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Boehringer Ingelheim
BI Trial No.: 205.418
16.1.1 Protocol and amendments
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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
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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:
___________________________
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16.1.1 Protocol and amendments
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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
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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:
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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.
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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.
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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
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*
**
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
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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®).
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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).
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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INTRODUCTION
1.1
MEDICAL BACKGROUND
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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.
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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].
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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.
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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.
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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.
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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).
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RATIONALE, OBJECTIVES, AND BENEFIT - RISK
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
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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
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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.
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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].
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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
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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.
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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.
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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.
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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).
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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
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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.
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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.
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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.
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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).
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TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
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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
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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
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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.
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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).
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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.
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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
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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.
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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.
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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
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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).
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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
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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).
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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
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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)
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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
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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
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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.
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VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACODYNAMICS
5.1.1
Endpoint(s) of efficacy
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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.
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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)
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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
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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.
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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.
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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
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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
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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
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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.
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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.
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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.
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INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
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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
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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.
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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
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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).
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•
•
•
•
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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).
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•
•
•
•
•
•
•
•
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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)
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- 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.
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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.
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6.2.3
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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.
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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.
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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.
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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:
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H12:
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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)
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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
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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.
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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
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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
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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
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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
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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%.
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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
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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.
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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.
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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.
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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.
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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
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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
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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-
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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.
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APPENDICES
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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
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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
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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.
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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.
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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.
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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!
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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.
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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.
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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.
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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.
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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
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ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S))
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Page 116 of 149
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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 $E!tf-employed, these should be tasks y ou have to do most days.
SLEEPING
2
4
3
5
HOW M UCH DISCOMFORT OR DISTRESS HAVE YOU FELT DURING THE LAST 2 WEEKS?
A Very
Gre;t Oe;~~l
6.
How m uch d iscomfort or distress
hav e y ou felt over the last 2
weeks as a result of CHEST
TIGHTNESS?
AGru t
De'!
A Good
M o<ler;t'='
Oul
Amou nt
2
3
4
Som•
Very
None
Li~1f..e
5
6
7
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ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATIENT ID
SELF-ADMINISTERED
DATE
Page 2oi5
IN GENERAL. HOW MUCH OF THE TIME DURING THE LAST 2 WEEKS DID YOU:
All of
the Time
7.
8.
9.
Mo$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
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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
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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
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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
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ASTHMA CONTROL QUESTIONNAIRE (ACQ)
5 Dec 2011
Page 122 of 149
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EQ-5D HEALTH QUESTIONNAIRE
~Q-50
He.nlth Questionnnit·e
(Euglish vcnio11 for the US)
-
5 Dec 2011
Page 125 of 149
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PAPER PATIENT DIARY CARD
5 Dec 2011
Page 128 of 149
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AM3 PATIENT INSTRUCTION CARD
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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
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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
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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
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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.
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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
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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.
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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.
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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
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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
]
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PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE
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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.
~
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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
~
~
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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
~
~
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Please go to the next page
@Boehringer Ingelheim
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Boehringer Ingelheim
BI Trial No.: 205.418
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144
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-
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Page 142 of 149
Trial Protocol
~"0
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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~!
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Overall, how satisfied are you with your inhaler?
Respimat®!
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©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
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Boehringer Ingelheim
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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
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Boehringer Ingelheim
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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
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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
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Section to be changed
Description of change
148
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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.
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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.
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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
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Description of change
Rationale for change
151
Page
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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.
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152
U12-2466-01
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15 Apr 2010
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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
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16.1.1 Protocol and amendments
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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
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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
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BI Trial No.: 205.418
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155
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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:
___________________________
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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
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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:
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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.
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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.
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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
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*
**
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
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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®).
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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).
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
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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.
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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].
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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.
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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.
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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.
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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).
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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
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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
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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.
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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].
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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
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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.
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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.
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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.
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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).
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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
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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.
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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.
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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.
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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).
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TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
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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
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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
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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.
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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).
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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.
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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
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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.
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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.
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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
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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).
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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
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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).
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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
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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)
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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
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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
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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.
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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACODYNAMICS
5.1.1
Endpoint(s) of efficacy
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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.
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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)
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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
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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.
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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.
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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
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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
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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
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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.
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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.
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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.
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INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
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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
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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.
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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
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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).
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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).
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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)
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- 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.
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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.
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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.
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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.
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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.
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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:
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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)
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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
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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.
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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
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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
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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
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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
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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%.
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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
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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.
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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.
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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.
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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.
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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
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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
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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-
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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.
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APPENDICES
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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
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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
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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.
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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.
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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.
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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!
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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.
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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.
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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.
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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.
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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
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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 $E!tf-employed, these should be tasks y ou have to do most days.
SLEEPING
2
4
3
5
HOW M UCH DISCOMFORT OR DISTRESS HAVE YOU FELT DURING THE LAST 2 WEEKS?
A Very
Gre;t Oe;~~l
6.
How m uch d iscomfort or distress
hav e y ou felt over the last 2
weeks as a result of CHEST
TIGHTNESS?
AGru t
De'!
A Good
M o<ler;t'='
Oul
Amou nt
2
3
4
Som•
Very
None
Li~1f..e
5
6
7
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ASTHMA QUALITY OF LIFE QUESTIONNAIRE (S) PATIENT ID
SELF-ADMINISTERED
DATE
Page 2oi5
IN GENERAL. HOW MUCH OF THE TIME DURING THE LAST 2 WEEKS DID YOU:
All of
the Time
7.
8.
9.
Mo$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
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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
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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
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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
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ASTHMA CONTROL QUESTIONNAIRE (ACQ)
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EQ-5D HEALTH QUESTIONNAIRE
~Q-50
He.nlth Questionnnit·e
(Euglish vcnio11 for the US)
-
5 Dec 2011
Page 125 of 149
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16.1.1 Protocol and amendments
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Page
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PAPER PATIENT DIARY CARD
5 Dec 2011
Page 128 of 149
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AM3 PATIENT INSTRUCTION CARD
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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
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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
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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
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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.
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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
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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.
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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.
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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
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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
]
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Page 140 of 149
PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE
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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)
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o;: .~
IJJ ....
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;;:::
IJJ
IJJ
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(:-VI
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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
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0
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0
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D
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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
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D 0
D 0
D 0
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D 0
D 0
D
0
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D
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0
0
0
D
D
0
0
0
Boehringer Ingelheim
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-
5 Dec 2011
Page 142 of 149
Trial Protocol
~"0
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"0
"0
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;;::
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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
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©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
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Boehringer Ingelheim
BI Trial No.: 205.418
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BI Trial No.: 205.418
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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
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Boehringer Ingelheim
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297
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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
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Trial Protocol
5 Dec 2011
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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
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Section to be changed
Description of change
299
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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.
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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.
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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
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Description of change
Rationale for change
302
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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.
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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;
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304
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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
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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.
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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.
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U12-2466-01
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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.
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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.
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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.
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16.1.1 Protocol and amendments
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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.
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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.
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Change 1:
regulatory.
315
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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.
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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.
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Page
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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.
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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.
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319
Page
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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.
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16.1.1 Protocol and amendments
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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.
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16.1.1 Protocol and amendments
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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.
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16.1.1 Protocol and amendments
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BI Trial No.: 205.418
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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.
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16.1.1 Protocol and amendments
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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.
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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
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16.1.1 Protocol and amendments
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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.
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BI Trial No.: 205.418
16.1.1 Protocol and amendments
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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.
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16.1.1 Protocol and amendments
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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
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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
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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.
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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
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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
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330
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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.
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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
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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.
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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
___________________________
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BI Trial No.: 205.419
16.1.1 Protocol and amendments
Boehringer Ingelheim
BI Trial No.: 205.419
5
Page
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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
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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
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Boehringer Ingelheim
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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
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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
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BI Trial No.: 205.419
16.1.1 Protocol and amendments
Boehringer Ingelheim
BI Trial No.: 205.419
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
10
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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.
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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®).
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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).
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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TDMAP
TinA
tmax
tmax,ss
TNF
TSAP
USA
USPI
Vz/F
γ-GT
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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
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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
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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.
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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].
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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.
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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.
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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.
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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).
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RATIONALE, OBJECTIVES, AND BENEFIT - RISK
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
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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
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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.
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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].
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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
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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.
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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.
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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.
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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.
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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).
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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.
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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.
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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).
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TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
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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
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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
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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.
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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
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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.
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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
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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-
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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.
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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.
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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.
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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.
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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
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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)
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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
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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).
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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.
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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.
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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACODYNAMICS
5.1.1
Endpoint(s) of efficacy
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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).
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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)
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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.
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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.
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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.
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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.
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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
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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
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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.
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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).
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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
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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.
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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.
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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)
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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)
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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.
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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.
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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.
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INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
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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
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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.
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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
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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).
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•
•
•
•
•
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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).
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•
•
•
•
•
•
•
•
•
•
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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)
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- 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.
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•
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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.
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•
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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
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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.
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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.
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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:
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H12:
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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)
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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
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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.
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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.
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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.
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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.
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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.
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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%.
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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
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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.
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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.
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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.
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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.
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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
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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
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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-
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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.
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APPENDICES
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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
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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
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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.
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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.
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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.
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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!
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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.
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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.
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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.
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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.
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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
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ASTHMA QUALITY OF LIFE QUESTIONNAIRE (AQLQ (S))
21 Apr 2010
Page 113 of 137
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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
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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
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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
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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
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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
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ASTHMA CONTROL QUESTIONNAIRE (ACQ)
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EQ-5D HEALTH QUESTIONNAIRE
(00-so
He.nlth Questionnnit·e
(Euglish vcnio11 for the US)
21 Apr 2010
Page 122 of 137
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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
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PAPER PATIENT DIARY CARD
21 Apr 2010
Page 125 of 137
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AM3 PATIENT INSTRUCTION CARD
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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
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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
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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.
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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
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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.
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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.
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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
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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
]
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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
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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
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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
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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
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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:
___________________________
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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
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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:
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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.
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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.
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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
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*
**
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
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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®).
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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).
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
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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.
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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].
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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.
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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.
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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.
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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).
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RATIONALE, OBJECTIVES, AND BENEFIT - RISK
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
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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
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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.
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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].
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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
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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.
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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.
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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.
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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