1004 New mathematical model for the determination of the slow dissociation kinetics of the long antimuscarinic Tiotropium bromide and BEA 2108 BR in comparison to ipratropium bromide from human muscarinic receptors. BC5.A06. 15 October 1998 U99-1019 The protective effect and safety of 36 µg inhaled tiotropium (Ba 679) against exercise-induced bronchoconstriction in patients with bronchial asthma (double-blind, randomised, placebo-controlled, parallel study). 205.203. 20 October 1998 U02-1222 . Evaluation of local tolerability of an acidic (pH=2.7) ® solution for inhalation administered via the RESPIMAT device in 32 asthmatic adults. A single-dose (4 puffs), cross-over randomized study. 205.248. 22 Jan 2002 U06-2246 Ba 679 BR (Tiotropium): Partial validation of an existing LC-MS/MS method for the determination of tiotropium in human plasma with reduced sample volume. PA599. 23 November 2006 U07-1752 Ba 679 BR (Tiotropium bromide): Partial validation of an existing LC-MS/MS method for the determination in acidified human urine. PA614. 23 July 2007. U08-2081 A Randomised, DoubleBlind, Placebo-Controlled, Crossover Efficacy and Safety Evaluation of 8Week Treatment Periods of Two Doses [5 µg (2 actuations of 2.5 µg) and 10 µg (2 actuations of 5 µg)] of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler as Add-on Therapy in Patients with severe persistent Asthma. 205.341. 22 Oct 2008. U09-1701 A 16-week randomised, placebo-controlled, double-blind, double-dummy, parallel-group study comparing the efficacy and safety of tiotropium inhalation solution delivered by the Respimat inhaler (2 puffs of 2.5 mcg once daily) with that of salmeterol from… 205.342. 14 Aug 2009. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10. APPENDICES Page 103 U12-2467-02 Trial Protocol 21 Apr 2010 Page 101 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.1 104 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 102 of 137 INSTRUCTIONS FOR THE USE OF THE RESPIMAT INHALER Instructions for Use Respimat® inhaler How to use your Respimat® inhaler This leaflet explains how to use and care for your Respimat® inhaler. Please read and carefully follow these instructions. The Respimat® inhaler releases medication slowly and gently, making it easy to inhale it into your lungs. The Respimat® inhaler enables you to inhale the medicine contained in a cartridge. You will need to use this inhaler only ONCE A DAY. Each time you use it take two PUFFS. In the box you will find the Respimat® inhaler and the Respimat® cartridge. Before the Respimat ® inhaler is used for the first time, the cartridge provided must be inserted. Respimat® inhaler and the Respimat® cartridge Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 105 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 103 of 137 Inserting the cartridge and preparation for use The following steps 1-6 are necessary before first use: 1) With the grey cap closed, press the safety catch (E) and pull off the clear base (G). 2) Take the cartridge (H) out of the box. Push the narrow end of the cartridge into the inhaler until it clicks into place (2a). The cartridge should be pushed gently against a firm surface to ensure that it has gone all the way in (2b). Do not remove the cartridge once it has been inserted into the inhaler. 3) Replace the clear base (G). Do not remove the clear base again. Safety catch 1 2a 2b 3 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 106 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 104 of 137 To prepare the Respimat® inhaler for first-time use 4) Hold Respimat® inhaler upright, with the grey cap (A) closed. Turn the clear base (G) in the direction of the red arrows on the label until it clicks (half a turn). 5) Open the grey cap (A) until it snaps fully open. 6) Point the Respimat® inhaler towards the ground. Press the dose release button (D). Close the grey cap (A). 4 5 Repeat steps 4, 5 and 6 until a cloud is visible. Then repeat steps 4, 5 and 6 three more times to ensure the inhaler is prepared for use. 6 Your Respimat® inhaler is now ready to use. These steps will not affect the number of doses available. After preparation your Respimat® inhaler will be able to deliver 60 puffs. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 107 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 105 of 137 Using the Respimat® inhaler You will need to use this inhaler only ONCE A DAY. Each time you use it take two PUFFS. I) Hold Respimat® inhaler upright, with the grey cap (A) closed, to avoid accidental release of dose. Turn the clear base (G) in the direction of the red arrows on the label until it clicks (half a turn). I II) II III) Open the grey cap (A) until it snaps fully open. Breathe out slowly and fully, and then close your lips around the end of the mouthpiece without covering the air vents (C). Point your Respimat® inhaler to the back of your throat. While taking in a slow, deep breath through your mouth, press the dose release button (D) and continue to breathe in slowly for as long as you can. Hold your breath for 10 seconds or for as long as comfortable. Repeat steps I and II one more time so that you get the full dose. You will need to use this inhaler only ONCE A DAY. Close the grey cap until you use your Respimat® inhaler again. If the Respimat® inhaler has not been used for more than 3 days release one puff towards the ground. If the Respimat® inhaler has not been used for more than 21 days repeat steps 4 to 6 until a cloud is visible. Then repeat steps 4 to 6 three more times. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 108 Page U12-2467-02 21 Apr 2010 Page 106 of 137 Trial Protocol When to get a new Respimat® inhaler The Respimat® inhaler contains 60 puffs (30 doses). The dose indicator shows approximately how many doses are left. When the pointer enters the red area of the scale, there is, approximately, medication for 15 puffs (7 days) left. Once the dose indicator has reached the end of the red scale (i.e., all 60 doses have been used), the Respimat® inhaler is empty and locks automatically. At this point, the base cannot be turned any further. What if... What if... Reason What to do I can’t turn the base easily. a) The Respimat® inhaler is already prepared and ready to use. a) The Respimat® inhaler can be used as it is. b) The Respimat® inhaler is locked after 60 puffs (30 doses). b) Prepare and use your new Respimat® inhaler. I can’t press the dose release button. The clear base has not been turned. Turn the clear base until it clicks. (half a turn) The clear base springs back after I have turned it. The clear base was not turned far enough. Prepare the Respimat® inhaler for use by turning the clear base until it clicks. (half a turn) I can turn the clear base past the point where it clicks. Either the dose release button With the grey cap closed, has been pressed, or the clear turn the base until it clicks. base has been turned too far. (half a turn) How to care for your inhaler Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at least once a week. Any minor discoloration in the mouthpiece does not affect the performance of your Respimat® inhaler. If necessary, wipe the outside of your Respimat® inhaler with a damp cloth. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 109 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 107 of 137 Further information The Respimat® inhaler must not be disassembled after inserting the cartridge and replacing the clear base. Do not touch the piercing element inside the base. Keep out of the reach and sight of children. Do not freeze. Boehringer Ingelheim Pharma GmbH & Co. KG D - 55216 Ingelheim Germany 0123 HI-Master-Version-Respimat-20080831 PLEASE ALWAYS ENTER THE DATE OF FIRST PRIMING ON THE MEDICATION LABEL! Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.2 110 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 108 of 137 INSTRUCTIONS FOR THE USE OF THE MDI Instructions for Use Please read and carefully follow these instructions. You will need to use this inhaler only TWICE A DAY (morning and evening). Each time you use it take two PUFFS. There is enough trial medication for 30 days when the MDI is used according to the directions for use. Testing the inhaler 1. When using the inhaler for the first time or when you have not used the inhaler for a week or more, test that it is working properly. Remove the mouthpiece cover (gently squeeze the sides with your thumb and forefinger and pull apart). Hold MDI as illustrated in the figure below and shake well. Point mouthpiece away from you and release one puff into the air by pressing the MDI. Using the MDI inhaler 1. Remove the mouthpiece cover. 2. Hold MDI as illustrated in the figure below and shake the inhaler 4 or 5 times to ensure the contents of the inhaler are evenly mixed. 3. Hold the MDI upright between fingers and thumb with your thumb on the base, below the mouthpiece. Breathe out as far as is comfortable and then place the mouthpiece in your mouth between your teeth and close your lips around it. Do not bite. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 111 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 109 of 137 4. Breath in through your mouth. Just after starting to breathe in, press down on the top of the MDI to release a puff while still breathing in steadily and deeply. 5. While holding your breath, take the MDI from your mouth and take your finger from the top of the MDI. Continue holding your breath as long as is comfortable. 6. Keep the MDI upright and wait about half a minute before repeating steps 1-5 to inhale the second puff from the MDI. 7. After use always replace the mouthpiece cover (by firmly pushing until it snaps into place) to keep out dust and fluff. How to care for your inhaler It is important to clean the MDI at least once a week to prevent the inhaler from blocking up. To clean the MDI: 1. Remove the mouthpiece cover. 2. The metal canister should NOT be removed from the plastic casing at any time. 3. Wipe the outside and inside of the mouthpiece and the plastic casing with a dry cloth or tissue. 4. Replace the mouthpiece cover. NEVER put the metal canister in water. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.3 Page 112 U12-2467-02 Trial Protocol 21 Apr 2010 Page 110 of 137 INSTRUCTIONS FOR RETURN OF MALFUNCTIONING RESPIMAT INHALERS Respimat® inhalers, with the used cartridge in situ, that appeared to malfunction, will be returned to the Boehringer Ingelheim OPU responsible for packaging and labeling as soon as possible. The name, address and contact person are listed below: Boehringer Ingelheim Pharma GmbH & Co. KG Business Unit Development Dpt. Quality & Records Management 55216 Ingelheim am Rhein Germany The following information should be included when the inhaler is returned: a) Medication number b) Visit number c) Date of malfunction d) Description of malfunction and cause of malfunction (if known) e) Person identifying malfunction f) Malfunctioned after amount of days or weeks of treatment g) BI personnel contacted and date contacted h) Date shipped to Boehringer Ingelheim i) Trial number / country j) Investigator’s name/ center number l) Date of return to the investigator The original of the Product/Device Complaint Form should be included with the returned inhaler. In parallel, a scanned copy of the form should be send to the responsible CTSU coordinator of the trial via email. A copy of the form should be filed with the Drug Dispensing Log. All inhalers and cartridges should be wrapped in bubble wrap or a similar packing material, placed in a secure shipping box (not a packing envelope) and shipped by overnight express. Any questions regarding shipping and handling should be directed to the local Clinical Monitor. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.4 113 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 111 of 137 ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA Classification of medium ICS doses Table 10.4: 1 Definition of medium daily doses of ICS adapted from GINA 2009 [P10-03196] Drug Medium daily Dose (µg) Beclomethasone dipropionate Budesonide Ciclesonide Flunisolide Fluticasone Mometasone furoate Triamcinolone acetonide ≥500 and ≤1000 ≥400 and ≤800 ≥160 and ≤320 ≥1000 and ≤2000 ≥250 and ≤500 ≥400 and ≤800 ≥1000 and ≤2000 As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the investigator for the equivalent correct dosage. There are specific requirements per country. Please refer to the ISF for a detailed list. Reversibility testing [P05-12782] At the screening visit (Visit 1), following the completion of three acceptable prebronchodilator forced expiratory manoeuvres, salbutamol (albuterol) will be administered to each patient in order to document the degree of reversibility. Immediately after (within 10 min) pre-bronchodilator forced expiratory manoeuvres and after a gentle and incomplete expiration, a dose of 100 µg of salbutamol (albuterol) is inhaled in one breath to total lung capacity (TLC). The breath is then held for 5–10 s before the subject exhales. Four separate doses (total dose 400 µg) are delivered at approximately 30-s intervals (this dose ensures that the response is high on the salbutamol dose–response curve). Three additional, acceptable post-bronchodilator forced expiratory manoeuvre tests are recorded ≥10 min and up to 15 min later after the last dose of salbutamol (albuterol) is inhaled. Calculation of predicted normal values according to ECSC [R94-1408] For height measured in inches Males: FEV1 predicted (L) = 4.30 x [height (inches)/39.37] - 0.029 x [age (yrs)] - 2.49 Females: FEV1 predicted (L) = 3.95 x [height (inches)/39.37] - 0.025 x [age (yrs)] - 2.60 For height measured in meters Males: FEV1 predicted (L) = 4.30 x [height (m)] - 0.029 x [age (yrs)] - 2.49 Females: FEV1 predicted (L) = 3.95 x [height (m)] - 0.025 x [age (yrs)] - 2.60 Patients with ages 18-25 will have predicted FEV1 calculated with age 25. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 114 Page U12-2467-02 21 Apr 2010 Page 112 of 137 Trial Protocol The race correction factors in table 10.4: 2 will apply. Table 10.4: 2 Race correction factors Correction factor FEV1 Races / Ethnicities Caucasian Orientals Hong Kong Chinese Orientals Japanese Americans Polynesians North Indians & Pakistanis South Indians African Descent Other Correction factor FVC 1.0 1.0 0.89 0.9 0.9 0.87 0.87 1.0 1.0 1.0 1.0 0.9 0.9 0.87 0.87 1.0 Calculation of variation of absolute FEV1 values The value of Visit 1 is regarded as 100% and the following formula applies: FEV1 variation (%) = FEV1 pre-dose at Visit 2 (L) FEV1 pre-bronchodilator at Visit 1 (L) x 100 - 100 Calculation of number of pack years Pack years = Number of cigarettes/day 20 x years of smoking The following equivalents for the tobacco content should be used for smokers other than cigarettes smokers [R08-5197]: • • • • One plain or filter cigarette = 1 gram of tobacco One cigar = 5 grams of tobacco One cheroot or cigarillo = 3 grams of tobacco One gram of pipe tobacco = 1 gram of tobacco Calculation of pack years based on tobacco contents: Pack years = Number of gram/day 20 x years of smoking Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.5 Page 115 U12-2467-02 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S)) 21 Apr 2010 Page 113 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 116 U12-2467-02 21 Apr 2010 Page 114 of 137 Trial Protocol ASTHMA QUALITY OF LI FE QUESTIONNAIRE (S) PATI ENT ID - - - - - - - DATE _ _ _ _ _ _ _ _ __ SELF-ADMINISTERED Page 1 oi 5 Please c o mpl et e all q ue st ions by circling the number t hat b est des cribes how you have been d uring the last 2 w eeks as a re-sult of your asth ma . HOW LIM ITED HAVE YOU BEEN DURING THE LAST 2 WEEKS IN THES E ACTIVITIES AS A RESULT OF YOUR ASTHMA? 1. 2. 3. O:xtremdy Urnite d Modeu-te Umitation Some A Li~tte Limitt'd Umit oltiOI'I Umit;a~ioto ;al lim ited STRENUOUS A CTIVITIES (such as hurrying, exercising, running up st airs, sport s) 2 3 4 s 6 7 M ODERATE ACTIVITIES (such as w alking, housew orl<, gardening, shopping, c limbing st airs) 2 3 4 s 6 7 pet s/children, visiting f riends/relativ es) 2 3 4 s 6 7 WORK-RELATED ACTIVITIES (tasks y ou have to do at work~) 2 3 4 s 6 7 6 7 v~ No~ ~t SOCIAL ACTIVITIES (such a s t a lking. pla ying with 4. "If S. you are not employed or $E!tf-employed, these should be tasks you have to do most days. SLEEPING 2 s 4 3 HOW M UCH DISCOMFORT OR DISTRESS HAVE YOU FELT DURING THE LAST 2 WEEKS? A Very G re~t Oe;~~1 6. How m uch d iscomfo rt or distress hav e you felt over the last 2 w eeks as a result of CHEST TIGHTNESS? AGru t De;a! A Good Moder;t'=' Amount Some Oul 2 3 4 s Very None Li~tf.e 6 7 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 117 U12-2467-02 21 Apr 2010 Page 115 of 137 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID SELF-ADMINISTERED DATE Pag e 2oi 5 IN GENERAL, HOW MUCH OF THE TIME DURING THE LAST 2 W EEKS DID YOU: 7. 8. 9. Al'ly o f the rwnc ..... 5 6 7 4 5 6 7 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 All of Mo~t A Good the Time oi the oi the Ti~ Time Feel CONCERNED ABOUT HAVING ASTHMA ? 2 3 4 Feel SHORT OF BREATH as a result of your ast hma? 2 3 Experience asthm a symptom s as a RESULT OF BEING EXPOSED TO CIGARETTE SMOKE? 2 10 . Experience a WHEEZE in your chest? Si~ Some of '!h.oeTime A L~de of ~he Time H~rdly None T ime 11 . Feel y ou had to AV OID A SITUATION OR ENVIRONMENT BECAUSE OF CIGARETTE SMOKE? HOW M UCH DISCOMFORT OR DISTRESS HAVE YOU FELT DURING THE LAST 2 WEEKS? A V"Y A Gr ert A Good Moe!etol~e G.rcat Oc ~J ""' Ou l Amouf'lt 2 3 4 1 2 . How much d iscomfort or distress have you felt over the last 2 weeks as a result of COUGHING? Som• v •.., Not~c u~tte 5 6 7 IN GENERAL, HOW M UCH OF THE TIM E DURING THE LAST 2 WEEKS DID YOU: ... A!l of AUHfc of the r~. Som• o f the Time Ti~ the rwnc ..... 2 3 4 5 6 7 2 3 4 5 6 7 Mo n of the Titno: Time 1 3. Feel FRUSTRATED as a result of your ast hma? 14 . Experience a feeling of CHEST HEA VINESS? 2 A G ood Sit of the Hardly AAy o f None T ime Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 118 U12-2467-02 21 Apr 2010 Page 116 of 137 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID SELF-ADMINISTERED DATE Page 3oi 5 IN GENERAL, HOW M UCH OF THE TIM E DURING THE LAST 2 WEEI<S DID YOU: A Good Sit of ~he Some o f the A L<tt!e of the Any o f r~, Time T irm: the rune 2 3 4 5 6 7 1 6 . Feel t he need to CLEAR Y OUR THROAT? 2 3 4 5 6 7 1 7. Experience asthm a symptom s as a RESULT OF BEING EXPOSED TO DUST? 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 20. WAKE UP IN T HE MORNING WITH ASTHMA SYMPTOMS? 2 3 4 5 6 7 2 1. Feel A FRAID OF NOT HAVING YOUR A STHMA M EDICATION AVAILABLE? 2 3 4 5 6 7 22 . Feel bothered by HEAV Y BREATHING? 2 3 4 5 6 7 23. Experience asthm a symptom s as a RESULT OF THE WEATHER OR AIR POLLUTION OUTSIDE? 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 A!l of th< Mo~ ~be 1 5. 18 . Feel CONCERNED ABOUT THE NEED TO USE M EDICATION for your asthma? H ~rdly Nol'\e of "" T ime Experience OIFFICULTY BREATHING OUT as a result of y our asthma ? 19. of Time T ime Fee l y ou haC! to A V OI D A SITUATION OR ENVIRONMENT BECAUSE OF DUST? 24 . Wer e y ou WOKEN AT NIGHT by your asthma? 2b . A V U IU UH LIM I I (jO JN(j U U I ~I Ut BECAUSE OF THE WE.A THER OR AIR POLLUTION? 3 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 119 U12-2467-02 21 Apr 2010 Page 117 of 137 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID SELF-ADMINISTERED DATE Page 4 oi 5 IN GENERAL, HOW M UCH OF THE TIM E DURING THE LAST 2 WEEKS DID YOU: ... AU of Mo~ ~he A G ood Sit Som• A Little H~rdl•t Nol'\e of ;he Time o f the l imo=- of the Any o f oitn. Ti~ Me rame T ime 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 of Tin e Time 26 . Experience asthm a symptom s as a RESULT OF BEING EXPOSED TO STRONG SM ELLS OR PERFUME? 27. Feel AFR.AID OF GETTING OUT OF BREA TH? 28. Feel y ou had to AV OID A SITUATION OR ENVIRONMENT BECAUSE OF STRONG SMELLS OR PERFUME ? 29. Has y our asthma INTERFERED WITH GETTING A GOOD NIGHT'S SLEEP? 30. Have a feeling of FIGHTING FOR AIR? HOW LIM ITED HAVE YOU BEEN DURING THE LAST 2 WEEKS? Severil Very Few Not 0Wt.e Not Done No Umit .ltion 3 1. Think of the OVERALL RANGE OF ACTIVITIES t hat you would have liked to have done during the last 2 weeks. How much has your range of act ivities been lim it ed by your asthma? 2 4 3 4 5 6 7 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 120 U12-2467-02 21 Apr 2010 Page 118 of 137 Trial Protocol ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATI ENT ID - - - - - - - DATE _ _ _ _ _ _ _ _ _ ___ SELF-ADMINISTERED Page5oi 5 HOW LIM ITED HAVE YOU BEEN DURING THE LAST 2 WEEKS? lirnitat:oo Limit.J:OO Limita:ion A U l:!!e Net at all 4 5 6 7 Moderate 32. Overall, among ALL THE ACTIVITIES that you have done during the last 2 weeks, how limited have you been by your asthma? 2 3 DOMAIN CODE: Symptoms: 6, 8, 10, 12, 14,16, 18, 20, 22J 24, 29, 30 Activity Limitation: 1,2, 3, 4, 5, 11, 19, 25, 28, 31., 32 Emotional Function: 7, 1 ~ 15, 21, 27 Environmental Stillluli : 9, 17, 23, 26 5 Some limited Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.6 Page 121 U12-2467-02 Trial Protocol ASTHMA CONTROL QUESTIONNAIRE (ACQ) 21 Apr 2010 Page 119 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 122 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 120 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 123 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 121 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.7 Page 124 U12-2467-02 Trial Protocol EQ-5D HEALTH QUESTIONNAIRE (00-so He.nlth Questionnnit·e (Euglish vcnio11 for the US) 21 Apr 2010 Page 122 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 125 U12-2467-02 Trial Protocol 21 Apr 2010 Page 123 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 126 U12-2467-02 21 Apr 2010 Page 124 of 137 Trial Protocol Be.s.t imagfu3b~ be3hb state 100 To help people say how good or bad a health state i.s, we have drawn a scale (rather like. a them10meter) on which the best state you can imagine. is marked I 00 and the worst state you can imagine i.s marked 0. We. would like you to indicate on this scale how good or bad your own he.alth is today, in your opinion. Please do this by drawing a line from the box below to whichever point on the scale indicates how good or bad your health state is today. Your own health state today 9 0 a o 7 0 6 0 5. 0 4 0 3 0 2 0 I 0 0 Worst inu.gin3ble bultbstate Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.8 127 Page U12-2467-02 Trial Protocol PAPER PATIENT DIARY CARD 21 Apr 2010 Page 125 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.9 AM3 PATIENT INSTRUCTION CARD 128 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 126 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 129 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 127 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 130 U12-2467-02 Trial Protocol 21 Apr 2010 Page 128 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 131 U12-2467-02 Trial Protocol 21 Apr 2010 Page 129 of 137 Using the AM3 During Your Vacation As soon as you arrive at your travel destination, please activate t he •vacation mode": 1. Press and h ol d t he • button. 2. While holdin g th e button, press and hold t he "ESC" button. 3 . Hold both buttons for approximately 2 seconds. ESC 6·6- The following screen wi ll appear: I I Do you want to change to - i 1--------.,-,-------t= vacation mode? Yes No :: Selecting "Yes• sets the clock t o t he local time zone of your t ravel destination. • If you select"No",the clock w ill not be changed. OK Durin g your vacation t h e following screen w ill app ear every time you t urn on the AM3: I Are you on vacation? ; I Yes = No • • Selecting "Yes• starts w ith the scheduled session. • Selecting "No" t urns off the AM3. ESC Using t he AM3 When You Ret urn Home ESC As soon as you return h om e, please activate the" hom e mode": 1. Press and h ol d t he • 6 • button. 2. While holdin g th e • button, press and hold t he "ESC" button. 3. Hold bot h buttons for approximately 2 seconds. 6- The following screen will appear: Do you want to change to home mode? :: • 1-----:-: Ye- s- - - - - j I ! No ESC Page2 • Selectin g "Yes• set.s the clock t o your home time zone. • If you select "No",the clock will not be changed. ~ 0( V· 782034_USEN Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.10 132 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 130 of 137 DEFINITION ASTHMA EXACERBATION Asthma exacerbation For the purposes of this trial, an asthma exacerbation in general is defined by the sponsor as • an episode of progressive increase in one or more asthma symptoms, like shortness of breath, cough, wheezing, or chest tightness, or some combination of these symptoms. Respiratory distress is common. The symptoms should be outside the patient´s usual range of day-to-day asthma and should last for at least two consecutive days and/or • a decrease of patient´s best morning PEF of ≥ 30% from the patient´s mean morning PEF for at least two consecutive days. Relevant PEF deteriorations are marked on the AM3 data reports downloaded at each visit. During the screening period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the first 7 days after Visit 1. During the treatment period, patient's mean morning PEF is defined as the mean value of all best morning PEF values obtained during the complete screening period including the morning of Visit 2. Severe asthma exacerbation Severe asthma exacerbations are defined by the sponsor as a subgroup from all asthma exacerbations according to sponsor´s definition given above that require an initiation of treatment with systemic (including oral) corticosteroids for at least 3 days. PEF decreases marked on AM3 report A asymptomatic PEF-decrease as described above is considered an asthma exacerbation per protocol, regardless of being accompanied by asthma symptoms, need for additional asthma medication or if considered medically relevant or not. At every AM3 download, the report includes an alert section summarizing all relevant PEF-decreases (PD alerts) that occurred since the last visit. The investigator needs to discuss the report with the patient and decide which PD-alerts are valid (explained by decreased lung function) and which are not valid (e.g. explained by non-compliance as for instance device was used by other person than patient or PEF measurement done incorrectly). For each valid PD alert, the investigator needs to document this finding as adverse event in the eCRF. If symptomatic, examples of AE verbatims would be asthma aggravation, asthma Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 133 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 131 of 137 exacerbation or bronchitis. If asymptomatic, the AE verbatim would be ´asymptomatic peak expiratory flow decrease´ if no symptoms were reported. In addition, the Asthma exacerbation verification page in the eCRF needs to be entered. Note: if a respiratory tract infection without asthma worsening was the reason of PEF decrease (e.g. bronchitis), then this would only be documented as AE, not as asthma exacerbation per protocol. For each non-valid PD alert, the investigator needs to document the rationale on the AM3report. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.11 134 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 132 of 137 CLINICAL LAB PARAMETERS Laboratory specimens will be collected in the evening. Blood samples need to be taken prior to the salbutamol (albuterol) dosing. Lab parameters will be analysed by the local laboratory of each participating site. Lab samples may be stored overnight. The local lab should be contacted to discuss the required overnight storage conditions (fridge or room temperature). The haematological parameters will include the following: • • • • • • Haemoglobin Haematocrit Absolute and relative eosinophil count (to be recorded on eCRF) Red blood cell count White blood cell count (to be recorded on eCRF) including differential test (neutrophils, lymphocytes, monocytes, eosinophils, basophils) Platelet count The blood chemistry parameters will include the following: • • • • • • • • • • • Total serum IgE (to be recorded on eCRF) LDH γ-GT SGOT SGPT Calcium Inorganic phosphorus Creatinine (to be recorded on eCRF) Potassium Sodium Chloride Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 10.12 Page 135 U12-2467-02 Trial Protocol 21 Apr 2010 Page 133 of 137 PHARMACOKINETIC METHODS 10.12.1 Planned analyses for pharmacokinetic evaluations Concentrations will be used for calculations in the format that is reported in the bioanalytical report. The data format for descriptive statistics of concentrations will be identical with the data format of the respective concentrations. For the calculation of pharmacokinetic parameters, only concentrations within the validated concentration range will be used. The actual sampling times will be used for the evaluation of plasma concentrations. If the actual sampling time was not recorded or is missing for a certain time point, the planned time should generally be used for this time point instead. For pre-dose samples, the actual sampling time will be set to zero. Noncompartmental pharmacokinetic parameters will be determined using the WinNonlinΤΜ software program (Professional version 4.1 or higher, ) or another validated program. The following descriptive statistics will be calculated for analyte concentrations as well as for all primary and secondary pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. The descriptive statistics of pharmacokinetic parameters will be calculated using the individual values with the number of decimal places as provided by the evaluation program. Then the individual values as well as the descriptive statistics will be reported with three significant digits in the clinical trial report. Plasma concentrations will be plotted graphically versus time for all patients as listed in the drug plasma concentration-time tables. For the presentation of the mean profiles, the arithmetic mean and the planned blood sampling times will be used. 10.12.2 Handling of missing data Drug concentration-time profiles: Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not analyzed), BLQ (below the limit of quantification) and NOP (no peak detectable) will be ignored and not replaced by zero at any time point (including the lag phase). Descriptive statistics of concentrations at specific time points will be calculated only when at least 2/3 of the individuals have concentrations within the validated concentration range. The overall sample size to decide whether the '2/3' rule is fulfilled will be based on the total number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, NOA, NOP will be included). Pharmacokinetic parameters: During the noncompartmental analysis, concentration data identified with NOS, NOR, and NOA will not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag phase is defined as the period between time zero and the first time point with a concentration above the quantification limit. All other BLQ and/or NOP values of the profile will be ignored. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 136 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 134 of 137 If the predose concentration before the first dose is less than or equal to 5% of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements and calculations (i.e. the predose value will not be changed to zero). If the predose value before the first dose is greater than 5% of Cmax, the subject will be dropped from all statistical evaluations. The individual pharmacokinetic parameters will be calculated and listed separately. Every effort will be made to include all concentration data in an analysis. If that were not to be possible, a case to case decision iwill be taken as to whether the value should only be excluded from half-life estimation or the complete analysis. ∗ If a concentration is only excluded from half-life determination, it will be used for all other calculations (e.g. descriptive statistics) and for graphical presentation. ∗ If a concentration value is excluded from all calculations, it will not be presented graphically or used for the calculation of descriptive statistics and parameter determination. However the excluded concentration itself will be listed in the clinical trial report associated with an appropriate flag. Descriptive statistics of parameters are calculated only when at least 2/3 of the individual parameter estimates of a certain parameter are available. If the actual sampling time will not be recorded or will be missing for a certain time point, the planned time will generally be used for this time point instead. Pharmacokinetic parameters which cannot be determined will be identified by "not calculated" (NC). 10.12.3 Derivation of PK parameters Individual Cmax(,ss), tmax(,ss), Cmin(,ss), and Cpre,N values will be directly determined from the plasma concentration time profiles of each patient. If the same Cmax(,ss) concentration occurs at different time points, tmax(,ss) is assigned to the first occurrence of Cmax(,ss). Estimation of λz(,ss): The apparent terminal rate constant λz(,ss) will be estimated from a regression of ln(C) versus time over the terminal log-linear disposition portion of the concentration-time profiles. At least three data points should be used in the calculation of λz(,ss). In addition, the lower (tλz,start(ss)) and upper (tλz,end(ss)) limit on time for values to be included in the calculation of λz,ss will be listed. t1/2(ss): The terminal half-life will be calculated from the terminal rate constant using the equation t1/2(ss) = ln2 λ z(ss) AUC: The area under the curve will be calculated using the linear up/log down algorithm. If an analyte concentration is equal to or higher than the preceding concentration, the linear trapezoidal method will be used. If the analyte concentration is smaller than the preceding concentration, the logarithmic method will be used. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 137 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 135 of 137 Linear trapezoidal rule (t2 > t1 and Ct2 ≥ Ct1): The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by: AUCt1- t2 = 0.5 × (t 2 − t1 )× (C t1 + C t2 ) Logarithmic trapezoid rule (t2 > t1 and Ct2 < Ct1): The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by: AUC t1− t2 = (t 2 − t 1 ) × (C t2 − C t1 ) ln (C t2 /C t1 ) AUCτ,ss: The area under the plasma concentration-time curve at steady state over a uniform dosing interval τ will be calculated using the extra- or interpolated concentration at time tτ (time at the end of the dosing interval). The actual sampling time of the trough value Cpre,N will be set to 0. MRTih(,ss): MRTih(,ss) calculation in the steady state will be performed according to the following equation: MRTih,ss = AUMC ss AUC τ,ss AUMCss is the area under the first moment curve at steady state. CL/F,ss: The apparent clearance at steady state following extravascular multiple dose administration will be calculated as follows: CL/F,ss = Dose AUCτ ,ss Vz/F,ss: The apparent volume of distribution during the terminal phase after (multiple) extravascular administration (at steady state) will be determined according to the following equation: Vz F(,ss ) = CL F(,ss) λ z(,ss) fet1-t2,ss: The fraction excreted is calculated according to fe t1- t2(,ss) = Ae t1- t2(,ss) Dose ×100 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 138 Page U12-2467-02 Trial Protocol 21 Apr 2010 Page 136 of 137 where Aet1-t2,ss is the total quantity of the analyte that is excreted in urine over the time interval t1 to t2 (at steady state). This may represent the product of urine volume and urine analyte concentration for one time interval, as well as the cumulative amounts excreted calculated as the sum of the excreted amounts of subsequent time intervals. CLR,t1-t2,ss: The renal clearance (CLR) will be calculated as the quotient of the quantity of the analyte that is excreted in urine from the time point t1 until the time point t2 (Aet1-t2(,ss)) and the area under the concentration-time curve within the same time interval (AUCt1-t2(,ss)). CL R, t1− t2(,ss) = Ae t1− t2(,ss) AUCt1− t2(,ss) RA: The accumulation ratio RA will be calculated as follows: RA,Cmax = C max,ss C max RA,AUC = AUC τ ,ss AUC τ LI: The linearity index (LI) will be calculated as follows: LI = AUC τ ,ss AUC 0−∞ gMean, gCV: The geometric mean (gMean) and coefficient of variation, gCV (given in %), will be calculated by the formulae: [ ⎡ n ⎤ gMean = exp ⎢ 1n ∑ ln(x i )⎥ = exp ln(x i ) ⎣ i =1 ⎦ gCV(%) = 100 ⋅ exp [Var(ln(x i ))] − 1 where Var(ln(x i )) = [ 1 n ∑ ln(x i ) − ln(x i ) n − 1 i =1 ] 2 ] Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 11. 139 Page U12-2467-02 Trial Protocol SUMMARY OF CLINICAL TRIAL PROTOCOL MODIFICATIONS This is the original protocol without any modifications. Summary of Clinical Trial Protocol Modifications Sheet (SOMS) Number of CTP modification Date of CTP modification EudraCT number BI Trial number BI Investigational Product(s) Title of protocol To be implemented only after approval of the IRB/IEC/Competent Authorities To be implemented immediately in order to eliminate hazard – IRB / IEC / Competent Authority to be notified of change with request for approval Can be implemented without IRB/IEC/ Competent Authority approval as changes involve logistical or administrative aspects only Section to be changed Description of change Rationale for change 21 Apr 2010 Page 137 of 137 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 140 U12-2467-02 21 Apr2010 Page 2 of137 Trial Protocol CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 J.lg once daily) compared with placebo and salmeterol HFA MDI (50 J.lg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.419 I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Name: , MD Signature:. Signed signature page is located in the ele Affiliation: Date: _ __ onic Clinical Trial Master File The Netherlands Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Page 141 U12-2467-02 Page 16.1.1.2 Protocol amendments ........................................................................................ 141 0205-0419--protocol-revision-02 ............................................................................... 142 ctp-revision-1-signature-ci.......................................................................... 291 ctp-revision-2-signature-ci.......................................................................... 292 ctp-am-1-china-english ............................................................................................... 293 ctp-am-1-japan ............................................................................................................ 298 ctp-am-1-signature-ci.................................................................................. 310 protocol-am-01-germany ............................................................................................ 311 protocol-am-01-signature-ci........................................................................ 317 ctp-am-1-usa ............................................................................................................... 318 ctp-am-1-signature-usa ............................................................................................... 327 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Page 142 U12-2467-02 Clinical Trial Protocol Doc. No.: U10-1635-03 EudraCT No.: 2009-018005-43 BI Trial No.: 205.419 BI Investigational Product(s): Tiotropium bromide Inhalation Solution Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Clinical Phase: III Trial Clinical Monitor: Boehringer Ingelheim bv, Medical department Comeniusstraat 6, 1817 MS Alkmaar, The Netherlands Phone: , Fax: , MD Co-ordinating Investigator: , The Netherlands Phone: , Fax: Status, Version, and Date of Protocol: Final Protocol, Version 1.0, 21 April 2010 Status, Version, and Date of Revised Protocol: Revised Protocol (based on modification 2) Version 3.0, 5 December 2011 Page 1 of 147 149 Proprietary confidential information. © 2011 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. TITLE PAGE Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 Page 143 U12-2467-02 5 Dec 2011 Page 2 of 149 Trial Protocol CO-ORDINATING INVESTIGATOR SIGNATURE Trial Title: A Phase III randomised, double-blind, placebo-controlled, parallelgroup trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma Trial Number: 205.419 I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Name: , MD Signature:__________________________ Signed signature page is located in the electronic Clinical Trial Master File Affiliation: The Netherlands Date: ___________________________ Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 144 Page U12-2467-02 5 Dec 2011 Page 3 of 149 Trial Protocol LOCAL SIGNATURES (PRINCIPAL INVESTIGATOR OF SITE AND LOCAL CLINICAL MONITOR (CML)) Local Clinical Monitor <optional, delete if not applicable>: Date Name Full name Organisation/Department <Add other signatories if applicable.> I herewith certify that I agree to adhere to the trial protocol and to all documents referenced in the trial protocol. Principal Investigator (site): Date Name Full name Organisation/Department Signed signature page is located in the electronic Clinical Trial Master File Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Page 145 U12-2467-02 Boehringer Ingelheim BI Trial No.: 205.419 Trial Protocol 5 Dec 2011 Page 4 of 149 CLINICAL TRIAL PROTOCOL SYNOPSIS Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 21 April 2010 Title of trial: Trial number: 205.419 Revision date: 5 December 2011 A Phase III randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 and 5 µg once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in patients with moderate persistent asthma , MD, Co-ordinating Investigator : , The Netherlands Trial site(s) : Multi-centre, Multi-national Clinical phase: III Objective(s): Evaluate the long term efficacy and safety of tiotropium (2.5 and 5 µg once daily administered in the evening) inhalation solution delivered by the Respimat® inhaler compared to placebo and salmeterol (administered twice daily) in patients with moderate persistent asthma Methodology: Randomised, double-blind, placebo- and active-controlled, parallel-group design comparing tiotropium versus placebo and salmeterol over 24 weeks on top of maintenance therapy with an inhaled corticosteroid controller medication No. of patients: total entered: 1000 each treatment: 250 Diagnosis : Asthma Main criteria for inclusion: Outpatients of either sex, age 18 - 75 years, never-smokers or ex-smokers with < 10 pack years and smoking cessation at least one year prior to enrolment. Patients must have at least a 3-month history of asthma that was diagnosed before the age of 40, and a current diagnosis of moderate persistent asthma (according to GINA guideline). Patients need to be still symptomatic, i.e. not fully controlled with their current maintenance treatment (assessed by ACQ mean score and pulmonary lung function tests). Maintenance treatment with medium dose of inhaled corticosteroids (Appendix 10.4) is required. Test products : Tiotropium inhalation solution 2.5µg (2 actuations of 1.25 µg) and 5 µg (2 actuations of 2.5 µg) once daily in the evening mode of admin. : Oral inhalation via Respimat® inhaler dose: Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 146 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 5 of 149 Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 21 April 2010 Trial number: 205.419 Revision date: 5 December 2011 Comparator product 1: Salmeterol hydrofluoroalkane (HFA 134a) metered dose inhaler (MDI) dose: 50 µg (2 actuations of 25 µg per actuations) twice daily (morning and evening) mode of admin. : Oral inhalation from HFA MDI Comparator product 2: Placebo inhalation solution dose: Not applicable mode of admin. : Oral inhalation via Respimat® inhaler Comparator product 3: Placebo MDI dose: Not applicable mode of admin. : Oral inhalation via HFA MDI Duration of treatment: 24 weeks Criteria for efficacy: Co-primary endpoints: peak FEV1 response (within 3 hours post evening dosing) and trough FEV1 response after 24 weeks treatment Secondary endpoints: Peak FVC; trough FVC; FEV1 (AUC0-3h); FVC (AUC0-3h); individual in-clinic FEV1/FVC/PEF measurements; Asthma Quality of Life Questionnaire (AQLQ (S)); Home assessment: PEF am/pm (last weekly mean of treatment period), use of PRN rescue medication; daytime and nocturnal symptoms; asthma symptom free days, control of asthma (Asthma Control Questionnaire; ACQ) after 24 weeks treatment. In a subset of patients: FEV1 (AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h), FVC (AUC0-24h) Other endpoints: Home assessments during treatment period PEF am/pm; FEV1 am/pm; PEF variability Meta-analysis on combined data from the two twin trials 205.418 and 205.419. Primary endpoint: Control of asthma (Asthma Control Questionnaire) after 24 weeks treatment. Secondary endpoints: time to first exacerbation; time to first severe asthma exacerbation. ACQ at each visit. Criteria for pharmacokinetics: Plasma and urine samples for the quantification of tiotropium will be obtained in a subset of patients following the administration of the first dose and following administration of tiotropium for 4 weeks (i.e., at steady state). Additionally, a predose and 5 minute post-dose blood sample will be obtained on study days 7, 14 and 21 to confirm the achievement of steady-state. Enough patients will be included in this subset to ensure at least 80 patients will complete the PK sampling visits. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 147 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 6 of 149 Tabulated Trial Protocol Name of company: Boehringer Ingelheim Name of finished product: Tiotropium Inhalation Solution - Respimat® Inhaler Name of active ingredient: Tiotropium bromide Protocol date: 21 April 2010 Trial number: 205.419 Revision date: 5 December 2011 Criteria for health economics: Health care resource utilisation (HCRU) and Quality of Life assessed by EQ-5D Criteria for pharmacogenomics: Unspecified pharmacogenetic testing Criteria for safety: Adverse events, vital signs, vital status information Other criteria: In a subset of patients: patient satisfaction and preference questionnaire (PASAPQ) Statistical methods: For the two co-primary FEV1 endpoints: restricted maximum likelihood (REML)based mixed effects model with repeated measures (MMRM) with terms for treatment, investigative site, visit, and treatment by visit interaction as fixed categorical effects, and baseline and fixed covariates baseline by visit interaction. The comparisons with salmeterol are not part of the inferential analysis. Standard statistical parameters (number of non-missing values, mean, standard deviation (SD), median, quartiles, minimum, and maximum) or frequency tables will be calculated where appropriate for all parameters. Meta analysis: primary endpoint (ACQ): pooled analysis of the twin trials with trial numbers 205.418 and 205.419. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 148 Page U12-2467-02 5 Dec 2011 Page 7 of 149 Trial Protocol FLOW CHART Trial periods Treatment* Screening Visit 0 1 2 Week Day Time window** -1 -4 -28 ±4 0 1 Informed consent1 Instruct patient on washout/restrictions1 Demographics Medical History/Baseline conditions2 Physical examination (incl. vital signs) Review smoking status ECG, laboratory and pregnancy test4 Inclusion/exclusion criteria Dispense rescue medication Respimat® and MDI training Randomisation Dispense trial medication Administration of trial medication in clinic5 Collect trial medication Drug accountability Blood sample for pharmacogenetics6 Pharmacokinetic sampling7 Training eDiary with PEF-meter Issue eDiary with PEF-meter Download eDiary with PEF-meter Collect eDiary with PEF-meter Issue paper diary card Review/collect paper diary card ACQ9 AQLQ (S)9 EQ-5D9 PASAPQ9 Review exacerbation and HCRU Medication washout check11 Pulmonary function test12 Vital signs (seated) Adverse events Concomitant therapy Termination of trial medication Vital status collection18 Completion of trial X X X X X X X X X X X X X1 X X X X X X10 X X13 X X 2A7 2B7 2C7 3 4 5 6 7 7 ±1 14 ±1 21 ±1 4 28 ±2 8 56 ±2 16 112 ±4 24 168 ±4 27 189 +7 X X X X X X X X3 X3 X3 X X X X X X 16 Follow up X X X X X X 16 X X X X X X X X X X X X X X X X X X X X X X X X3 X3 X3, 8 X3 X8 X8 X8 X X X10 X X X X X X X X X X X X X X X X X X X X14 X15 X X X X X14 X15 X X X X X14 X15 X X X X X14 X15 X X X X X X X X X X X16 X X8 X X X3 X X X X17 X3 X X14 X15 X3 X3 X3 X X X18 X Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 149 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 8 of 149 * ** Visit 0 and 7 may be conducted during business hours. Visits 1 to 6 will always start in the evening. Each Respimat® inhaler and MDI contains drug supply for 30 days which must be obeyed regarding visit flexibility after randomisation. 1 All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions (see Section 4.2.2). A separate consent for pharmacokinetic sampling should be signed if patients are participating in the pharmacokinetic substudy. A separate consent for pharmacogenetic sampling should be signed if patients are participating in the pharmacogenetic substudy. The interval between Visit 0 and Visit 1 may be between 1 and 28 days depending on medication washout requirements and restrictions. A preliminary check of in-/exclusion criteria is recommended at Visit 0 to avoid unnecessary washout procedures in non-eligible patients. Including asthma background characteristics. To be completed by all patients who took at least one dose of trial medication including those who discontinue early. Vital status information has to be collected on the originally planned follow up visit date (Visit 7). Haematology and blood chemistry (local laboratory). White bloodcell count, eosinophil count (absolute and relative), total serum IgE and creatinine levels will be documented in eCRF at Visit 1. Urine pregnancy test required for all women of child-bearing potential. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (LTRA) (if applicable), 2. trial medication from assigned MDI, 3. trial medication from assigned Respimat®. Patient’s ICS should be administered without change in posology (bid/qd; am/pm), i.e. as prescribed by patient’s treating physician prior to trial entry. Blood sample for pharmacogenetics will be drawn from all randomised patients that received at least one dose of trial medication and that gave a separate informed consent. Participation in the pharmacogenetic subset is not a pre-requisite for participation in the trial. The blood sample will be drawn at preferably Visit 2 or at any other subsequent visit after randomisation. PK in a subset of patients at selected sites (separate informed consent should be obtained first). e-Diary compliance check (see Section 4.3 and Section 6.1). First ACQ, then AQLQ (S), then EQ-5D and then PASAPQ will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. ACQ at screening will be used for assessment of degree of asthma control. If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). Refer to Section 4.2.2.1. Pre-bronchodilator FEV1 at Visit 1 and pre-dose FEV1 at Visit 2 must be within ± 30% variation prior to randomisation based on absolute FEV1 values. If the variation of FEV1 in the screening period exceeds ± 30%, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). 10 minutes pre- and 15 to 30 minutes post-bronchodilator PFT after inhalation of 4 puffs (100 µg/puff) salbutamol/albuterol. 10 minutes prior to trial drug administration (pre-dose) and until 3 hours post-dose. In a subgroup of patients at selected sites at Visit 6: 10 minutes prior to trial drug administration and until 24 hours post-dose. In conjunction with pulmonary function testing until 3 hours post-dose (measured immediately before PFT). Rescue medication only. Only in selected countries. After any premature withdrawal of patients who took at least one dose of trial medication, vital status information should be collected (see Section 6.2.3). 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 150 Page U12-2467-02 5 Dec 2011 Page 9 of 149 Trial Protocol TIMING OF TRIAL PROCEDURES DURING THE TREATMENT PERIOD 3 hour pulmonary function test without pharmacokinetic sampling1 Timing related to evening inhalation of study drug -1h -30’ -15’ -10’ Administer patient’s usual ICS medication followed by trial medication2 5' 15' 4 4 30’ 1h 2h 3h X X X X X X X X X AM3 Å ------ Æ Patient self-administration of questionnaires3 Å -------------- Æ Vital signs (seated) X Pulmonary function test 1 0 X X X Order of procedures if performed at the same time point: - Vital signs followed by pulmonary function testing - Use of AM3 device followed by filling out questionnaires Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat®). ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. At Visit 6, the PASAPQ will be patient self-administered as fourth questionnaire in selected countries. Only at Visit 5 and only in a subset of patients at selected sites. 2 3 4 Pharmacokinetic plasma sampling at Visits 2A (day 7), 2B (day 14), and 2C (day 21)1 Timing related to evening inhalation of study drug -1h -30’ -15’ 0 5’ Administer patient’s usual ICS medication followed by trial medication2 Å --------------------- Æ AM3 PK plasma sampling 1 2 X X X At selected sites only. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat®). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments 151 Page U12-2467-02 Boehringer Ingelheim BI Trial No.: 205.419 5 Dec 2011 Page 10 of 149 Trial Protocol 3 hour pulmonary function test with 24 hour pharmacokinetic sampling at Visit 2 and Visit 31, 2 Timing related to evening inhalation of study drug -1h Administer patient’s usual evening ICS medication followed by trial medication3 Administer patient’s usual morning ICS medication followed by trial medication4 AM3 Patient self-administration of questionnaires6 PK plasma sampling PK urine collection 1 2 3 4 5 6 7 8 9 7 -30' -15' -10' 0 2' 5' 7' 10' 15' 30' 1h 2h 3h 6h 12h 24h8,9 X X X5 Å ----- Æ Å -------------- Æ X X Å ----------------------- Æ X X X X X X Å ---------------------------------------------------- Æ X X Å --- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X X X Å --------------- Æ Order of procedures if performed at the same time point: - PK plasma sampling (as close to planned time point as possible!), vital signs and pulmonary function testing - Use of AM3 device followed by filling out questionnaires At selected sites only. Patients may stay overnight. Refer to Section 5.5.2 for more information. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat ®). Morning trial drug administration will occur between 06.00 and 08.00 am and 12 hours (± 5 minutes) after the time of the pm administration. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI. Patient should use AM3 device immediately upon arising and prior to inhalation of medication. ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. Patients must empty bladder at the end of each urine collection interval. All urine voided during the sampling intervals -1 to 0 pre-dose and 0 to 2, 2 to 6 and 6 to 24 hours post-dose will be collected in containers. Patients should continue urine collection at home. Urine fraction must be kept cold at all times. Patient should return 30 minutes prior to last PK sample. Refer to Section 5.5.2 and Investigator Site File (ISF) chapter 10 for instructions. PK blood sample should be collected 15 minutes prior to the administration of next dose ICS and trial medication, i.e., at time point 23:45. Patients must void urinary bladder into the 6-24 container up to 5 minutes prior to the inhalation of the next day ICS and tiotropium doses (i.e., up to 23:55 hours after last dosing). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments 152 Page U12-2467-02 Boehringer Ingelheim BI Trial No.: 205.419 5 Dec 2011 Page 11 of 149 Trial Protocol 24 hour pulmonary function test after 24 weeks (Visit 6)1, 2 Timing related to evening inhalation of study drug -1h -30' -15' -10' 0 30' 1h 2h 3h 4h 11h10' 11h50' 12h 12h30' 13h 14h 15h 16h 18h 20h 22h 23h 23h50' Administer patient’s usual evening ICS medication followed by trial medication3 Administer patient’s usual morning ICS medication followed by trial medication4 AM3 Patient self-administration of questionnaires6 1 2 3 4 5 6 X X X5 Å -Æ Å -------- Æ Vital signs (seated) X X X X X Pulmonary function test X X X X X X X X X X X X X X X X X Order of procedures if performed at the same time point: - Vital signs followed by pulmonary function testing - Use of AM3 device followed by filling out questionnaires At selected sites only. Requires overnight stay. Evening trial drug administration will occur between 06.00-08.00 pm and within ± 30 minutes of time of administration at Visit 2. Medications are administered in a fixed sequence (as described in footnote 5 of the main flowchart). Time Point zero is defined as the time of complete inhalation (i.e. end time of second inhalation from Respimat ®). Morning trial drug administration will occur between 06.00 and 08.00 am and 12 hours (± 5 minutes) after the time of the pm administration. Medications are administered in the following fixed sequence: 1. ICS (if regular posology) and leukotriene modifier (if applicable), 2. trial medication from assigned MDI. Patient should be woken 40 minutes (± 10 minutes) prior to the start of the initial morning PFT (11h50’ time point). Patient should use AM3 device immediately upon arising and prior to inhalation of medication. ACQ followed by AQLQ (S) and then EQ-5D will be patient self-administered at the beginning of the visit and should precede any discussion with a health professional. The PASAPQ will be patient self-administered as fourth questionnaire in selected countries. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 153 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 12 of 149 TABLE OF CONTENTS TITLE PAGE ...................................................................................................... 1 CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................ 4 FLOW CHART ................................................................................................... 7 TABLE OF CONTENTS ................................................................................. 12 ABBREVIATIONS ........................................................................................... 16 1. INTRODUCTION................................................................................ 20 1.1 MEDICAL BACKGROUND ............................................................................ 20 1.2 DRUG PROFILE ............................................................................................... 21 1.2.1 Inhalation solution and Respimat® Inhaler ................................................ 25 2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT ..................................................................................... 26 2.1 2.2 2.3 3. RATIONALE FOR PERFORMING THE TRIAL ........................................ 26 TRIAL OBJECTIVES ....................................................................................... 27 BENEFIT - RISK ASSESSMENT.................................................................... 28 DESCRIPTION OF DESIGN AND TRIAL POPULATION.......... 29 3.1 OVERALL TRIAL DESIGN AND PLAN ...................................................... 29 3.1.1 Administrative structure of the trial ........................................................... 30 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S) ..................................................................................... 31 3.3 SELECTION OF TRIAL POPULATION ...................................................... 31 3.3.1 Main diagnosis for study entry .................................................................... 32 3.3.2 Inclusion criteria............................................................................................ 32 3.3.3 Exclusion criteria ........................................................................................... 34 3.3.4 Removal of patients from therapy or assessments ..................................... 36 3.3.4.1 Removal of individual patients ................................................................... 36 3.3.4.2 Discontinuation of the trial by the sponsor ................................................. 37 4. TREATMENTS .................................................................................... 39 4.1 TREATMENTS TO BE ADMINISTERED .................................................... 39 4.1.1 Identity of BI investigational product and comparator product(s) .......... 39 4.1.2 Method of assigning patients to treatment groups ..................................... 40 4.1.3 Selection of doses in the trial ........................................................................ 41 4.1.4 Drug assignment and administration of doses for each patient ................ 41 4.1.5 Blinding and procedures for unblinding ..................................................... 44 4.1.5.1 Blinding ...................................................................................................... 44 4.1.5.2 Procedures for emergency unblinding ........................................................ 45 4.1.6 Packaging, labelling, and re-supply ............................................................. 45 4.1.7 Storage conditions ......................................................................................... 47 4.1.8 Drug accountability ....................................................................................... 47 4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT .................................................................................................... 48 4.2.1 Rescue medication, emergency procedures, and additional treatment(s) 49 4.2.1.1 Rescue medication ...................................................................................... 49 4.2.1.2 Emergency procedures ............................................................................... 49 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 154 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 13 of 149 4.2.1.3 Additional treatments ................................................................................. 49 4.2.2 Restrictions..................................................................................................... 51 4.2.2.1 Restrictions regarding concomitant treatment ............................................ 51 4.2.2.2 Restrictions on diet and life style ............................................................... 55 4.3 TREATMENT COMPLIANCE ....................................................................... 55 5. VARIABLES AND THEIR ASSESSMENT ..................................... 56 5.1 EFFICACY - CLINICAL PHARMACODYNAMICS ................................... 56 5.1.1 Endpoint(s) of efficacy .................................................................................. 56 5.1.1.1 Primary Endpoints ...................................................................................... 56 5.1.1.2 Secondary Endpoints .................................................................................. 56 5.1.1.3 Other Endpoints .......................................................................................... 58 5.1.2 Assessment of efficacy ................................................................................... 58 5.2 SAFETY .............................................................................................................. 63 5.2.1 Endpoint(s) of safety ..................................................................................... 63 5.2.2 Assessment of adverse events ....................................................................... 63 5.2.2.1 Definitions of adverse events ..................................................................... 63 5.2.2.2 Adverse event and serious adverse event reporting.................................... 65 5.2.3 Assessment of safety laboratory parameters .............................................. 66 5.2.4 Electrocardiogram......................................................................................... 67 5.2.5 Assessment of other safety parameters ....................................................... 67 5.3 OTHER ............................................................................................................... 68 5.3.1 Other endpoints ............................................................................................. 68 5.3.2 Other assessments.......................................................................................... 68 5.3.3 Pharmacogenetic evaluation......................................................................... 70 5.3.3.1 Methods of sample collection ..................................................................... 70 5.3.3.2 Analytical determinations ........................................................................... 70 5.4 APPROPRIATENESS OF MEASUREMENTS ............................................. 70 5.5 DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS .................................................................................. 71 5.5.1 Pharmacokinetic endpoint(s)........................................................................ 71 5.5.2 Methods of sample collection........................................................................ 73 5.5.3 Analytical determinations............................................................................. 74 5.6 BIOMARKER(S) ............................................................................................... 75 5.7 PHARMACODYNAMICS ................................................................................ 75 5.8 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP...... 75 6. INVESTIGATIONAL PLAN ............................................................. 76 6.1 VISIT SCHEDULE ............................................................................................ 76 6.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................ 78 6.2.1 Screening and run-in period(s) .................................................................... 78 6.2.2 Treatment period(s) ...................................................................................... 79 6.2.3 End of trial and follow-up period ................................................................ 83 7. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..................................................................................... 85 7.1 7.2 7.3 STATISTICAL DESIGN - MODEL ................................................................ 85 NULL AND ALTERNATIVE HYPOTHESES .............................................. 86 PLANNED ANALYSES .................................................................................... 88 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 155 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 14 of 149 7.3.1 Primary analyses ........................................................................................... 88 7.3.2 Secondary analyses ........................................................................................ 89 7.3.3 Safety analyses ............................................................................................... 90 7.3.4 Interim analyses............................................................................................. 91 7.3.5 Pharmacokinetic analyses ............................................................................. 91 7.3.6 Pharmacodynamic analyses.......................................................................... 91 7.3.7 Pharmacogenetic analyses ............................................................................ 91 7.3.8 Health economic analyses ............................................................................. 91 7.3.9 PASAPQ analysis .......................................................................................... 91 7.4 HANDLING OF MISSING DATA .................................................................. 91 7.5 RANDOMISATION .......................................................................................... 92 7.6 DETERMINATION OF SAMPLE SIZE ........................................................ 93 8. INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS ............................................................................................ 95 8.1 8.2 8.3 8.3.1 8.3.2 8.3.3 8.4 8.4.1 8.4.2 8.5 8.6 8.7 8.8 9. STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT .......................................................................................................... 95 DATA QUALITY ASSURANCE ..................................................................... 97 RECORDS .......................................................................................................... 97 Source documents .......................................................................................... 97 Direct access to source data and documents ............................................... 97 Storage of records .......................................................................................... 98 LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS .............................................................................................................................. 98 Listedness ....................................................................................................... 98 Expedited reporting to health authorities and IECs/IRBs ........................ 98 STATEMENT OF CONFIDENTIALITY ....................................................... 98 COMPLETION OF TRIAL .............................................................................. 99 PROTOCOL VIOLATIONS ............................................................................ 99 COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF TRIAL RELATED INJURY............................................................................. 99 REFERENCES ................................................................................... 100 9.1 9.2 10. 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 PUBLISHED REFERENCES ......................................................................... 100 UNPUBLISHED REFERENCES ................................................................... 102 APPENDICES .................................................................................... 104 INSTRUCTIONS FOR THE USE OF THE RESPIMAT INHALER ........ 105 INSTRUCTIONS FOR THE USE OF THE MDI ........................................ 111 INSTRUCTIONS FOR RETURN OF MALFUNCTIONING RESPIMAT INHALERS ....................................................................................................... 113 ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA ........ 114 ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S)) ............. 116 ASTHMA CONTROL QUESTIONNAIRE (ACQ) ..................................... 122 EQ-5D HEALTH QUESTIONNAIRE........................................................... 125 PAPER PATIENT DIARY CARD ................................................................. 128 AM3 PATIENT INSTRUCTION CARD ...................................................... 129 DEFINITION ASTHMA EXACERBATION ............................................... 133 CLINICAL LAB PARAMETERS ................................................................. 135 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 156 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 15 of 149 10.12 PHARMACOKINETIC METHODS ............................................................. 136 10.12.1 Planned analyses for pharmacokinetic evaluations ................................. 136 10.12.2 Handling of missing data ............................................................................ 136 10.12.3 Derivation of PK parameters ..................................................................... 137 10.13 PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE .. 140 11. SUMMARY OF CLINICAL TRIAL PROTOCOL MODIFICATIONS ............................................................................ 145 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 157 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 16 of 149 ABBREVIATIONS °C °F µg ACQ ACRN Ae AE Aet1-t2,ss Degree Celsius Ddegree Degree Fahrenheit Microgram Asthma Control Questionnaire Asthma Clinical Research Network Amount of analyte that is eliminated in urine Adverse Event Amount of analyte that is eliminated in urine from the time point t1 to time point t2 (Ae0-2, Ae2-6 at steady state) ALT Alanine aminotransferase am Ante meridiem AM3 Asthma Monitor® 3 ANCOVA Analysis of Variance AQLQ(S) Standardised Asthma Quality of Life Questionnaire AST Aspartate aminotransferase ATS American Thoracic Society AUC Area under the curve Area under the plasma concentration-time curve at steady AUCτ,ss state over a uniform dosing interval τ at steady state AUCt1-t2,ss Area under the concentration time curve of analyte in plasma over the time interval t1 to t2 at steady state AUMCss Area under the first moment curve at steady state b.i.d. Bis in die (twice daily) BAC Benzalkonium chloride BARGE trial Beta-Adrenergic Response by Genotype trial BDI Baseline Dyspnoea Index BI Boehringer Ingelheim BLQ Below the limit of quantification CA Competent Authority CCDS Company Core Data Sheet CFC Chlorofluorocarbon CL/F,ss Apparent clearance of analyte in the plasma after extravascular administration Renal clearance of analyte in plasma from the time point t1 to CLR,t1-t1 time point t2 Cmax [pg/mL] Maximum measured concentration of the analyte in plasma Cmax,ss Maximum measured concentration of analyte in plasma at steady state Cmin,ss Minimum concentration of analyte in plasma at steady state CML Clinical Monitor Local COPD Chronic obstructive pulmonary disease Cpre,ss Predose concentration of analyte in plasma at steady state CRA Clinical Research Assistant/Associate CRO Contract Research Organisation Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 CTMF CTP CTR CVA CZ DNA DPI DSMB ECG eCRF ECSC EDC EDTA EEC EQ-5D ERS ERT EU FAS FDA fet1-t2 FEV1 [L] FVC [L] GCP gCV GINA gMean h HCRU HFA HPLC/MS/MS ICH ICS IEC IgE INN IRB ISF IVRS IWRS kg L LABA LARGE trial 158 Page U12-2467-02 Trial Protocol Clinical Trial Master File Clinical Trial Protocol Clinical Trial Report Cerebrovasculair accident Climate Zone Deoxyribonucleic acid Dry powder inhaler Drug safety monitoring board Electrocardiogram Electronic Case Report Form European Community for Steel and Coal Electronic Data Capture Ethylenediaminetetraacetic acid European Economic Community Quality of life questionnaire developed by EuroQol group European Respiratory Society eResearch Technology European Union Full Analysis Set Food and Drug Administration Fraction of analyte eliminated in urine from time point t1 to time point t2 Forced expiratory volume in one second Forced vital capacity Good Clinical Practice Geometric coefficient of variation Global Initiative for Asthma Geometric mean Hour(s) Health Care Resource Utilization Hydrofluororalkane High Performance Liquid Chromatography/ Mass Spectrometry/Mass Spectrometry International Conference on Harmonisation Inhaled CorticoSteroids Independent Ethics Committee Immunoglobulin E International Non-proprietary Name Institutional review board Investigator Site File Interactive Voice Response System Interactive Web Response System Kilogram Litre(s) Long-acting beta-adrenergic Long-Acting Beta Agonist Response by Genotype trial 5 Dec 2011 Page 17 of 149 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 LDH LI LOCF LTRA max MCID MD MDI MedDRA mg min mL MMRM MRTih NA NC nnACh No. NOA NOP NOR NOS OPU PASAPQ PEF(R) [L/sec] PFT pg PK pm pMDI PRN q.d. RA RDC REML ROW SABA SAE SD SGOT SGPT SNP SOMS SOP SPC SUSAR 159 Page U12-2467-02 Trial Protocol Lactate dehydrogenase Lineary Index Last observation carried forward Leukotriene Receptor Antagonist (leukotriene modifier) Maximal Minimum clinically important difference Multiple dose Metered dose inhaler Medical Dictionary for Regulatory Activities Milligram Minimal; minute Millilitre(s) Mixed effect model with repeated measures mean residence time of analyte in the body after inhalation Not applicable Not calculated Non-neuronal acetylcholine Number Not analysed No peak detectable No valid result No sample Operative Unit (of BI) Patient satisfaction and preference questionnaire Peak expiratory flow (rate) Pulmonary function test Picogram Pharmacokinetic(s) Post meridiem Pressurized Metered Dose Inhaler As occasion requires Quaque die (once daily) Accumulation ratio Remote Data Capture (eCRF) Restricted maximum likelihood Rest of World Short-acting beta-adrenergic Serious Adverse Event Standard deviation or single dose Serum glutamic oxaloacetic transaminase Serum glutamic pyruvic transaminase Single nucleotide polymorphisms Summary of Clinical Trial Protocol Modifications Sheet Standard Operating Procedure Summary of product characteristics Suspected Unexpected Serious Adverse Reaction 5 Dec 2011 Page 18 of 149 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 T, t [h or min] t.b.d. t½,ss t1/2 TCM TDMAP TinA tmax tmax,ss TNF TSAP ULN USA USPI Vz/F γ-GT 160 Page U12-2467-02 Trial Protocol Time To be determined Terminal half-life of analyte in plasma at steady state Terminal half-life of analyte in plasma Trial Clinical Monitor Trial data management and analysis plan Tiotropium in Asthma Time from dosing to the maximum concentration of the analyte in plasma Time from dosing to the maximum concentration of analyte in plasma at steady state Tumor Necrosis Factor Trial Statistical Analysis Plan Upper Limit of Normal United States of America US prescribing information Apparent volume of distribution of analyte during the terminal phase following an extravascular dose Gamma glutamyltransferase 5 Dec 2011 Page 19 of 149 Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 161 Page U12-2467-02 Trial Protocol 1. INTRODUCTION 1.1 MEDICAL BACKGROUND 5 Dec 2011 Page 20 of 149 Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular products play a role. The overall worldwide prevalence of asthma is about 5%, affecting 300 million people worldwide with over 60 million affected in the United States and Europe and high variability from country to country. Researchers estimate that an additional 100 to 150 million persons are likely to have asthma by 2025 with the projected increase of world’s urban population from 45% to 59% [P10-03196]. Central to the various phenotypic patterns of asthma is the presence of chronic underlying airway inflammation. The inflammatory cell components involved are variable, but with overlapping patterns that reflect the different phenotypes of the disease, such as intermittent versus persistent or acute versus chronic manifestations.The inflammation causes airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment [P10-03196]. According to the worldwide accepted guidelines of GINA (Global Initiative for Asthma 2009) [P10-03196] asthma is categorised into different severity categories and three levels of asthma control. The severity assessment is based on level of symptoms, airflow limitation, and lung function variability. Asthma severity can be intermittent, or it can be persistently mild, moderate or severe. The classification of asthma by severity is useful for initial assessment of the patient and initial treatment decisions. Due to the variability of asthma severity over time and individual patient’s response to treatment, a periodic assessment of the achieved asthma control is more relevant for ongoing treatment decisions. Asthma control is categorized into three levels based on daytime and nocturnal symptoms, limitations of activities, need for reliever treatment, lung function and exacerbations. Asthma can be controlled, partly controlled or uncontrolled. The aim of any asthma treatment is to achieve and maintain control for prolonged periods, thereby considering the safety of treatment, potential for adverse effects, and the cost of treatment required to achieve this goal. Asthma severity can be classified into so called GINA steps 1 to 5. The severity of asthma determines the treatment to be required. For many patients, medication must be taken everyday to control symptoms, to improve lung function and to prevent exacerbations. Medications are optionally also required to relieve acute symptoms such as wheezing, chest tightness, and cough. The role of long-acting anticholinergics as controller medication remains still to be eludicated in the treatment of asthma but appears to be promising based on preclinical findings and a successful proof-of-concept trial with tiotropium in patients with severe persistent asthma who were not fully controlled despite adequate treatment with at least high-dose ICS and LABAs. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 162 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 21 of 149 In this present study we will investigate if patients with moderate persistent asthma who are not fully controlled despite treatment with medium doses inhaled corticosteroids would benefit from tiotropium. The effects on pulmonary function and patient-reported outcomes of two different doses of tiotropium will be compared to placebo and salmeterol. 1.2 DRUG PROFILE Please refer to the "Investigator’s Brochure" [U92-0551] for the detailed outline of the existing quality, non-clinical and clinical data of tiotropium. Tiotropium is a quaternary ammonium compound developed as a long-acting orally inhaled anticholinergic bronchodilator and approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Two product formulations have been investigated in clinical trials. The first formulation is a single-dose capsule containing 18 µg of tiotropium (equivalent to 22.5 µg of tiotropium bromide monohydrate) formulated in a powder blend with lactose monohydrate. The inhalation powder formulation has been registered in about 100 countries (Spiriva® Handihaler®) and is presently being used in Phase IV clinical studies. The second product is an aqueous solution of tiotropium formulated with the excipients benzalkonium chloride and EDTA (2.5 µg tiotropium per actuation, 2 actuations per dose), which is intended for oral inhalation only via the Respimat® inhaler. The Respimat® inhaler is a novel propellant-free inhaler, which may prove to be an alternative to metered-dose and dry powder inhalers (MDIs and DPIs). The Respimat®inhaler is designed to deliver a single dose of Spiriva® in two actuations. Tiotropium in the Respimat® inhaler has been tested in a set of Phase III clinical studies, has been registered in several countries of the European Union and filed for New Drug Application in the United States of America. The beneficial effect of tiotropium on bronchoconstriction is well established and clinically used for years in the treatment of chronic obstructive pulmonary disease (COPD). The following text describes the pharmacological properties of tiotropium on a molecular level. Investigations on mucus (hyper-) secretion, potential anti-inflammatory effects as well as on anti-remodelling properties of tiotropium are reviewed. Receptor binding In vitro studies with human and animal muscarinic receptor subtypes (M1, M2, and M3) and with human and animal isolated tracheal preparations established tiotropium as a potent, selective and reversible muscarinic receptor antagonist. No other receptor interactions were detected at relevant concentrations. Association and dissociation from muscarinic receptors (M1, M2, and M3) were slow compared to ipratropium. The dissociation half-life of tiotropium-M3-complexes at 23°C was 34.7 hours compared to 0.26 hours for ipratropiumM3-complexes. Tiotropium-M2-complexes and ipratropium-M2-complexes dissociate more rapidly than M3- or M1-receptor-complexes. This pattern suggests a “kinetic receptor subtype selectivity” of occupation and blockade of M3>M1>M2-receptors [U99-1004]. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 163 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 22 of 149 Mucus modifying effects In a model of ovalbumine-induced asthma in guinea pigs [P05-05129] tiotropium prevented goblet cell hyperplasia and reduced the histologically assessed mucus gland area. In particular, the ovalbumine-stimulated increase in mucus gland area was reduced to baseline by inhalative treatment with tiotropium. These effects may positively influence mucus hypersecretion and airway plugging, and may thus improve lung function in asthma patients. Anti-inflammatory properties First in vitro investigations on the inflammatory potential of acetylcholine, the endogenous ligand of muscarinic receptors, were performed by Sato et al. [R05-0813]. Acetylcholine induced the release of neutrophil and monocyte chemotactic activity in bovine airway epithelial cells. Furthermore, acetylcholine stimulated alveolar macrophages to release eosinophil chemotactic mediators [R05-2327]. In a similar trial [P07-12448] acetylcholine stimulated different primary airway cells and cell lines to release inflammatory chemotactic factors. The acetylcholine-induced release of neutrophil chemotactic factors was abolished by tiotropium bromide suggesting an effect mediated by M3 receptors. Anti-inflammatory effects have also been shown for oxitropium bromide, another antimuscarinic, by Profita et al. in sputum cells derived from COPD patients [P05-11064]. In vivo investigations in an asthma model in guinea pigs have shown that eosinophilic inflammation was in part prevented by tiotropium [P07-10315]. Anti-remodeling effects In the above mentioned guinea pig asthma model ovalbumine induced an increase in airway smooth muscle mass measured morphometrically as well as on the alpha smooth muscle myosin heavy chain expression level. This may reflect airway smooth muscle hyperplasia observed in asthma patients. This pathophysiological proliferative effect on airway smooth muscles in guinea pigs was significantly reduced by inhaled tiotropium [P05-05129]. The above mentioned non-bronchodilating effects may contribute to beneficial long-term effects of tiotropium in the treatment of chronic airway diseases, including asthma. Comprehensive information about the development program of tiotropium is provided in the "Investigator´s Brochure" [U92-0551]. Renal impairment Tiotropium is mainly excreted renally. Increased plasma concentrations were described in patients with moderate to severe renal impairment (creatinine clearance ≤ 50mL/min). A dose reduction based on renal dysfunction cannot be recommended. Tiotropium should only be used in patients with moderate to severe renal impairment if the expected benefit outweighs the potential risk. As with all predominantly renally excreted drugs, tiotropium use should be monitored closely in patients with moderate to severe renal impairment. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 164 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 23 of 149 Drug-Drug Interaction Drug interactions of tiotropium with other drugs are unlikely due to the small dose and very low steady state plasma levels of tiotropium and the lack of inhibition of cytochrome P 450 isoenzymes by tiotropium [U97-2651]. The Respimat® Inhaler The Respimat® is a multi-dose inhaler differing from currently marketed dry powder and pressurized metered dose inhalers (pMDIs) by several features, including: (1) relatively slow aerosol delivery (1.5 seconds spray duration) that facilitates a better inhalation coordination for the patient, (2) high fine particle fraction of the spray permitting increased efficiency of drug delivery to the target organ, (3) a delivered dose independent of patient’s inspiratory flow, (4) propellant-free environment-friendly formulation, (5) convenience of a multidose inhaler, and (6) technological advances that enhance the proper use by the patient (e.g. a dose indicator and a locking mechanism that prevent tail-off of dosing after the declared number of doses). Tiotropium inhalation powder/HandiHaler® in Patients with Asthma Four randomized clinical trials have been conducted in patients with asthma using the inhalation powder capsule formulation of tiotropium [U96-0240, U98-3174, U98-3274, U991019]. These trials in the general (and exercise-induced) asthma population have demonstrated that tiotropium provides some degree of bronchodilation in asthmatic patients. Dose-dependency and convincing pharmacodynamic duration of action were not shown. Tiotropium did provide dose-related protection against methacholine induced bronchoconstriction in patients with mild to moderate asthma. The incidence of adverse events was low in all four asthma trials using doses up to 36 µg inhalation powder/HandiHaler® over 21 to 28 days of treatment. The type and rate of events were not different from those seen in the trials with COPD patients, aside from “asthma exacerbation”. The most common events were asthma exacerbation, upper respiratory infection, headache and dry mouth. Tiotropium inhalation solution/Respimat® in Patients with Asthma Three trials have been conducted with Spiriva® Respimat® in patients with asthma: Trial 205.248 [U02-1222]: local tolerability of Spiriva® Respimat® placebo formulation in hypersensitive asthmatic patients Trial 205.248 was a Phase II, single-dose, randomised, double-blind (within-device), fourway crossover trial conducted to evaluate the local tolerability of an acidic solution (pH = 2.7) for inhalation with the Spiriva® Respimat® placebo solution. This trial was conducted in 34 hypersensitive asthmatic patients. No adverse effects were attributed to the acidic solution, which was well tolerated. Neither spirometric parameters nor vital signs were changed by study treatment. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 165 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 24 of 149 Trial 205.341 [U08-2081]: Phase II proof-of-concept, severe persistent asthma This trial was an 8-week randomised, placebo-controlled, double-blind, 3-way crossover comparison of 5 µg and 10 µg Spiriva® Respimat® and placebo Respimat® administered once daily in the morning as add-on therapy in 100 adult asthmatics with maximized controller medication, who were still symptomatic. The primary endpoint of peak FEV1 response showed statistically significant superiority for both doses of Spiriva® Respimat® compared to placebo, with these results supported by the analysis of secondary endpoints. Thus, clinical proof of concept has been demonstrated for the 5 and 10 µg doses of Spiriva® Respimat® as add-on therapy in a population of patients with symptomatic severe persistent asthma. The 5 µg Spiriva® Respimat® administered as once daily in the morning was shown to be well tolerated with a comparable safety profile to placebo. Treatment with 10 µg Spiriva® Respimat® was similarly effective, generally well tolerated with comparable safety profile to placebo too; however, the higher occurrence of dry mouth is interpreted as sensitive indicator of a systemic anticholinergic reaction. Trial 205.342 [U09-1701]: Phase II proof-of-concept, moderate persistent asthma This trial was a 16-week randomised, placebo- and active-controlled, double-blind, doubledummy, parallel-group study comparing the efficacy and safety of Spiriva® Respimat® (5 µg once daily) in the evening with that of salmeterol HFA MDI (2 puffs of 25 µg twice daily) both in addition to maintenance ICS in moderate persistent asthma patients homozygous for arginine at ADRB2. The primary endpoint of this study, the change in mean weekly morning PEF from baseline to the last week of treatment,demonstrated the statistical non-inferiority of 5 µg Spiriva® Respimat® versus salmeterol and its superiority versus placebo. Thus, 5 µg Spiriva® Respimat® was as effective as salmeterol in the treatment of patients homozygous for arginine at the 16th amino acid position of the β2-adrenergic receptor (B16-Arg/Arg) with moderate persistent asthma. Spiriva® Respimat® showed an acceptable safety profile with no marked differences compared to salmeterol or placebo. Relevance of the B16-Arg/Arg genotype for the adrenergic or anticholinergic response The implications of selecting this subgroup of patients by receptor genotype are discussed extensively in the Investigator's Brochure [U92-0551]. Trial 205.342 [U09-1701] investigated the effect of Spiriva® Respimat® in B16-Arg/Arg patients with moderate persistent asthma for whom previously published studies suggested that they might not benefit from a LABA such as salmeterol therapy [P04-11193 and P0907838]. There is currently no evidence or mechanistic rationale to assume that the anticholinergic response is different in asthma patients homozygous for arginine at ADRB2. For this reason, the efficacy profile shown in patients homozygous for B16-arginine is most likely relevant for the general population with moderate persistent asthma. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 166 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 25 of 149 In conclusion: Two BI trials 205.341 [U08-2081] and 205.342 [U09-1701] showed a significant efficacy signal and a favourable safety profile for tiotropium administered via the Respimat® inhaler in moderate or severe persistent asthma in patients adequately treated with ICS according to current treatment guidelines. All trials for tiotropium Respimat® in asthma were and will be conducted only with an appropriate maintenance treatment with an ICS. 1.2.1 Inhalation solution and Respimat® Inhaler Active ingredient solution The tiotropium inhalation solution is aqueous based. The pH value is adjusted to pH 2.9 ± 0.2, near the stability optimum of the active substance. Administration of tiotropium inhalation solution is achieved with the Respimat® inhaler in combination with a drug reservoir/cartridge. The drug is delivered from the Respimat® inhaler as two actuations per dose. As a multi-dose device and solution, the drug formulation contains ethylenediaminetetraacetic acid, disodium salt (EDTA) and the bacteriostatic agent benzalkonium chloride (BAC), which have been reported to induce bronchospasm in some patients inhaling such solutions from a nebulizer. However, the doses of EDTA and BAC administered with two actuations of the Respimat® are well below the amounts for which bronchospasm has been reported with nebulized solutions. Additionally, clinical data for the Respimat® inhaler with a variety of drug substances (including tiotropium) indicates that it is unlikely that patients using the Respimat® inhaler will experience an EDTA or preservativerelated bronchospasm (see Section 6.2.4.4.4 of the tiotropium Investigator's brochure for further information) [U92-0551]. Details of the Respimat® device and the cartridge for active ingredient solution and the instructions for use are found in Appendix 8.2 of the tiotropium Investigator's Brochure [U92-0551] and in this protocol (Section 10.1). Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 167 Page U12-2467-02 Trial Protocol 2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT 2.1 RATIONALE FOR PERFORMING THE TRIAL 5 Dec 2011 Page 26 of 149 Airway smooth muscle tone is controlled by sympathetic and parasympathetic influences as well as a range of other mediators. The predominant neural constrictor pathway is cholinergic but its impact depends on the influence of a range of other involved mediators. As consequence, anticholinergics have been explored as anti-obstructive therapies with variable responses in the different obstructive airway diseases. Neuronally released acetylcholine stimulates M3 muscarinic receptors on the airway smooth muscle and mucus glands causing bronchoconstriction and mucus (hyper-) secretion. Classically regarded as a neurotransmitter of the parasympathetic nervous system, acetylcholine is suggested to be also synthesized in many other cell types found in the airways as concluded from the expression of choline acetyl transferase, the enzyme responsible for the acetylcholine synthesis. Acetylcholine produced by these non-neuronal cells is commonly referred to as non-neuronal acetylcholine (nnACh). Additional components of the cholinergic system, in particular muscarinic receptors have been detected in nearly all cell types present in the lungs. Consequently, increasing evidence suggests that non-neuronal acetylcholine may play a role in various pathophysiological processes relevant in the course of chronic airway diseases. Taken together, these effects suggest that tiotropium, an anticholinergic, might have (beside its well characterized bronchodilatory mode of action) additional important characteristics which could be of potential therapeutic benefit for the patient. Preclinical in vivo studies in a guinea pig asthma model revealed that tiotropium attenuates airway inflammation as well as remodelling processes in these models [P05-05129 and P07-10315]. A published Cochrane Database review concluded that “the role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma” [P05-01207]. Anticholinergics are considered as a first-line therapy in COPD and there is a large body of evidence demonstrating its efficacy and safety, whereas, the place of anticholinergics in the treatment of asthma is less well-defined, particularly in patients with not optimally controlled or uncontrolled asthma. Patients with severe persistent asthma who are inadequately controlled despite treatment with a combination of inhaled steroids/long- acting ß2-agonists therapy are a therapeutic challenge with significant unmet medical need. An additional anticholinergic bronchodilator may provide added benefits for these patients. For some patients still symptomatic on maintenance therapy with an ICS alone, treatment with a longacting anticholinergic could be an alternative bronchodilator controller medication instead of a long-acting ß2-agonist. Short-acting anticholinergic agents such as ipratropium bromide, alone or in combination with ß2-agonists, are used in the management of chronic asthma in many countries. They are recognized particularly as alternative bronchodilators for patients who experience adverse effects such as tachycardia, arrhythmia and tremor from rapid-acting ß2-agonists (Global Initiative for Asthma (GINA) (2009) [P10-03196]). A meta-analysis of trials in which nebulized ipratropium bromide was added to a nebulized ß2-agonist [P99-02952] showed that Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 168 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 27 of 149 ipratropium bromide has an additional effect when nebulized together with a rapid-acting ß2agonist for exacerbations of asthma.The anticholinergic not only produced a statistically significant improvement in pulmonary function, but also significantly reduced the risk of hospital admission. According to the results of Beck R, et al. [P86-0614] a beneficial effect of ipratropium inhalation added to the standard care could be shown. Therefore clinical efficacy of inhaled tiotropium as a long acting anticholinergic can be expected. As tiotropium offers a superior time-response profile as a bronchodilator to ipratropium in COPD, tiotropium also likely will be more effective and have sustained antiobstructive effects for 24 hours in asthma. The 24-hour duration of action profile may be of special value in a population suffering from nocturnal events of, e.g., shortness of breath, which is the case in moderate and severe but still not optimally controlled asthma. Two completed phase II proof-of-concept trials (205.341 and 205.342) confirmed clinically relevant effectiveness of the 5 µg dose of tiotropium inhalation solution in patients with severe and moderate persistent asthma. Two identical 1-year phase III trials (205.416 and 205.417) are currently in conduct to confirm the safety and efficacy of 5 µg tiotropium inhalation solution (on top of at least ICS and LABA) in patients with severe persistent asthma. Trials 205.418 and 205.419 will be performed to evaluate the safety and efficacy of 2.5 and 5 µg tiotropium inhalation solution (on top of ICS) in patients with moderate asthma. Comprehensive information about the development program of tiotropium is provided in the "Investigator’s Brochure" [U92-0551]. Refer to Section 4.1.3 for the selection of doses in the trial. Please refer to Section 3.2 for a discussion on the trial design, including the choice of control groups, and to Section 4.1.3 for information on the selection of doses in the trial. 2.2 TRIAL OBJECTIVES This is one of two confirmatory phase III trials with identical protocols (twin trials with BI trial numbers 205.418 and 205.419). The primary objective of each trial is to evaluate the long term (24 weeks) efficacy and safety of two doses (2.5 µg and 5 µg) of tiotropium inhalation solution (administered once daily) compared to placebo and to salmeterol (50 µg; administered twice daily) on top of maintenance therapy with inhaled corticosteroid controller medication in patients with moderate persistent asthma. The comparisons of tiotropium versus salmeterol and placebo versus salmeterol are not part of the inferential analysis. A 24 hour PK profile of tiotropium is only available for COPD patients. In this trial PK samples will be collected from 80 patients to confirm this 24 hour profile in asthma patients. A substudy will be done to explore the onset of action of the study medication. The substudy will comprise of 2 additional PFTs (5 and 15 minutes post-dose) at Visit 5 only and will be completed in approximately 480 patients. Refer to Section 5 for the endpoints. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 2.3 169 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 28 of 149 BENEFIT - RISK ASSESSMENT The favourable benefit-risk ratio based on the so far acquired knowledge about inhaled tiotropium is the rationale to conduct further studies with tiotropium in asthma. The incidence of adverse events was low in all four asthma trials using doses up to 36 µg inhalation powder/HandiHaler® over 21 to 28 days of treatment. The type and rate of events were not different from those seen in the trials with COPD patients, aside from “asthma exacerbation”. The most common events were asthma exacerbation, upper respiratory infection, headache and dry mouth. Single doses of placebo inhalation solution/Respimat® were well tolerated, as evaluated in 32 mild asthmatic patients. During a crossover efficacy and safety evaluation trial (205.341) of 8-week treatment periods of two doses (5 and 10 µg ) tiotropium inhalation solution delivered by the Respimat® inhaler as add-on therapy in patients with severe persistent asthma the overall occurrence of adverse events was similar between the placebo and 5 µg tiotropium groups (39.8% and 42.3% of patients, respectively, reported at least one adverse event), but slightly higher in the 10 µg tiotropium group (49.5% of patients reported at least one adverse event). The most common treatment-emergent adverse events were nasopharyngitis and asthma (MedDRA preferred term classification including aggravated asthma and exacerbation of asthma), with both being reported overall by 28 patients (26.2%). The only treatment-emergent adverse event reported in more than one patient was dry mouth, which was considered drug-related in 4 patients (3.9%) only in the 10 µg tiotropium group [U08-2081]. During the double-blind treatment and follow-up period of trial 205.342, mean (standard deviation) duration of double-blind exposure to trial medication was 109.6 (21.3) days (placebo), 110.9 (16.2) days (tiotropium), and 111.8 (16.8) days (salmeterol). During the double-blind treatment and follow-up periods, the overall incidence of AEs was similar in the active treatment and placebo groups: 52 (41.3%) placebo patients; 51 (39.8%) tiotropium patients; 56 (41.8%) salmeterol patients. Few AEs were considered drug-related and the incidences of such AEs were also similar across groups: 4 (3.2%) placebo patients, 6 (4.7%) tiotropium patients, and 3 (2.2%) salmeterol patients. The most common AEs by preferred term were asthma exacerbation (including preferred term asthma) and nasopharyngitis [U091701]. In conclusion, the studies conducted in asthmatic patients provided no evidence of serious adverse effects with suspected causal relationship to tiotropium treatment. The administration of tiotropium can be considered as safe for patients. For detailed information regarding the safety of tiotropium in COPD, please refer to the "Investigator’s Brochure" [U92-0551]. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 170 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 29 of 149 3. DESCRIPTION OF DESIGN AND TRIAL POPULATION 3.1 OVERALL TRIAL DESIGN AND PLAN This is a randomised, double-blind, double-dummy, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of 2.5 and 5 µg of tiotropium inhalation solution delivered by the Respimat® inhaler (once daily) compared with placebo and salmeterol HFA MDI (50 µg twice daily) over 24 weeks in moderate persistent asthma patients treated with medium doses of inhaled corticosteroids. After signing informed consent and an initial screening visit, patients will enter a 28-day screening period. Patients who meet all inclusion and none of the exclusion criteria will be randomised into the 24-week treatment period in which they will receive either 2.5 µg tiotropium (2 puffs of 1.25 µg) once daily, 5 µg tiotropium (2 puffs of 2.5 µg) once daily, 50 µg salmeterol (2 puffs of 25 µg) twice daily or placebo in a double-dummy fashion. Patients will be evaluated for an additional 21 days following completion of the randomised treatment period. Visit 0 and Visit 7 may be conducted during business hours. Visit 1 to Visit 6 will always start in the evening. Patients who withdraw prematurely from the randomised treatment period will be followed up regarding their vital status. They will be contacted at their predicted normal exit date from the trial, i.e. completion of the 24 week treatment period plus 21 days follow-up period. Pulmonary function testing will be conducted at the screening visit (Visit 1) and vital signs will be measured in conjunction with pulmonary function tests until three hours post-dosing at all visits (except at Visits 2A, 2B and 2C) during the randomised treatment period. Asthma exacerbations according to protocol-specific definition (see Appendix 10.10) will be documented together with additional observations including utilisation of healthcare resources, adverse events and concomitant therapies. Three paper-based questionnaires (ACQ, AQLQ (S) and EQ-5D) will be patient self-administered during the treatment period. In selected countries a fourth questionaire (PASAPQ) will be patient self-administered at V6. The ACQ will also be self-administered at Visit 1. The ACQ mean score at Visit 1 and Visit 2 will be used to determine the patient's eligibility. The patient will record morning and evening PEF and FEV1 and use an electronic diary throughout the screening and treatment period. Physical examination will be performed together with an evaluation of the patient's smoking status and asthma background characteristics at Visit 1. Blood samples for clinical laboratory testing will be obtained and a 12-lead ECG will be recorded at Visit 1 to evaluate the patient's eligibility. Urine pregnancy testing will be done at Visit 1 in females of childbearing potential. The physical examination, laboratory testing, pregnancy testing, ECG and evaluation of the patient's smoking status will be repeated on completion of patient's participation in the randomised treatment period of the trial. Analysis of clinical laboratory samples will be performed by the local laboratory of each site. Depending on patient's informed consent, a blood sample for pharmacogenetics will be drawn at Visit 2 (or any subsequent visit) from all randomised patients that received at least one dose of trial medication. If a patient signed an informed consent for participation in the PK substudy, blood samples for pharmacokinetic evaluation will be drawn over 24 hours at Visits Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 171 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 30 of 149 2 and 3 and pre- and post-dose at Visit 2A, 2B and 2C (in a subset of patients at selected sites). Pulmonary function testing over 24 hours will be performed at Visit 6 in a subset of patients at sites capable of performing 24 hour measurements. Adverse events will be documented throughout the trial, i.e. starting with informed consent and ending 21 days after last administration of trial medication. All trial relevant documentation will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). Trial relevant documentation for the trial sites will be filed in the Investigator Site File (ISF) at the investigator sites. 3.1.1 Administrative structure of the trial Sponsor: Clinical trial drug supplies including trial, training and rescue medication will be provided by the sponsor. Co-ordinating Investigator: The co-ordinating investigator was selected by the sponsor. He will review the trial protocol, any subsequent amendments to the protocol and the (draft) Clinical Trial Report (CTR). He will provide his signature on the final protocol signature page and amendments and will provide his signature on the (draft) Clinical Trial Report (CTR) indicating that, to the best of Co-ordinator’s knowledge, the final CTR accurately describes the conduct and results of the Trial. Targeted group of Investigators: Pulmonologists/qualified sites with access to the requested patient population. The following local facilities/equipment are required at the investigational site: clinical laboratory, ECG, scale and sphygmomanometer. The sites have to be able to perform the 3 hour PFT measurements in the evening. Selected sites have to be able to perform the (24 hour) PK and/or 24 hour PFT measurements. DSMB: A DSMB will not be implemented on trial level, but might be implemented on project level. If so, safety review meetings will be held as per separate DSMB charter Central laboratory: The sample transport logistics (from site to sponsor) for PK and pharmacogenetic samples will be the responsibility of the central lab. The central lab will provide sampling and shipment materials. IVRS: : An interactive voice response system (IVRS) will be used for randomisation to a treatment group in this trial and for appropriate re-supply of medication to patients. The ability to unblind will be available to the investigator via the IVRS. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 172 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 31 of 149 CROs: A CRO will provide MasterScope® CT and AM3® devices for the complete duration of the trial. All contracts and relevant meeting minutes will be stored by Boehringer Ingelheim in the clinical trial master file (CTMF). 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S) The trial design has been selected to allow comparison of the effects on pulmonary function and patient-reported outcomes of different doses of tiotropium to placebo and salmeterol in patients with moderate persistent asthma that is not fully controlled although the patients are treated with medium doses inhaled corticosteroids. The selection of evening administration in this patient subgroup was mainly to consider nocturnal control of airway patency. In trials 205.341 [U08-2081] and 205.342 [U09-1701] no untoward events happened to patients treated with placebo and the overall incidence of AEs and the incidence of asthma exacerbations were similar in active treatment and placebo arms. Based on these data, a 'placebo' (i.e. no second controller medication) treatment group in this trial could be considered safe, because all patients are at least on a maintenance treatment with a stable dose of an anti-inflammatory medication (inhaled corticosteroid). Moreover, all patients will be provided with so-called rescue medication (open-label salbutamol (albuterol) HFA MDI). Boehringer Ingelheim intends to conduct a Phase 3 program that will fulfil global registration requirements. According to EU regulations, inclusion of an active comparator treatment arm is required. BI decided to use Serevent® HFA MDI as approved and commercially available in the EU as the active comparator. Washout requirements prior to pulmonary function testing and other medication restrictions (see Section 4.2.2) are given to reduce possible influences on pulmonary function testing and ensure patient's safety during the trial. The permitted concomitant asthma medication (see Section 4.2) should be kept stable during the complete trial period with the exception of acute treatment of asthma exacerbations. The data collected in a controlled, double-blind, randomised and placebo-controlled trial will provide useful information to health care providers and patients regarding the efficacy and safety of 2 doses of tiotropium inhalation solution delivered by the Respimat® inhaler added to inhaled corticosteroids in the treatment of not fully controlled moderate asthma in comparison to placebo and salmeterol. 3.3 SELECTION OF TRIAL POPULATION A sufficient number of patients of either sex with a diagnosis of moderate persistent asthma will be enrolled in the study to ensure approximately 1000 adult patients are entered (randomised) in the trial. Additional sites may be initiated and 'non-productive' sites may be closed to ensure sponsor's timelines. Randomisation will end when the trial clinical monitor has determined that enough patients are evaluable. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 173 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 32 of 149 Participation in the PK part of the trial is optional and not a prerequisite for patients to participate in the trial. Several sites capable of performing 24 hour PK sampling will be selected to participate in the PK part of the trial. All participating patients at these sites will be asked to consent to the PK visits until at least 80 patients have completed the PK substudy. Participation in the 24 hour PFT visit (at Visit 6) is optional and not a prerequisite for patients to participate in the trial. All sites capable of performing 24 hour PFT measurements will be selected to perform the 24 hour PFT visit. All participating patients at these sites will be asked to consent to the 24 hour PFT visit. The number of patients participating in the 24 hour PFT measurements is not limited. Several sites will be selected to perform a PFT at 5 and 15 minutes post-dose at Visit 5. A total of approximately 480 patients will be asked to participate (120 patients in each treatment arm). The Patient satisfaction and preference questionnaire (PASAPQ) will be patient selfadministered in selected countries at Visit 6. Every effort should be made to keep patients in the trial until they complete all trial procedures. Patients who discontinue after randomisation may not be re-enrolled at a later date. A record will be kept of all patients who fail to complete all trial visits and their reason for discontinuation. A log of all patients included into the study (i.e. having given informed consent) will be maintained in the ISF at the investigational site irrespective of whether they have been treated with investigational drug or not. 3.3.1 Main diagnosis for study entry Outpatients with a history of asthma and a current diagnosis of moderate persistent asthma (according to GINA guideline) and who are symptomatic (partly controlled) despite their current maintenance treatment with at least a medium dose of inhaled corticosteroids are eligible for inclusion if they fulfil all the inclusion criteria (Section 3.3.2) and none of the exclusion criteria (Section 3.3.3). 3.3.2 Inclusion criteria 1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1). 2. Male or female patients aged at least 18 years but not more than 75 years. 3. All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5. 4. The initial diagnosis of asthma must have been made before the patient's age of 40. Boehringer Ingelheim BI Trial No.: 205.419 16.1.1 Protocol and amendments Boehringer Ingelheim BI Trial No.: 205.419 174 Page U12-2467-02 Trial Protocol 5 Dec 2011 Page 33 of 149 If the patient is > 40 years and the diagnosis has not yet been recorded in the patient's medical files, the investigator should assess whether the patient's medical history (e.g. symptoms and prescribed medications) confirms the patient suffered from asthma since before the age of 40. If so, this patient may be considered for inclusion after consultation with the Clinical Monitor Local (CML). 5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 to 30 minutes after 400 µg salbutamol (albuterol)) resulting in a FEV1 increase of ≥ 12% and ≥ 200mL (see Appendix 10.4). NOTE: If this criterion is not met, the reversibility test may (in combination with the ACQ) be repeated once within two weeks (see Section 6.1). 6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (see Appendix 10.4) (alone or in a fixed combination with a LABA or SABA) for at least for 4 weeks prior to Visit 1. 7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ (see Appendix 10.6) mean score of ≥ 1.5. NOTE: If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see Section 6.1). 8. All patients must have a pre-bronchodilator FEV1 ≥ 60% and ≤ 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to ECSC [R94-1408] (see Appendix 10.4). 9. Variation of absolute FEV1 values of Visit 1 (pre-bro