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CLINICAL PROTOCOL
Sponsor Name
Protocol Title
Protocol Number
Protocol Date
Version Number
Amendment Number
IND Number
NDA Number
Primary Author
Contributing Authors
Best Pharmaceutical, Inc
Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study
Comparing the Safety and Effectiveness of Drug A 20 mg Once Daily
Versus Placebo Using 24-Hour Ambulatory Blood Pressure
Monitoring In Patients With mild to moderate
ABC01
27March2007
Final 1.0
0
999,999
Not applicable
Best Protocol Author, MD
Best SAP Author, PhD
Best CSR Author, MD
Drug Name
Phase of Development
Indication
Drug A
III
Mild to moderate hypertension
Study Sponsor: Best Pharmaceutical, Inc.
Wonderful Road, Suite 909
Rockville, MA 20850
Phone: 999-999-9999
Fax: 999-999-8888
Web: www.bestpharma.com
CONFIDENTIAL
This document is a confidential communication of the Sponsor. Acceptance of this
document constitutes the agreement by the recipient that no unpublished information
contained herein will be published or disclosed without prior written approval.
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Protocol Signature Page
Best Pharmaceutical, Inc
Protocol ABC01
Original Approval Date: March XX, 2007
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study
Comparing the Safety and Effectiveness of Drug A 20 mg Once Daily Versus
Placebo Using 24-Hour Ambulatory Blood Pressure Monitoring (ABPM) In
Patients with Mild to Moderate Hypertension
Protocol Final Version 1.0 Approval
This protocol has been verified and approved by:
_____________________________________________
<name and degree>
<title>
__________________
Date
<company>
______________________________________________
<name and degree>
<title>
__________________
Date
<company>
______________________________________________
<name and degree>
<title>
__________________
Date
<company>
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TABLE OF CONTENTS
Protocol Signature Page .................................................................................................................... 2
List of Abbreviations ......................................................................................................................... 5
1. PROTOCOL SYNOPSIS .............................................................................................................. 6
2. Background Information ............................................................................................................... 9
2.1 Background ......................................................................................................................... 9
2.2 Study Rationale ................................................................................................................... 9
2.3 Toxicity and Pre-clinical experience ................................................................................... 9
2.4 Clinical experience .............................................................................................................. 9
2.5 Summary of Potential Risks and Benefits ........................................................................... 9
3. Study Objectives ......................................................................................................................... 10
3.1 Primary objectives............................................................................................................. 10
3.2 Secondary objectives ......................................................................................................... 10
4.0 Study Design ............................................................................................................................. 11
4.1 Study Endpoints ................................................................................................................ 11
4.2 Overall Study Design ........................................................................................................ 11
4.3 Randomization/Blinding Procedure .................................................................................. 11
4.4 Stopping Rules .................................................................................................................. 11
4.5 Maintenance of Randomization Codes and Procedure for Breaking Codes ..................... 12
5.0 Study Population ....................................................................................................................... 14
5.1 Inclusion Criteria............................................................................................................... 14
5.2 Exclusion Criteria ............................................................................................................. 14
6.0 Investigational Medicine Products ............................................................................................ 16
6.1 Study Treatment ................................................................................................................ 16
6.2 Concomitant Medications and Prohibited Medications .................................................... 16
7.0 Study Procedures....................................................................................................................... 18
7.1 Visit 1 (Week -4, Screening) ............................................................................................. 18
7.2 Visit 2 (Week -3, Placebo Run-in)..................................................................................... 18
7.3 Visit 3 (Week -2, Placebo Run-in)..................................................................................... 19
7.4 Visit 4 (Week -1, Placebo Run-in)..................................................................................... 19
7.5 Visit 5 (Week 0 Baseline) or Visit 4A (Week -1A Placebo Run-In) .................................. 19
7.6 Visit 6 (Week 0, Baseline/Randomization) ....................................................................... 20
7.7 Visit 7 (Week 2, Double-Blind Treatment)........................................................................ 20
7.8 Visit 8 (Week 4, Double-Blind Treatment)........................................................................ 21
7.9 Visit 9 (Week 6 End of Study/Early Termination)............................................................. 21
7.10 Visit 10 (Week 6 End of Study/Early Termination)......................................................... 21
8.0 Clinical Assessment .................................................................................................................. 23
8.1 12-lead Electrocardiogram ................................................................................................ 23
8.2 Physical Examination ........................................................................................................ 23
8.3 Pregnancy Test and ........................................................................................................... 23
8.4 Laboratory Assessments .................................................................................................... 23
8.5 Office Blood Pressure and ABPM Measurements ............................................................ 24
9.0 Safety Assessment ..................................................................................................................... 25
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9.1 Adverse Event and AE reporting ....................................................................................... 25
10.0 Statistical Consideration and Analysis .................................................................................... 26
10.1 General Statistical Method .............................................................................................. 26
10.2 Analysis Population......................................................................................................... 26
10.3 Subject Disposition ......................................................................................................... 26
10.4 Demographic and Baseline Characteristics ..................................................................... 26
10.5 Protocol Deviation .......................................................................................................... 27
10.6 Efficacy Analysis ............................................................................................................ 27
10.7 Safety Analysis ................................................................................................................ 27
10.8 Sample Size Estimation/Justification .............................................................................. 27
11.0 Ethics....................................................................................................................................... 28
12.0 Data Handling and Record Keeping ....................................................................................... 29
13.0 Financing and Insurance ......................................................................................................... 30
14.0 Publication Policy ................................................................................................................... 31
15.0 Reference List ......................................................................................................................... 32
APPENDIX A Schedule of Study Evaluations........................................................................... 33
APPENDIX B Blood Pressure Measurement: Office and Ambulatory Blood Pressure Monitoring
........................................................................................................................................................ 34
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List of Abbreviations
Ambulatory Blood Pressure Monitoring
ABPM
Adverse Event
AE
Blood Pressure
BP
Case Report Form
CRF
Diastolic Blood Pressure
DBP
Eelectrocardiogram
ECG
Last observation carried forward
LOCF
Systolic Blood Pressure
SBP
…
…
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1. PROTOCOL SYNOPSIS
Protocol Number:
Title:
Indication:
Objectives:
Study Design:
Treatments:
Procedures/Visits:
Study Population:
Efficacy Measures:
ABC01
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study
Comparing the Safety and Effectiveness of Drug A 20 mg Once Daily
Versus Placebo Using 24-Hour Ambulatory Blood Pressure Monitoring
(ABPM) In Patients with Mild to Moderate Hypertension.
Mild to moderate hypertension.
1. The primary objective of the study is to compare the
antihypertensive effectiveness using change from Baseline in mean
seated office cuff diastolic blood pressure of Drug A 20 mg once
daily to placebo.
2. The secondary objective is to evaluate the safety of low-dose Drug
A compared to placebo and change from Baseline at Week 6 or end
of study in mean 24-hour and mean daytime ambulatory Diastolic
Blood Presssure (from time of dosing until 8:00PM) as measured by
ABPM.
The study will employ a randomized, double-blind design in patients with
mild to moderate hypertension. The study includes a 3- to 4-week
single-blind placebo run-in phase and a 6-week double-blind treatment
phase.
All patients will receive placebo tablets once daily for 3 – 4 weeks during
the single-blind, run-in phase. During the double-blind treatment phase,
patients will be randomized in a 1:1 ratio to receive either Drug A 20 mg
or placebo tablets once daily for 6 weeks.
Study visits will be scheduled to fit within the window for trough blood
pressure (BP) measurements (i.e., prior to next dose and between 22–26
hours after previous dose [24±2 hours]).
Approximately 300 patients at approximately 10 sites will be enrolled
into the placebo run-in phase. It is expected that 20% of patients will not
qualify for randomization based on office BP entry criteria and an
additional 25% of patients will not qualify based on ABPM entry criteria.
The study will randomize approximately 180 patients into the
double-blind treatment. The study population will include males and
females ≥ 18 years of age with mild to moderate hypertension (defined as
a seated diastolic blood pressure (DBP) ≥ 95 mmHg and ≤ 110 mmHg).
Primary Endpoint: The primary efficacy endpoint is the change from
Baseline in mean seated office cuff DBP (24±2 hours) at Week 6 or end
of study.
Secondary Endpoints:
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
Safety Measures:
Statistical Analysis:
Change from Baseline in seated office systolic blood pressure (SBP)
at Weeks 2, 4, 6 or end of study and DBP at Weeks 2 and 4 or end of
study,
 Change from Baseline to Week 6 or end of study in mean 24-hour
and mean daytime ambulatory DBP (time of dose until 8:00 PM) as
measured by ABPM,
 Change from Baseline to Week 6 or end of study in mean 24-hour
and mean daytime (time of dose until 8:00 PM) ambulatory SBP as
determined by ABPM,
 Proportion of patients with seated office cuff DBP reduced > 4
mmHg from baseline at Week 6 or end of study,
 Proportion of patients who are normalized by office BP
measurements (defined as a trough seated SBP <135 mmHg and/or
DBP <85 mmHg at Week 6 or end of study), and
 Proportion of patients with a reduction in ambulatory mean 24-hour
DBP > 10 mmHg from baseline at Week 6 or end of study.
Patient safety will be assessed by monitoring and reporting of adverse
events (AE) that occur during the study. Further safety assessments will
include physical examinations, 12-lead electrocardiogram (ECG), and
clinical laboratory tests.
Efficacy analyses will be conducted for two populations: Modified
Intent-to-Treat (ITT) and Per Protocol (PP). Descriptive statistics will be
presented for the observed blood pressure values, but analysis will be
performed on change from baseline. Change from baseline will be
calculated as BPt – BP0 where BPt is defined as the blood pressure
measurement obtained at time = t (Week 2, 4, or 6) and BP0 is the
baseline blood pressure (Randomization, Week 0). The primary efficacy
endpoint is the change from Baseline in mean seated office cuff DBP
(24±2 hours) at Week 6 or end of study. The primary analysis is the
comparison of the two treatment groups using the ITT and PP
populations.
Secondary efficacy analyses will be conducted for the ITT and PP
populations. In addition, analyses for change from baseline for the
primary efficacy endpoint will be presented in both ITT and PP
populations, examining the effect of race (Caucasian versus
Non-Caucasian), gender (male versus female), and age (< 65 years versus
≥65 years) at Week 6 or end of study. These subgroup analyses by
demographics will be performed for the primary efficacy endpoint but not
for the secondary efficacy endpoints. For analyses conducted on efficacy
results obtained at the various scheduled visits, missing values in the ITT
population will be imputed using the last observation carried forward
(LOCF) method except for mean ambulatory SBP and DBP by ABPM.
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Continuous efficacy endpoints (e.g., change from baseline in seated and
standing systolic and diastolic office blood pressures) will be compared
across treatment groups using a fixed-effect two-way analysis of variance
(ANOVA) with center and treatment as factors. Categorical response
variables (e.g., proportion of normalized patients with SBP <135 mmHg
and/or DBP<85 mmHg) will be compared using the
Cochran-Mantel-Haenszel test stratified by center.
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2. Background Information
2.1 Background
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2.2 Study Rationale
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2.3 Toxicity and Pre-clinical experience
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2.4 Clinical experience
<placeholder>
2.5 Summary of Potential Risks and Benefits
<placeholder>
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3. Study Objectives
The objective of this study is to evaluate the safety and effectiveness of Drug A 20 mg once daily
versus placebo using 24-hour Ambulatory Blood Pressure Monitoring (ABPM) in patients with
mild to moderate hypertension.
3.1 Primary objectives
The primary objective of the study is to compare the antihypertensive effectiveness using change
from Baseline in mean seated office cuff diastolic blood pressure of Drug A 20 mg once daily to
placebo.
3.2 Secondary objectives
The secondary objective is to evaluate the safety of low-dose Drug A compared to placebo and
change from Baseline at Week 6 or end of study in mean 24-hour and mean daytime ambulatory
DBP (from time of dosing until 8:00PM) as measured by ABPM.
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4.0 Study Design
4.1 Study Endpoints
4.1.1 Efficacy Endpoints
<see the protocol synopsis>
4.1.2 Safety Endpoints
<see the protocol synopsis>
4.2 Overall Study Design
The study is a phase III, prospective, randomized, double-blind, placebo-controlled clinical trial to
evaluate the safety and effectiveness of Drug A 20 mg once daily versus placebo using 24-hour
Ambulatory Blood Pressure Monitoring (ABPM) in patients with mild to moderate hypertension.
The study includes a 3- to 4-week single-blind placebo run-in phase and a 6-week double-blind
treatment phase.
The study will receive approval from the institutional review board (IRB)/ethics committee (EC)
at each site and will be conducted in accordance with the principles outlined in the Declaration of
Helsinki. Written informed consent will be obtained from all subjects.
This study will be at 20 sites in Europe, North America and Asian Pacific.
4.3 Randomization/Blinding Procedure
A centralized, center-blocked randomization procedure will be used for treatment assignment by
means of an Interactive Voice Response System (IVRS). Subjects will be randomized 1:1 into
2 groups (Drag A n=90, placebo n=90).
Subjects and study personnel will be blinded to treatment groups (active study drug vs. placebo).
4.4 Stopping Rules
4.4.1 Subject Withdrawal
A subject (or subject's legal guardian) is free to withdraw consent and discontinue participation in
the study at any time, without prejudice to further treatment according to standard practice.
If a subject becomes pregnant, or is discovered to be pregnant, during study participation, the
Sponsor should be notified. A detailed, comprehensive medical review (for the subject and fetus)
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will be conducted prior to continuing or discontinuing study participation. Pregnancy will not be
considered an SAE.
If a subject’s participation in the study is terminated early, all available data, including the
incidence of AEs and the reason for discontinuation, will be recorded on the Case Report Form
(CRF). If a serious adverse event (SAE) occurs within 30 days after the last study dose, the
investigator should follow the SAE until the event is resolved or the subject is lost to follow-up.
Resolution means the subject has returned to the baseline state of health or the condition is stable
and the Investigator does not expect any further improvement or worsening of the adverse event.
In all cases, the appropriate information will be recorded on the CRF.
4.4.2 Sponsor or Investigator Withdrawal
Any of the following are considered reason for the Investigator to remove a subject from the
study:

The subject is uncooperative/non-compliant and will not or cannot adhere to study
responsibilities, including all eligible study visits

The subject was erroneously enrolled in the study

The subject suffers an intolerable AE

The sponsor terminates the study.
A subject's participation in the study may be discontinued at any time at the discretion of the
Investigator.
If the Sponsor, an Investigator, or a regulatory agency discovers a condition during the study to
indicate that the study or site should be terminated, this action may be taken after appropriate
consultation between the Sponsor and the Investigator. Conditions that might warrant
termination of the study include, but are not limited to the following criteria.

The discovery of an unexpected, serious, or unacceptable risk to a subject enrolled in
the study

The decision on the part of the Sponsor to suspend or discontinue testing, evaluation,
or development of the study drug

Failure of the Investigator to comply with pertinent regulatory authority regulations

Submission of knowingly false information from the research facility to the Sponsor,
or other regulatory authority

Insufficient adherence to protocol requirements
4.5 Maintenance of Randomization Codes and Procedure for Breaking Codes
Unblinding of treatment assignment during the study is discouraged and should occur only if it is
absolutely necessary to identify treatment assignment in an emergency situation due to an adverse
event (AE). If the Investigator deems identification of the study medication as necessary for the
purpose of providing urgent subject care, unblinding should proceed and the Sponsor’s Chief
Medical Officer and/or PI should be notified. Every effort should be made to contact the
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Sponsor’s Chief Medical Officer and/or PI prior to unblinding. If this is not possible, then the
Investigator can proceed with determining the study medication assignment by using the
Interactive Voice Response System and monitor as soon as possible.
Note: Causality should be assessed by the Investigator prior to unblinding of treatment assignment
but must not delay treatment in an emergency situation.
The date and reason for the unblinding must be recorded in the subject’s medical record and on
the subject’s CRF.
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5.0 Study Population
A total of 180 eligible subjects will be randomized to the Drug A or placebo treatment groups.
5.1 Inclusion Criteria
Patients will be eligible to participate in this study after the nature and purpose of the protocol
have been explained to them and appropriate informed consent has been obtained. The
confirmation of the informed consent before the patient's participation in the study will be
documented in source documents and on the Case Report Form (CRF).
The presence of inclusion criteria and the absence of exclusion criteria will be verified on the CRF
and patient eligibility for study participation must be documented in source documents.
Patients must meet all of the following criteria in order to be randomized into the trial:
1. Patients must be males or females ≥ 18 years of age.
2. Patients must have a history of Stage I to Stage II hypertension (defined as a seated DBP ≥ 95
mmHg and ≤ 110 mmHg at Baseline-Week 0).
3. Patients must be able to communicate effectively with the study personnel.
4. Patients must be adequately informed of the nature and risks of the study and give written
informed consent prior to screening.
5. Patients must be ambulatory and able to maintain a normal daily activity schedule.
6. Patients must have a mean 24-hour ambulatory diastolic blood pressure (DBP) ≥85 and ≤105
mmHg as determined by ABPM at the end of the Baseline (Visit 6).
7. Patients must have a mean seated diastolic blood pressure ≥95 and ≤110 mmHg at the end of
the baseline (Visit 6).
8. Patients under treatment for hypertension must be willing and able to discontinue all previous
anti-hypertensive medications for the duration of the study.
9. Women of childbearing potential must be using a medically acceptable form of birth control
for the duration of the trial, must have a negative serum pregnancy test at screening, and must
have a negative urine pregnancy test prior to randomization (Visit 6).
5.2 Exclusion Criteria
Patients may not be selected if any of the following criteria exist:
1. Patients who have a known hypersensitivity or allergy to metoprolol tartrate or vehicle
components.
2. Patients who have insulin-dependent or uncontrolled Diabetes Mellitus (glycosolated
hemoglobin >9%) or hypoglycemia.
3. Systolic blood pressure > 179 mmHg either at the screening visit or at the end of the
single-blind placebo run-in phase of the study as measured by “office” cuff pressure.
4. Difference >10 mmHg in office measured mean diastolic blood pressures between any two
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5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
office visits during the run-in phase of the study.
Patients who have hypertension secondary to a disease or condition or who have a history of
malignant hypertension including retinal hemorrhages, exudates and papilledema.
Patients who have an AV block greater than first degree including sick sinus syndrome.
Patients who have chronic atrial fibrillation or recurrent tachyarrhythmia
Patients who have significant bradycardia defined as a resting heart rate < 50 beats per
minute (bpm).
Patients who have clinically significant aortic or mitral valve disease.
Patients with target organ damage or clinical cardiovascular disease that would preclude their
safe inclusion in a placebo-controlled trial. This would include unstable angina pectoris,
previous myocardial infarction or CVA in the last 6 months, congestive heart failure,
transient ischemic attack (TIA).
Patients who have severe peripheral vascular disease
Patients with significant thyroid, renal or hepatic disease [TSH > 1.5 times upper limit of
normal, urine protein >1+, creatinine >2.2 mg/dL, AST (SGOT) and/or ALT (SGPT) greater
than twice the upper limit of normal].
Patients who perform alternate shift or night work
Patients with arm circumference >42 cm (ABPM Cuff)
Patients with any history of alcohol abuse, illicit drug use, significant mental illness, physical
dependence to any opioid in the past year, or any history of drug abuse or addiction in the
past year.
Patients who have a history or presence of bronchospastic disease (e.g., asthma, chronic
obstructive pulmonary disorder [COPD]).
Women who are pregnant or breast-feeding, or who are not using or are not willing to use a
medically accepted method of birth control.
Patients who have received an investigational drug or device within a period of 30 days prior
to enrollment (Visit 2) in the study.
Patients who require concurrent use of prohibited prescription (Rx) or over-the-counter (OTC)
medications.
Patients who have previously participated in a study of the Sponsor’s metoprolol tartrate ER
tablets.
Patients who, in the opinion of the Investigator, have any other medical condition which
renders the patient unable to complete the study or which would interfere with optimal
participation in the study or produce significant risk to the patient.
Patients participating in or planning to enroll in a weight reduction program during the time
of the study
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6.0 Investigational Medicine Products
6.1 Study Treatment
6.1.1 Study Treatment Administration
All patients will receive placebo tablets once daily for 3 – 4 weeks during the single-blind, run-in
phase. During the double-blind treatment phase, patients will be randomized in a 1:1 ratio to
receive either Drug A 20 mg or placebo tablets once daily for 6 weeks.
6.1.2 Interruption of Study Treatment
Interruption of treatment is not permitted. The dosage cannot be reduced, and, if a patient cannot
tolerate the dose, he or she will be discontinued from the study.
6.1.3 Study Treatment Compliance
The investigational medication will be counted to assess compliance at each visit. Patients who
take = 80% of the prescribed doses will be considered compliant. Patients who fall below this
threshold will be counseled and re-instructed on dosing procedures. If a patient is chronically
non-compliant (i.e. takes <80% of prescribed dose at two consecutive visits), the patient will be
asked to terminate from the study. Medication compliance will be recorded on the CRF for each
visit.
6.2 Concomitant Medications and Prohibited Medications
6.2.1 Allowed Medications
Patients will be allowed to take acetaminophen, antacids, low-dose aspirin or nonsteroidal
anti-inflammatory drug (NSAID) therapy, hydroxymethyl glutaryl coenzyme A (HMG CoA)
reductase inhibitors, antibiotics, and other drugs considered medically necessary by the
Investigator.
6.2.2 Prohibited Medications
Prohibited medications include the following:
• All anti-hypertensive drugs; nitrates or other vasodilators; betablockers (including ophthalmic);
are prohibited prior to entry into the single-blind run-in phase
• MAO Inhibitors
• Theophylline or beta-agonists
• Steroids, not including topical steriods
• Bile acid-binding resins;
• High-dose NSAID or aspirin therapy (defined as doses required treating arthritis)
• Herbal, Rx, OTC, and/or dietary supplements containing ephedra and other sympathomimetic
amines
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• Potassium supplements
• Investigational drugs (beginning 30 days prior to enrollment and continuing through the duration
of the trial)
6.2.3 Restricted Medications
• Total daily dose of aspirin cannot exceed 162 mg.
• Use of decongestants and antihistamines containing decongestants within two (2) days before
any visit is prohibited.
• Use of Selective Serotonin Reuptake Inhibitors (SSRI) is permitted if the patient is on a stable
dose of the SSRI for at least three (3) months prior to Screening, is known to be compliant with
his/her medication, and agrees to maintain their current stable dose of the SSRI for the duration of
the study
• Use of Tricyclic antidepressants (TCA) is permitted if the patient is on a stable dose of the TCA
for at least three (3) months prior to Screening, is known to be compliant with his/her medication,
and agrees to maintain their current stable dose of the TCA for the duration of the study.
• Chronic use of large doses of non-steroidal anti-inflammatory drugs (NSAIDs) is not permitted
for the duration of this trial.
• Use of medications for erectile dysfunction including sildenafil, vardenafil, tadalafil and
alprostadil 2 days prior to any visit is prohibited.
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7.0 Study Procedures
The schedule of visits and procedures to be conducted at each visit are summarized in APPENDIX
A. The study includes a 3- to 4-week single-blind placebo run-in phase and a 6-week double-blind
treatment phase. All study visits should be scheduled at 1- or 2-week intervals as specified;
however, visit schedules may be adjusted by up to 3 days to accommodate the needs of the patient
or clinic.
7.1 Visit 1 (Week -4, Screening)
The prospective patients will visit the study site and be examined by the study physician. The
screening visit may occur up to 10 days prior to entry into the placebo run-in phase. The following
procedures will be performed at the screening visit:
• Medical/ Medication History
• Informed Consent
• Review Inclusion/Exclusion Criteria
• Physical Examination including pulse, respirations and temperature
• Measure height and weight
• Record all previous prescription and non-prescription medications (including nutriceuticals and
dietary supplements) taken within the 30 days before the Screening Visit.
• Check for use of prohibited medications
• 12-lead ECG
• Serum chemistries, CBC, urinalysis
• Serum Pregnancy (for women of childbearing potential)
• Office Blood Pressure Measurement
• Discontinue or start tapering current anti-hypertensive medication Patients with newly diagnosed
or untreated hypertension may precede directly into the placebo run-in period as soon as the
results of the screening laboratory tests are available and the patient meets all inclusion and
exclusion criteria. Patients who are currently receiving treatment for hypertension must be off all
pharmacologic treatment by the start of the placebo run-in period.
7.2 Visit 2 (Week -3, Placebo Run-in)
The following assessments will be done at this visit (visit to occur within 10 days of screening
visit):
• Confirm eligibility of Inclusion/Exclusion criteria
• Office Blood Pressure Measurement
• Vital Signs (respirations, pulse, weight)
• Adverse Events Assessment
• Concomitant Medication Assessment
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• Dispense Single-Blind Study Drug
• Schedule next visit
7.3 Visit 3 (Week -2, Placebo Run-in)
The following assessments will be done at this visit (visit to occur 1 week after Visit 2):
• Confirm eligibility of Inclusion/Exclusion criteria
• Office Blood Pressure Measurement
• Vital Signs (respirations, pulse, weight)
• Adverse Events Assessment
• Concomitant Medication Assessment
• Retrieve Single-Blind Study Drug
• Count Tablets and Check Compliance
• Dispense Single-Blind Study Drug
• Schedule next visit
7.4 Visit 4 (Week -1, Placebo Run-in)
The following assessments will be done at this visit (visit to occur 1 week after Visit 3):
• Confirm eligibility of Inclusion/Exclusion criteria
• Office Blood Pressure Measurement
• Vital Signs (respirations, pulse, weight)
• Adverse Events Assessment
• Concomitant Medication Assessment
• Retrieve Single-Blind Study Drug
• Count Tablets and Check Compliance
• Dispense Single-Blind Study Drug
• Schedule next visit
7.5 Visit 5 (Week 0 Baseline) or Visit 4A (Week -1A Placebo Run-In)
Patients will report to the clinic 6 days after completion of Visit 4 Patients with a mean sitting
DBP of ≥ 95mmHg will complete all the assessments for Visit 5. Patients with a sitting DBP <95
mmHg may continue in the placebo run-in phase for 1 additional week and will complete all
assessments required at Visit 4, which be captured as Visit 4A. At the end of the additional week,
patients will return to the clinic for Visit 5. Patients with a mean sitting DBP< 95 mmHg after 4
weeks (Visit 5) of placebo treatment should be withdrawn from the trial.
The following assessments will be done at the baseline visit:
• Confirm eligibility of Inclusion/Exclusion criteria
• Retrieve Single-Blind Study Drug
• Count Tablets and Check Compliance
• Perform Office Blood Pressure Measurement (see Section 6.1)
• Vital Signs (respirations, pulse, weight)
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• 12-lead ECG
• Chemistries, CBC, urinalysis
• Urine pregnancy test (for women of childbearing potential)
• Adverse Events Assessment
• Concomitant Medication Assessment
• Place ABPM device on patient and begin recording. Perform t-tube comparison at beginning of
recording as instructed. The patient is instructed to return to the Principal Investigator’s office the
next day to have the ABPM device removed.
• Have patient take Single-Blind Study Drug
• Schedule next visit
7.6 Visit 6 (Week 0, Baseline/Randomization)
This visit will occur one day after Visit 5. Patients who meet all of the inclusion criteria and who
do not have any exclusionary conditions may be randomized into the double-blind treatment phase.
Patients must meet both the ABPM minimum quality control requirements and the ambulatory
mean 24-hour diastolic blood pressure (M24DBP) inclusion criteria of ≥85 mmHg to qualify for
randomization. In the event a patient has a technically successful recording, but fails to meet the
minimum inclusion criteria (M24DBP > 85 mmHg), the patient should be dropped from the trial
at this time (screen failure). If a recording fails to meet the minimum quality control requirements
for a successful recording, the 24-hour ABPM may be repeated for an additional 24 hours. Please
re-dose the patient with single-blind placebo medication and ask the patient to return the next day
for removal of the device and determination of further study eligibility.
• Remove the ABPM device from the patient
• Download ABPM device and perform quality control on the ABPM data
• Record mean 24 hour diastolic BP observed on the CRF
• Office Blood Pressure Measurement
• Vital Signs (respirations, pulse, weight)
• Assess Eligibility for Randomization
• Adverse Events Assessment
• Concomitant Medication Assessment
• If patient meets criteria for randomization, dispense study drug for Double-Blind phase of study
(First dose taken in the office)
• Schedule Next Visit
7.7 Visit 7 (Week 2, Double-Blind Treatment)
The following assessments will be done at this visit (visit to occur two weeks after Baseline):
• Office (Trough) Blood Pressure Measurement
• Vital Signs (respirations, pulse, weight)
• Retrieve Double-Blind Study Drug
• Count Tablets and Check Compliance
• Dispense Double-Blind Study Drug
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• Adverse Events Assessment
• Concomitant Medication Assessment
• Schedule Next Visit
7.8 Visit 8 (Week 4, Double-Blind Treatment)
The following assessments will be done at this visit (visit to occur 2 weeks after Week 2):
• Office (Trough) Blood Pressure Measurement
• Vital Signs (respirations, pulse, weight)
• Retrieve Double-Blind Study Drug
• Count Tablets and Check Compliance
• Dispense Double-Blind Study Drug
• Adverse Events Assessment
• Concomitant Medication Assessment
• Schedule Next Visit
7.9 Visit 9 (Week 6 End of Study/Early Termination)
The following assessments will be done at this visit (visit to occur 2 weeks after Week 4):
• Office (Trough) Blood Pressure Measurement
• Vital signs-pulse, respirations, weight
• Retrieve Double-Blind Study Drug
• Count Tablets and Check Compliance
• Dispense Double-Blind Study Drug (Last Dose taken in the office)
• Place ABPM device on patient, perform t-tube comparisons, and begin recording as instructed.
The patient should be informed to return the device the next day.
• Adverse Events Assessment
• Concomitant Medication Assessment
• Schedule Next Visit
7.10 Visit 10 (Week 6 End of Study/Early Termination)
The following assessments will be done at this visit (visit to occur 1 day after visit 9):
• Office (Trough) Blood Pressure Measurement
• Vital Signs (respirations, pulse, weight)
• Remove the ABPM device
• Perform quality control-If the device fails quality control, the recording must be immediately
repeated for 24 hours. Please dose the patient and instruct the patient to return the next day for
device removal.
• Physical Examination
• 12-lead ECG
• Chemistries, CBC, urinalysis
• Adverse Events Assessment
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• Concomitant Medication Assessment
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8.0 Clinical Assessment
8.1 12-lead Electrocardiogram
12-lead ECG should be performed at Screening, Baseline and at the end of study. The ECG
reading will be assessed at site and the findings will be recorded on the CRFs.
8.2 Physical Examination
A general physical examination should be performed at Screening and at the end of study. Any
new abnormalities observed after baseline should be recorded as adverse event.
8.3 Pregnancy Test and
Serum pregnancy test for all women of childbearing potential should be performed at Screening.
An urine pregnancy test should be performed at Baseline to confirm the pregnancy status for
female subjects before randomization. Additional pregnancy test may be requested by the
investigator if necessary.
8.4 Laboratory Assessments
All assessments will be scheduled as indicated in the Appendix A. Schedule of assessments.
Additional assessments may be performed as clinical indicated. The total volume of blood loss
for laboratory assessments will be about 15 mL per visit.
Baseline laboratory assessment should be performed within 3 days prior to randomization.
All laboratory samples should be shipped to Best Central Lab for processing. Lab report will be
provided to investigators.
8.4.1 Hematology
Haemoglobin, haematocrit, platelet count, RBC, WBC with differenctial.
8.4.2 Serum Chemistry
Na+, K+, Ca++, CL-, BUN, total protein, albumin, ALK, ALT, AST, LDH, total bilirubin,
creatinine, blood glucose
8.4.3 Urinalysis
Gravity, pH, protein, kenton, RBC, WBC
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8.5 Office Blood Pressure and ABPM Measurements
Please see Appendix B for detailed instructions.
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9.0 Safety Assessment
9.1 Adverse Event and AE reporting
9.1.1 Definition of Adverse Event
Per the International Conference of Harmonisation (ICH), an AE is any unfavorable and
unintended medical occurance/sign (including an abnormal laboratory finding), symptom or
disease in a patient or clinical investigation subject administrated a pharmaceutical product and
which dose not necessarily have a causal relationship with this treatment. Pre-existing conditions
which worsen during a study are to be reported as AE, too.
9.1.2 Definition of Serious Adverse Event
A serious adverse event is any experience that suggests a significant hazard, contraindication, side
effect or precaution. It is any adverse event that at any dose fulfils at least one of the following
criteria:
• is fatal; (results in death; NOTE: death is an outcome, not an event)
• is Life-Threatening (NOTE: the term "Life-Threatening" refers to an event in which the subject
was at immediate risk of death at the time of the event; it does not refer to an event which could
hypothetically have caused a death had it been more severe).
• requires in-patient hospitalisation or prolongation of existing hospitalisation;
• results in persistent or significant disability/incapacity;
• is a congenital anomaly/birth defect;
• is medically significant or requires intervention to prevent one or other of the outcomes listed
above
9.1.3 AE Reporting and Follow-up
Non-serious adverse event occurs after the first study dose and during the study should be
recorded in CRFs and followed up until the end of the study.
Serious adverse event occurs after the informed consent is signed and up to 30 days after the last
study dose should be recorded in CRFs and followed during the study and up to 3 months after the
last study dose.
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10.0 Statistical Consideration and Analysis
10.1 General Statistical Method
<see the protocol synopsis>
10.2 Analysis Population
The following three analysis populations will be utilized:
Safety: The safety analysis population will include all subjects who were randomized, and
received at least one dose of study drug.
Modified Intent-to-treat (MITT): The MITT population will include all subjects who were
randomized, received at least one dose of study drug, and who have Baseline and at least one
post-baseline measurement for seated blood pressure.
Per Protocol (PP): The per protocol population will include all subjects in the MITT population
who meet the study treatment compliance criteria and had no major protocol violations. This
population will be determined before breaking the blind.
10.3 Subject Disposition
Subject enrollment and disposition will be summarized for each treatment group and for the total
using all randomized subjects. The table will present the number and percentage of subjects who
were randomized, took study drug, completed the Treatment Period, and withdrew from the study.
The number and percentage of subjects who prematurely discontinued will also be summarized by
reasons for discontinuation.
For each population (Safety, MITT, and PP), the number and percentage of subjects included will
be reported by treatment group and total.
Enrollment and disposition, prematurely discontinued subjects, and subjects excluded from each
of the MITT and PP populations will be presented by treatment and subject in separate listings
using all randomized subjects.
10.4 Demographic and Baseline Characteristics
Demographics and Baseline characteristics will be summarized descriptively using the Safety,
MITT, and PP populations. An ANOVA with factor treatment will be performed for continuous
variables. A chi-square test will be used for the categorical variables.
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The percentage of subjects with medical histories will be tabulated by treatment group and body
system. Results of physical examination, ECG, at Screening will be summarized by treatment
group.
10.5 Protocol Deviation
Protocol deviations will be identified and documented based on a review of selected data listings
prior to treatment unblinding. Protocol deviations will be presented in a data listing and tabulated
by treatment for all randomized subjects.
10.6 Efficacy Analysis
<placeholder>
10.7 Safety Analysis
<placeholder>
10.8 Sample Size Estimation/Justification
<placeholder>
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11.0 Ethics
<Standard statement>
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12.0 Data Handling and Record Keeping
<Standard statement>
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13.0 Financing and Insurance
<Standard statement>
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14.0 Publication Policy
<Standard statement>
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15.0 Reference List
<Standard statement>
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APPENDIX A
Schedule of Study Evaluations
Study Phase
WEEK
VISIT NUMBER
Medical/Medication History
Informed Consent
Inclusion/Exclusion Criteria
Taper Medications[2]
Physical Examination
12-Lead ECG
Serum Pregnancy Test
Urine Pregnancy Test
Serum Chemistry
Hematology
Urinalysis
Vital Signs-respirations, pulse, weight
Office Blood Pressure [3]
Start 24-hour ABPM [4]
End 24-hour ABPM [4]
Dispense Medication
Check Medication Compliance
Assessment of AEs
Concomitant Medication
Screening [1]
1
X
X
X
X
X
X
X
X
X
X
X
X
X
Placebo Run-in
-3
-2
-1
-1A
2
3
4
4A*
X
X
X
X
Baseline
0
5
Double-Blind Treatment
0
2
4
6
6
6
7
8
9**
10**
X
X
X
X
X
X
X
X
X
X
X
X
P
P
X
X
X
P
X
X
X
P
X
X
X
X
X
X
X
X
X
X
X
X
P [5]
X
X
X
X
X
X
D [6]
X
X
[1] Screening to be conducted within 10 days of entry into placebo run-in period
[2] Once eligibility criteria are met discontinue (abruptly or taper at the PIs discretion) prohibited medications before starting placebo run-in phase
[3] Sitting and standing blood pressure (mean of 3 seated measurements taken 2 minutes apart; one standing blood pressure; 24±2 hours after previous dose of study medication)
[4] 24-hour ambulatory blood pressure monitor
[5] Last dose administered in office from bottle retrieved from patients after placement of ABPM recorder
[6] First dose administered in the office from the patient’s randomized study drug bottle after all procedures are complete.
P = single-blind placebo medication (dispense as required) D = randomized double-blind medication (dispense as required)
* Optional visit if blood pressure is not stabilized, or sitting DBP < 95 mmHg after 3 weeks of single-blind placebo run-in
** End of study visits. All procedures at these visits must be conducted for patients who discontinue early.
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X
X
X
X
X
X
X
D
X
X
X
D
X
X
X
D [5]
X
X
X
X
X
X
X
X
X
X
X
Confidential
APPENDIX B Blood Pressure Measurement: Office and Ambulatory Blood
Pressure Monitoring
Office BP Measurement Using the Sphygmomanometer: The non-dominant arm should be used
throughout the study to obtain blood pressure measurements that will be recorded in the source document
and the Case Report Form.
Blood pressure measurements should be performed using the following criteria:
• Inflate the cuff to a pressure approximately 30 mmHg greater than systolic, as estimated from the
disappearance of the pulse in the brachial artery by palpation.
• Place the stethoscope lightly over the brachial artery.
• Measure the blood pressure with the patient's arm supported at the level of the heart.
• Deflate the cuff slowly at a rate of 2 mmHg per heartbeat.
• The first appearance of sound (phase 1) is used to define systolic blood pressure. The disappearance of
sound (phase 5) is used to define diastolic blood pressure.
It is important to avoid miscuffing – the bladder width should be at least 40% of the arm circumference
and the bladder length should be a least 80% of the arm circumference. In patients with large upper arms, a
longer and wider cuff should be used (15 cm wide cuff should be adequate). Only study personnel properly
trained in the procedures required for this protocol should perform these blood pressure measurements.
Training documentation will be maintained at the investigative site to record this specialized training.
Sitting and standing blood pressure will be measured using an appropriately calibrated
sphygmomanometer. After sitting for five minutes, three blood pressures and one heart rate measurement
should be obtained and recorded at two-minute intervals. Then after standing for one minute, one blood
pressure should be measured and recorded. If the 3 consecutive seated diastolic BP readings are not within
5 mmHg of each other, then 2 additional seated BP readings should be obtained and incorporated into the
calculated mean pressures.
Ambulatory Blood Pressure Monitoring (ABPM)
Best Corelab Services will provide the ambulatory blood pressure recording device that has been validated
independently by the American Association for the Advancement of Medical Instrumentation. The device
is an automatic, portable monitor that will be used at all centers to record BP and heart rate over a 24-hour
period on 2 occasions (Baseline and Week 6 visit or Early Termination).
The ABPM studies should be performed under similar circumstances (i.e., a working weekday). If possible,
the device should be applied on the same day of the week and as close to the same time of day as feasible
on each occasion. For each evaluation, the patient should report to the clinic 24±2 hours after the previous
morning’s dose of study medication for ABPM placement. An experienced technician should test the
device for agreement with an appropriately calibrated sphygmomanometer using a t-tube and stethoscope.
The average of 3 simultaneous ABPM and sphygmomanometer diastolic BP measurements should agree
within 7 mmHg.
The ABPM start time should precede the day’s study drug ingestion. Thus, the ABPM recorder will be
manually initiated to indicate the beginning of the test and the start time will be recorded in the CRF and
source document. The patient time of the morning dose of study medication will also be recorded in the
CRF and source document. The device will be set to obtain readings every 15 minutes during the interval
of 0600h to 2200h (to coincide with the daytime, awake period) and every 20 minutes during the interval
of 2200h to 0600h (to coincide with the night time, sleeping period). The patient will be instructed to
return to the clinic 24 hours after the post-dosing ABPM start time.
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The patient should engage in their usual physical activity levels, but should avoid strenuous exercise
during the monitoring period. Additionally, sleeping during the daytime (e.g., a siesta) should be avoided
during the ABPM study period. During the actual BP measurements, the patient should be instructed to
hold their arm still and remain in place once cuff inflation begins. Data will be edited according to the
dedicated software program of the device. In addition, software will identify readings that are outside of
editing criteria and exclude them from the statistical analyses; however, these readings will remain as part
of the raw data report.
An ABPM recording will be considered adequate if:
1. The “Beginning of Test” time is 24±2 hours after the previous morning’s dose of study medication
2. The monitoring period is at least 24 hours in duration.
3. At least 70 valid readings were obtained (80% acceptance rate).
4. No more than 2 non-consecutive hours are missing a valid reading.
If the recording does not meet these minimal quality control criteria, the ABPM recordings should be
repeated once within 3 days. Patients will be instructed on the administration of the appropriate study
medications if a repeat ABPM is required. In the event the recording does meet the minimal quality control
criteria, however, the patient fails to meet the minimum inclusion BP criteria (M24DBP > 85 mmHg), the
ABPM should not be repeated and the patient should be dropped from the trial at this time (screen failure).
Patient must meet both the minimal QC criteria AND the M24DBP inclusion criteria for randomization.
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