Conditions: Heart Failure (HF)
Keywords: Cardiac Congestive Decompensation Heart Failure Left-Sided Myocardial Corlanor Ivabradine African American Black Michigan
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This study is a prospective, open-label, single-arm intervention study in African-American/Black subjects with heart failure and reduced ejection fraction (HFrEF).

There will be a 7-day screening period, a 57-day open-label treatment period, and a safety follow-up at day 87 or 30 days after the last administration of the investigational product.

Detailed description:
The goal of this study is to determine the impact of adding ivabradine therapy to the standard of care (SOC) in African-American/Black subjects with Heart Failure (HF) and reduced ejection fraction (HFrEF) on changes in heart rate (HR) from baseline (SOC alone). Changes in HR from baseline will be correlated with the changes from baseline in activity level of the subjects, as measured by both a standard 6-minute walk distance and an accelerometer device.

The primary hypothesis is that ivabradine effectively reduces HR between baseline and day 57 in African-American/Black subjects. Because mean reductions of approximately 5 beat per minute (bpm) have been observed in the overall placebo-treated subjects in the SHIFT study as well as in the placebo-treated subjects of the subgroup analysis of non-African-American/Black subjects enrolled in the SHIFT study, we will test whether the mean reduction with ivabradine exceeds 5 bpm, and estimate the degree to which the mean reduction with ivabradine exceeds 5 bpm.

Arms:
arm 1: The starting dose of ivabradine was 5 mg twice daily (BID), although investigators had the discretion to start participants at 2.5 mg BID if participant had a history of conduction defects, or bradycardia that could lead to hemodynamic compromise. Dose was adjusted at Day 15 (and at any other clinical visit) between 2.5 - 7.5 mg BID based on heart rate and signs/symptoms of bradycardia.

Interventions: intervention 1: Ivabradine
Intervention descriptions: intervention 1: Film-coated tablets taken orally with food twice a day. Tablets supplied in strengths of 5.0 mg and 7.5 mg. 5.0 tablets were split into equal halves for dosages of 2.5 mg.

Protocol document:
Prot_000.pdf: 
Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 1 of 78 
CONFIDENTIAL 
Title Page 
Protocol Title: 
Open-label, Single-arm Study Assessing the 
Efficacy and Safety of Ivabradine (Corlanor) in 
African-American/Black Subjects With Heart 
Failure and Left Ventricular Systolic Dysfunction 
Short Protocol Title: 
A Phase 4 Study of Ivabradine in 
African-American/Black Subjects with Heart 
Failure and Left Ventricular Systolic Dysfunction 
Protocol Number: 
20160231 
Investigational Product: 
Ivabradine 
Trade Name: 
Corlanor® 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone 
Number: 
1 (805) 447-1000 
Key 
Sponsor 
Contact 
Name: 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone 
Number: 
Email Address: 
EudraCT Number: 
NA 
NCT Number: 
Not applicable 
Protocol Date: 
Document Version 
Date 
Original 
18 May 2017 
Amendment 1 
02 April 2018 
Amendment 2 
14 February 2019 
Version/Date: 
Data Element 
Standards Version 
Date 
5.0 
20 March 2015 
NCT Number: NCT03456856 
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 2 of 78 
CONFIDENTIAL 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Amgen’s general 
number in the US (1-805-447-1000). 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 3 of 78 
CONFIDENTIAL 
 
 
Investigator's Agreement: 
I have read the attached protocol entitled Open-label, Single-arm Study Assessing the 
Efficacy and Safety of Ivabradine (Corlanor) in African-American/Black Subjects With 
Heart Failure and Left Ventricular Systolic Dysfunction, dated 14 February 2019, and 
agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by: me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator 
Date (DD Month YYYY) 
 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 4 of 78 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Protocol Synopsis ................................................................................................... 8 
2. 
Study Schema and Schedule of Activities ............................................................. 10 
2.1 
Study Schema ........................................................................................... 10 
2.2 
Schedule of Activities ................................................................................ 11 
3. 
Introduction ........................................................................................................... 13 
3.1 
Study Rationale ......................................................................................... 13 
3.2 
Background ............................................................................................... 13 
3.2.1 
Disease ..................................................................................... 13 
3.2.2 
Amgen Investigational Product Background:  
Ivabradine  ................................................................................ 14 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 15 
4.1 
Objectives and Endpoints .......................................................................... 15 
4.2 
Hypotheses ............................................................................................... 15 
5. 
Study Design ........................................................................................................ 15 
5.1 
Overall Design .......................................................................................... 15 
5.2 
Number of Subjects ................................................................................... 17 
5.2.1 
Replacement of Subjects ........................................................... 17 
5.2.2 
Number of Sites ......................................................................... 17 
5.3 
End of Study ............................................................................................. 17 
5.3.1 
End of Study Definition .............................................................. 17 
5.3.2 
Study Duration for Subjects ....................................................... 18 
5.4 
Justification for Investigational Product Dose ............................................ 18 
6. 
Study Population .................................................................................................. 18 
6.1 
Inclusion Criteria ....................................................................................... 18 
6.2 
Exclusion Criteria ...................................................................................... 19 
6.3 
Lifestyle Restrictions ................................................................................. 20 
6.3.1 
Meals and Dietary Restrictions .................................................. 20 
6.3.2 
Caffeine, Alcohol, and Tobacco ................................................. 21 
6.3.3 
Activity ....................................................................................... 21 
6.4 
Subject Enrollment .................................................................................... 21 
6.5 
Screen Failures ......................................................................................... 21 
7. 
Treatments ........................................................................................................... 22 
7.1 
Treatment Procedures............................................................................... 22 
7.1.1 
Investigational Products  ........................................................... 22 
7.1.2 
Non-investigational Products ..................................................... 22 
7.1.3 
Medical Devices ........................................................................ 23 
7.1.4 
Other Protocol-required Therapies ............................................ 23 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 5 of 78 
CONFIDENTIAL 
 
 
7.1.5 
Other Treatment Procedures ..................................................... 23 
7.1.6 
Product Complaints ................................................................... 23 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 24 
7.2 
Method of Treatment Assignment ............................................................. 24 
7.3 
Blinding ..................................................................................................... 24 
7.4 
Dose Modification ...................................................................................... 24 
7.4.1 
Hepatotoxicity Stopping Rules ................................................... 24 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 24 
7.4.2.1 
Amgen Investigational Product:  
Ivabradine ............................................................... 24 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 25 
7.6 
Treatment Compliance .............................................................................. 25 
7.7 
Treatment of Overdose ............................................................................. 25 
7.8 
Prior and Concomitant Treatment ............................................................. 25 
7.8.1 
Prior Treatment ......................................................................... 25 
7.8.2 
Concomitant Treatment ............................................................. 25 
8. 
Discontinuation Criteria ......................................................................................... 26 
8.1 
Discontinuation of Study Treatment........................................................... 26 
8.2 
Discontinuation From the Study ................................................................ 27 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 27 
8.2.2 
Reasons for Removal From Study ............................................. 27 
8.3 
Lost to Follow-up ....................................................................................... 27 
9. 
Study Assessments and Procedures .................................................................... 28 
9.1 
General Study Periods .............................................................................. 28 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 28 
9.1.2 
Treatment Period ....................................................................... 29 
9.1.3 
Safety Follow-up ........................................................................ 29 
9.1.4 
Early Termination ...................................................................... 29 
9.2 
Description of General Study Assessments and Procedures ..................... 29 
9.2.1 
General Assessments ............................................................... 29 
9.2.1.1 
Informed Consent .................................................... 29 
9.2.1.2 
Demographics ......................................................... 30 
9.2.1.3 
Medical History ........................................................ 30 
9.2.1.4 
Physical Examination .............................................. 30 
9.2.1.5 
Physical Measurements .......................................... 30 
9.2.1.6 
Substance Abuse History ........................................ 30 
9.2.2 
Efficacy Assessments ................................................................ 30 
9.2.2.1 
Electrocardiogram ................................................... 30 
9.2.2.2 
6-Minute Walk Test ................................................. 30 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 6 of 78 
CONFIDENTIAL 
 
 
9.2.2.3 
Accelerometer ......................................................... 30 
9.2.3 
Safety Assessments .................................................................. 31 
9.2.3.1 
Adverse Events ....................................................... 31 
9.2.3.2 
Vital Signs ............................................................... 35 
9.2.3.3 
Electrocardiograms (ECGs) ..................................... 35 
9.2.3.4 
Vital Status .............................................................. 35 
9.2.3.5 
Suicidal Risk Monitoring .......................................... 35 
9.2.4 
Clinical Laboratory Assessments ............................................... 35 
9.2.4.1 
Pregnancy Testing .................................................. 36 
9.2.4.2 
Prespecified Biomarker Assessments ..................... 36 
9.2.5 
Pharmacokinetic Assessments .................................................. 36 
9.2.6 
Pharmacodynamic Assessments ............................................... 36 
9.2.7 
Pharmacogenetic Assessments................................................. 36 
10. 
Statistical Considerations ...................................................................................... 36 
10.1 
Sample Size Determination ....................................................................... 36 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 37 
10.2.1 
Analysis Sets ............................................................................. 37 
10.2.1.1 
Full Analysis Set ...................................................... 37 
10.2.1.2 
Safety Analysis Set ................................................. 37 
10.2.2 
Covariates ................................................................................. 37 
10.2.3 
Subgroups ................................................................................. 37 
10.2.4 
Handling of Missing and Incomplete Data .................................. 37 
10.3 
Adaptive Design ........................................................................................ 37 
10.4 
Statistical Analyses ................................................................................... 37 
10.4.1 
Planned Analyses ...................................................................... 38 
10.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 38 
10.4.1.2 
Primary Analysis ..................................................... 38 
10.4.1.3 
Final Analysis .......................................................... 38 
10.4.2 
Methods of Analyses ................................................................. 38 
10.4.2.1 
General Considerations ........................................... 38 
10.4.2.2 
Efficacy Analyses .................................................... 38 
10.4.2.3 
Safety Analyses ...................................................... 39 
11. 
References ........................................................................................................... 41 
12. 
Appendices ........................................................................................................... 42 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 43 
12.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 45 
12.3 
Appendix 3.  Study Governance Considerations ....................................... 46 
Data Protection/Subject Confidentiality ..................................................... 48 
12.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 53 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 7 of 78 
CONFIDENTIAL 
 
 
Definition of Disease-related Event ........................................................... 53 
Definition of Adverse Event ....................................................................... 53 
Definition of Serious Adverse Event .......................................................... 54 
Recording Adverse Events, Disease-related Events (if 
applicable), and Serious Adverse Events .................................. 55 
Evaluating Adverse Events and Serious Adverse Events .......................... 55 
Reporting of Serious Adverse Event .......................................................... 57 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 63 
Collection of Pregnancy Information .......................................................... 64 
Collection of Lactation Information ............................................................ 66 
12.6 
Appendix 6.  Sample Storage and Destruction .......................................... 69 
12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments ..................................................................... 71 
12.8 
Appendix 8.  Six Minute Walk Test Instructions ......................................... 75 
12.9 
Appendix 9.  Six Minute Walk Test Recording Form .................................. 77 
List of Tables 
Table 2-1.  Schedule of Activities ................................................................................... 11 
Table 5-1.  Ivabradine Dose Titration at Day 15 Based on Heart Rate From 
Electrocardiogram .................................................................................. 17 
Table 7-1.  Study Treatment .......................................................................................... 22 
Table 12-1.  Analyte Listing ........................................................................................... 45 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ............................................... 72 
List of Figures 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ....................................................................................................... 58 
Figure 12-2.  Sample Pregnancy and Lactation Notification Worksheets ....................... 67 
 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 8 of 78 
CONFIDENTIAL 
 
 
1. 
Protocol Synopsis 
Protocol Title:  Open-label, Single-arm Study Assessing the Efficacy and Safety of 
Ivabradine (Corlanor) in African-American/Black Subjects With Heart Failure and Left 
Ventricular Systolic Dysfunction 
Short Protocol Title:  A Phase 4 Study of Ivabradine in African-American/Black 
Subjects with Heart Failure and Left Ventricular Systolic Dysfunction 
Study Phase:  4 
Indication:  Heart Failure (HF) 
Rationale 
The goal of this study is to determine the impact of adding ivabradine therapy to the 
standard of care (SOC) in African-American/Black subjects with HF and reduced ejection 
fraction (HFrEF) on changes in heart rate (HR) from baseline (SOC alone).  Changes in 
HR from baseline will be correlated with the changes from baseline in activity level of the 
subjects, as measured by both a standard 6-minute walk distance and an accelerometer 
device. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
• 
Determine whether ivabradine 
effectively reduces HR from baseline 
to day 57 in African-American/Black 
subjects. 
• 
Change in HR from baseline to 
day 57 
 
Hypotheses 
The primary hypothesis is that ivabradine effectively reduces HR between baseline and 
day 57 in African-American/Black subjects.  Because mean reductions of approximately 
5 beat per minute (bpm) have been observed in the overall placebo-treated subjects in 
the SHIFT study as well as in the placebo-treated subjects of the subgroup analysis of 
non-African-American/Black subjects enrolled in the SHIFT study, we will test whether 
the mean reduction with ivabradine exceeds 5 bpm, and estimate the degree to which 
the mean reduction with ivabradine exceeds 5 bpm. 
Overall Design 
This study is a prospective, open-label, single-arm intervention study in 
African-American/Black subjects with HFrEF.  
There will be a 7-day screening period, a 57-day open-label treatment period, and a 
safety follow-up at day 87 or 30 days after the last administration of the investigational 
product.   
Number of Subjects 
Approximately 30 to 100 subjects 
Summary of Subject Eligibility Criteria 
Subjects will be male or female ≥ 18 years of age, describing self as 
African-American/Black, with a diagnosis of HF confirmed by medical records, in stable 
condition, and treated with stable optimal pharmacological therapy.  Subjects must also 
have left ventricular ejection fraction (LVEF) ≤ 35% confirmed prior to enrollment, New 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 9 of 78 
CONFIDENTIAL 
 
 
York Heart Association class II to IV, and electrocardiogram documentation at the time 
of screening of sinus rhythm with resting HR ≥ 70 bpm. 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
The starting dose of ivabradine is 5 mg twice daily (BID).  In subjects with a history of 
conduction defects, or in subjects in whom bradycardia could lead to hemodynamic 
compromise, therapy is to be initiated at 2.5 mg BID based on investigator discretion.  At 
the day 15 visit, the dose will be titrated according to HR as defined in the table below.  
Ivabradine dose levels can be adapted to HR at any clinical visit if necessary. 
 
Initial Dose: 5 mg BID 
Initial Dose: 2.5 mg BID 
HR ≥ 60 bpm 
7.5 mg BID 
5.0 mg BID 
HR ≥ 50 bpm, < 60 bpm 
5.0 mg BID 
2.5 mg BID 
HR < 50 bpm and/or signs 
or symptoms of 
bradycardia 
2.5 mg BID 
Discontinue therapy 
Abbreviations: BID = twice daily; bpm = beats per minute; HR = heart rate 
Procedures 
There will be a 7-day screening period that will allow accurate measurement of baseline 
activity as measured by the accelerometer.  On day 1, eligible subjects with confirmed 
sinus rhythm and HR ≥ 70 bpm will be enrolled into a 57-day open-label treatment 
period.  A safety follow-up will be conducted at day 87 or 30 days after the last 
administration of the investigational product.   
For a full list of study procedures, including the timing of each procedure, refer to 
Section 9.2 and the Schedule of Activities in Section 2.2. 
Statistical Considerations 
The primary analysis for this study will be performed when all subjects have completed 
all planned study procedures.  This primary analysis will evaluate the effect of ivabradine 
on HR reduction at day 57 in African-American/Black subjects overall (the primary 
endpoint).  Descriptive statistics of the exploratory endpoints will be summarized.  Safety 
data will be tabulated. 
Efficacy analyses will be performed on the full analysis set (FAS), which includes all 
enrolled subjects.   
Safety analyses will be performed on the safety analysis set (SAS), which includes all 
enrolled subjects who receive at least 1 dose of investigational product on study. 
Efficacy analyses of the primary endpoint will test whether the mean reduction with 
ivabradine exceeds 5 bpm.  Summary statistics and least-square means along with 95% 
confidence interval, analyzed by the repeated-measures linear model, will be provided 
for the primary endpoint.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 
 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 10 of 78 
CONFIDENTIAL 
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
 
Abbreviations: BID = twice daily; IP = investigational product 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
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CONFIDENTIAL 
 
 
2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
Procedure 
Screening 
Period 
Treatment Period (Days) 
Safety Follow-Up Period/ Early 
Termination Visita 
(Phone Contact for  
Safety Follow-up only) 
Screening 
(7 days) 
Day 1 
± 2 days 
Day 15  
± 2 days 
(dose titration 
begins) 
Day 29 
± 2 days 
Day 57 
± 5 
days 
Day 87 or 30 days after the 
last dose of open-label IP 
Informed consent 
X 
 
 
 
 
 
Full physical examination  
X 
 
 
 
X 
 
Physical measurementsb  
(height and weight) 
X 
 
 
 
 
 
Medical historyc  
X 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
X 
 
X 
 
Laboratory assessments  
X 
 
 
 
 
 
Pregnancy test (urine) in women of 
childbearing potential only 
X 
Xi 
 
 
 
 
Adverse event collection/ recording/reporting 
Xf 
X 
X 
X 
X 
X 
Serious adverse event 
collection/recording/reportingf  
X 
X 
X 
X 
X 
X 
Page 1 of 2 
Footnotes defined on next page 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
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CONFIDENTIAL 
 
 
Table 2-1.  Schedule of Activities 
Procedure 
Screening 
Period 
Treatment Period (Days) 
Safety Follow-Up Period/ Early 
Termination Visita 
(Phone Contact for  
Safety Follow-up only) 
Screening 
(7 days) 
Day 1 
± 2 days 
Day 15  
± 2 days 
(dose titration 
begins) 
Day 29 
± 2 days 
Day 57 
± 5 
days 
Day 87 or 30 days after the 
last dose of open-label IP 
Disease-related event collection/ 
recording/reporting 
 
X 
X 
X 
X 
X 
Vital status 
 
 
 
 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
6-Minute walk test (6MWT) 
 
X 
 
 
X 
 
Accelerometerg 
X 
X 
X 
X 
X 
Xj 
Investigational producth 
 
X 
X 
X 
X  
 
Page 2 of 2 
Abbreviations:  6MWT = 6-Minute walk test; ECG = electrocardiogram; IP = investigational product 
a If a subject discontinues the study, the subject must return to the study clinic in 30 days after discontinuation.  
b Height in centimeters should be measured without shoes.  Weight in kilograms should be measured without shoes. 
c Medical history will include substance usage (eg, alcohol, tobacco, and caffeine). 
d Demographics will include sex, age, race and ethnicity. 
e Vital signs will include systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested and calm state 
for at least 5 minutes before blood pressure assessments are conducted.  If the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible.  The position selected for a subject should be the same that is used throughout the study and documented on the vital sign case 
report form (CRF). 
f Adverse events related to any study procedures/study activity are collected, recorded, and reported from signing of the informed consent.  All other adverse events 
including disease related events (DREs) are collected, recorded, and reported from day 1 (from first dose of investigational product).  Serious adverse events are 
collected, recorded, and reported from signing of the informed consent through 30 days after the last dose of IP or end-of-study/safety follow-up visit, whichever is 
later.   
g A 7-day screening with the accelerometer is required before day 1 dosing.  The subjects will be instructed to wear the accelerometer every day except to be 
recharged.  The accelerometer is to be worn daily from screening through the end of treatment period (day 57).   
h On day 1, ivabradine will be dosed in the clinic and then will be dispensed at each study visit.  At each clinic visit, the subject is to return investigational product for 
accountability.  On day 15, dose titration will begin (7.5 mg twice daily [BID]) and subjects will begin to take ivabradine at home.  The last dose of ivabradine will be 
taken on day 57.   
i If screening pregnancy test is done ≥ 7 days from day 1, a repeat pregnancy test will be done on day 1 prior to dosing. 
j If a subject discontinues from the study, the accelerometer and investigational product is to be returned to the study clinic. 
 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 13 of 78 
CONFIDENTIAL 
 
 
3. 
Introduction 
3.1 
Study Rationale 
The goal of this study is to determine the impact of adding ivabradine therapy to the 
standard of care (SOC) in African-American/Black subjects with heart failure (HF) and 
reduced ejection fraction (HFrEF) on changes in heart rate (HR) from baseline (SOC 
alone).  Changes in HR from baseline will be correlated with the changes from baseline 
in activity level of the subjects, as measured by both a standard 6-minute walk distance 
and an accelerometer device. 
3.2 
Background 
3.2.1 
Disease 
Chronic heart failure (HF) is a syndrome that results in inadequate systemic blood flow 
when normal neurohormonal mechanisms, namely, the sympathetic nervous system and 
the renin-angiotensin-aldosterone system, are exhausted or overwhelmed and are no 
longer able to deliver an adequate physiological response.  While several interventions 
including angiotensin-converting-enzyme inhibitors (ACEi), beta (β)-blockers, 
aldosterone antagonists, coronary revascularization, and biventricular pacing 
(Jessup and Brozena, 2003) have been shown to improve symptoms, reduce the rate of 
HF hospitalizations, and improve mortality, both mortality and morbidity related to HF 
remain high.  Chronic HF is associated with repeated hospitalizations, substantially 
reduced quality of life, a yearly mortality rate in the United States of 7.5%  
(Webster et al, 2006), and approximately 5.1 million persons in the US clinically manifest 
symptoms of chronic HF (Go et al, 2013).  The etiology of chronic HF in adults is 
primarily myocardial dysfunction secondary to ischemic heart disease, usually as a 
consequence of coronary artery disease and myocardial infarction, although 
hypertensive cardiomyopathy is prevalent in African‑American/Black subjects  
(Yancy et al, 2013; McMurray et al, 2012). 
Observational and interventional studies in adults demonstrate that relatively high resting 
HR is not only a biomarker correlated with poor clinical outcomes, but is also a validated 
surrogate marker and a modifiable risk factor for chronic HF (Swedberg et al, 2010; 
McAlister et al, 2009; Flannery et al, 2008; Lechat et al, 2001).  Recently reported data 
from registries and clinical studies suggest that more than half the patients with HF 
receiving β-blockers will nevertheless have a resting HR > 70 beats per minute (bpm) 
(Maggioni et al, 2012; Maggioni et al, 2010).  The ability to achieve further HR reduction 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  14 February 2019 
Page 14 of 78 
CONFIDENTIAL 
 
 
beyond what is achieved with β-blockers would therefore constitute a significant 
therapeutic advance. 
Racially diverse populations may exhibit differences in drug response that may be due, 
in part, to variations in gene sequences.  Functional single-nucleotide polymorphisms 
(SNPs) are common in the genes encoding β-adrenergic receptors (adrenergic receptors 
alpha2A, as well as beta-1 and beta-2-adrenergic receptor), and in a gene that regulates 
the response of these receptors to catecholamines, the G-protein receptor kinase 
5 (GRK5) (Liggett et al, 2006; Liggett et al, 2008).  Importantly, both the β-1 adrenergic 
receptor (ADRB1) Arg389 > Gly and the GRK5 Gln41>Leu SNPs are over-represented 
in African-American/Black subjects.  The ADRB1 Arg389>Gly SNP is found in about 
42% of African-American/Black and 27% of Caucasians, and the distribution of the 
GRK5 Gln41 > Leu SNP shows even more ethnic divergence, as it is found in about 
33% of African-American/Black but only 1% of Caucasians (Moore et al, 1999; 
Liggett et al, 2008).  Both SNPs result in a blunted response of the β-adrenergic receptor 
to catecholamines and may therefore affect individual clinical responses to β-blockers in 
patients with HF (Liggett et al, 2006; Liggett et al, 2008).   
3.2.2 
Amgen Investigational Product Background:  Ivabradine  
Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that 
reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively 
inhibiting the cardiac f-current (If), resulting in HR reduction with no effect on ventricular 
repolarization and no effects on myocardial contractility. 
Refer to the specific sections of the US product label for additional information related to 
the physical, chemical, and pharmaceutical properties and formulation(s), as well as 
pivotal clinical studies in HFrEF. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of ivabradine 
is provided in the Corlanor® (ivabradine) US Prescribing Information. 


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4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Determine whether ivabradine 
effectively reduces HR from baseline 
to day 57 in African-American/Black 
subjects. 
• 
Change in HR from baseline to 
day 57 
  
Exploratory 
Safety 
• 
Evaluate the safety and tolerability of 
ivabradine in African-American/Black 
subjects with HFrEF 
• 
Subject incidence of 
treatment-emergent adverse events 
• 
Vital signs at each scheduled 
assessment 
 
4.2 
Hypotheses 
The primary hypothesis is that ivabradine effectively reduces HR between baseline and 
day 57 in African-American/Black subjects.  Because mean reductions of approximately 
5 beat per minute (bpm) have been observed in the overall placebo-treated subjects in 
the SHIFT study as well as in the placebo-treated subjects of the subgroup analysis of 
non-African-American/Black subjects enrolled in the SHIFT study, we will test whether 
the mean reduction with ivabradine exceeds 5 bpm, and estimate the degree to which 
the mean reduction with ivabradine exceeds 5 bpm. 
5. 
Study Design 
5.1 
Overall Design 
Currently, there are no data available on the efficacy of ivabradine to reduce HR in 
African-American/Black subjects with HFrEF, due to the fact that the pivotal outcome 
study, SHIFT, was conducted outside of the US (Swedberg, et al, 2010).  
African-American/Black subjects have a significantly higher prevalence of HF and 
generally experience worse outcomes than Caucasians (Yancy et al, 2013). 


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Considering the absence of representation of African-American/Black subjects with 
HFrEF in SHIFT and the potential limitations of β−blockade in that population, as 
described above, the primary objective of this study is to assess the efficacy of 
ivabradine in reducing HR in that population on top of optimal SOC.   
As exploratory endpoints, 
 
 
 
 
 
 
 
 
This study is a prospective, open-label, single-arm intervention study in 
African-American/Black subjects with HFrEF.  Approximately 30 to 100 subjects will be 
enrolled to receive ivabradine in an open-label design. 
Eligible subjects will include African-American/Black subjects with chronic HFrEF, New 
York Heart Association (NYHA) classes II to IV, with baseline HR ≥ 70 bpm in sinus 
rhythm and a left ventricular ejection fraction (LVEF) ≤ 35% who are on stable 
(≥ 4 weeks) optimal HF therapy, including maximally tolerated dose of β-blockers.   
After signing the informed consent form, subjects will enter a 7-day screening period that 
will allow accurate measurement of baseline activity as measured by the accelerometer 
(which is a non-Amgen, medical device).  On day 1, eligible subjects with confirmed 
sinus rhythm and HR ≥ 70 bpm will be enrolled into a 57-day open-label treatment 
period.  The starting dose of ivabradine is 5 mg twice daily (BID).  In subjects with a 
history of conduction defects, or in subjects in whom bradycardia could lead to 
hemodynamic compromise, therapy is to be initiated at 2.5 mg BID, based on 
investigator discretion.  On day 15, the dose will be titrated according to HR as defined 
in Table 5-1.  Ivabradine dose levels can be adapted to HR at any clinical visit if 
necessary. 


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Table 5-1.  Ivabradine Dose Titration at Day 15 Based on Heart Rate From 
Electrocardiogram 
 
Initial Dose: 5 mg BID 
Initial Dose: 2.5 mg BID 
HR ≥ 60 bpm 
7.5 mg BID 
5.0 mg BID 
HR ≥ 50 bpm, < 60 bpm 
5.0 mg BID 
2.5 mg BID 
HR < 50 bpm and/or signs 
or symptoms of 
bradycardia 
2.5 mg BID 
Discontinue therapy 
Abbreviations: BID = twice daily; bpm = beats per minute; HR = heart rate 
A safety follow-up will be conducted at day 87 or 30 days after the last administration of 
the investigational product.   
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
A minimum of 30 subjects with up to approximately 100 subjects with HFrEF will be 
enrolled in the study.   
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
5.2.2 
Number of Sites 
One to 3 investigative sites in the US will be included in the study.   
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when the last subject has completed the 
assessments for day 57. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 


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End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, safety follow-up), as 
applicable. 
5.3.2 
Study Duration for Subjects 
For an individual subject, the length of participation includes a 7-day screening period, a 
57-day open-label treatment period, and a 30-day safety follow-up period.   
5.4 
Justification for Investigational Product Dose 
Ivabradine will be initiated at 5 mg BID daily dosing (with option to reduce initial dosing 
to 2.5 mg BID based on investigator discretion), and the dose titration will follow the 
Corlanor® (ivabradine) US Prescribing Information, as indicated in Table 5-1.   
6. 
Study Population 
Eligibility criteria will be evaluated during screening.   
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
6.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent/assent prior to initiation of any 
study-specific activities/procedures. 
102 
Male or female subject ≥ 18 years of age, describing self as 
African-American/Black  
103 
Subject must have a diagnosis of HF confirmed by medical records, be in stable 
condition, and treated with stable optimal pharmacological therapy as per their 
personal physician’s care.   
104 
LVEF ≤ 35% confirmed by investigator 
105 
NYHA class II to IV assessed at the time of screening 
106 
Electrocardiogram (ECG) documentation at the time of screening of sinus rhythm 
with resting HR ≥ 70 bpm by local ECG reading 
107 
Subject must be able to complete a 6MWT and wear an accelerometer 


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6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
Disease Related 
201 
Recent myocardial infarction (≤ 2 months) or stroke (≤ 1 month) prior to 
enrollment 
202 
If the subject received within 3 months before or is scheduled to receive within 
42 days after enrollment any of the following:  revascularization, ventricular assist 
device, continuous or intermittent inotropic therapy, hospice care, major organ 
transplant, or is receiving renal replacement therapy by dialysis 
203 
If the subject received implantation of a cardioverter defibrillator or cardiac 
resynchronization therapy within 42 days before or is scheduled to receive 
implantation of a cardioverter defibrillator or cardiac resynchronization therapy 
within 42 days after enrollment 
204 
Severe primary valve disease or scheduled for surgery for valvular heart disease 
205 
Pacemaker with atrial or ventricular pacing (except bi-ventricular pacing) 
> 40% of the time, or with a stimulation threshold at the atrial or ventricular level 
≥ 60 bpm 
206 
Permanent atrial fibrillation or flutter 
207 
Sick sinus syndrome, sinoatrial block, or second and third degree 
atrio-ventricular block 
208 
History of symptomatic or sustained (≥ 30 sec) ventricular arrhythmia unless a 
cardioverter defibrillator was implanted 
209 
History of congenital QT syndrome 
210 
Any cardioverter defibrillator shock experienced within 1 month of enrollment 
211 
Hypertrophic obstructive cardiomyopathy, active myocarditis or constrictive 
pericarditis, or clinically significant congenital heart disease 
212 
Chronic antiarrhythmic therapy (except digitalis) 
213 
Scheduled outpatient intravenous (IV) infusions for HF (eg, inotropes, 
vasodilators [eg, nesiritide], diuretics) or routinely scheduled ultrafiltration 
214 
Evidence of digitalis intoxication within 7 days prior to screening 
215 
Systolic blood pressure > 180 mm Hg or < 90 mm Hg, or diastolic blood 
pressure > 110 mm Hg or < 50 mm Hg at any time during the screening phase 
216 
Known untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, active 
vasculitis due to collagen vascular disease 
217 
Have known acute or serious co-morbid condition (eg, major infection or 
hematologic, renal, hepatic, metabolic, gastrointestinal or endocrine dysfunction) 
that may interfere with the study, or severe concomitant non-cardiovascular 
disease that is expected to reduce life expectancy to less than 1 year or 
malignancy within 5 years prior to enrollment with the following exceptions: 
localized basal or squamous cell carcinoma of the skin or cervical intraepithelial 
neoplasia 


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Prior/Concomitant Therapy 
218 
Subjects taking QT prolonging medicinal products for cardiovascular (eg, but not 
limited to, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone) or 
non-cardiovascular disease (eg, but not limited to, pimozide, ziprasidone, 
sertindole, mefloquine, halofantrine, pentamidine, cisapride, IV erythromycin) 
219 
Subjects exposed to a strong CYP3A4 inhibitor (examples of strong CYP3A4 
inhibitors include; azole antifungals [eg, itraconazole], macrolide antibiotics 
[eg, clarithromycin, telithromycin], human immunodeficiency virus (HIV) protease 
inhibitors, [eg, nelfinavir], and nefazodone]) within 14 days prior to enrollment, or 
to a strong CYP3A4 inducer (examples of CYP3A4 inducers include; St. John’s 
wort, rifampicin, barbiturates, and phenytoin) within 28 days prior to enrollment 
220 
Subjects who received diltiazem or verapamil within 48 hours prior to enrollment 
Prior/Concurrent Clinical Study Experience 
221 
Previously received ivabradine prior to participation in this study 
222 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
Other Exclusions 
223 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 14 days after the last dose of 
investigational product.  Females of childbearing potential should only be 
included in the study after a confirmed menstrual period and a negative highly 
sensitive urine pregnancy test. 
224 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 14 days after the 
last dose of investigational product.  Refer to Appendix 5 for additional 
contraceptive information. 
225 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
226 
Subject likely not to be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
227 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
6.3 
Lifestyle Restrictions 
6.3.1 
Meals and Dietary Restrictions 
Ivabradine should be taken with meals.   


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6.3.2 
Caffeine, Alcohol, and Tobacco 
At screening and throughout the duration of the study, subjects are encouraged to limit 
intake of caffeine containing beverages, alcohol, and tobacco. 
6.3.3 
Activity 
Subjects are to maintain regular activities.   
6.4 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board (IRB) approval of the 
protocol, informed consent form, and all other subject information and/or recruitment 
material, if applicable (see Appendix 3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB and Amgen approved informed consent before commencement of 
study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (screening period starts 
when the subject signs and dates the informed consent form) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned manually.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
6.5 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demographics, screen failure details, eligibility 
criteria, medical history, concomitant medications, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened 1 time.  


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7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 7-1. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products  
The amount dispensed, amount returned, date dispensed, date returned, and lot number 
of the investigational product are to be recorded on each subject's CRF.  
Table 7-1.  Study Treatment 
Study Treatment 
Name 
Amgen Investigational Product:a 
Ivabradine (Corlanor) tablets 
Dosage Formulation 
Salmon colored, oval-shaped, film-coated tablets, scored on both 
edges debossed with “5” on one face and bisect on the other face per 
product specification PRDS-002165.  Ivabradine will be provided in 
bottles (60 tablets per bottle) labeled ivabradine 5 mg and ivabradine 
7.5 mg.  Subjects splitting the 5.0 mg tablets into equal halves will 
achieve the 2.5 mg dose of ivabradine.  Tablets cannot be crushed or 
liquefied.   
Unit Dose 
Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
5 mg BID daily.  After 14 days, tolerability to be assessed as well as 
resting HR with dose adjustment, as recommended in the Corlanor® 
(ivabradine) US Prescribing Information.  At the investigator’s 
discretion. 
Route of 
Administration 
Oral 
Accountability 
The amount dispensed, amount returned, date dispensed, date 
returned, and lot number of investigational product are to be recorded 
on each subject's CRF(s).   
Dosing Instructions 
Subjects will take the investigational product with food.   
Abbreviations: BID = twice daily; CRF = case report form; HR = heart rate 
a Ivabradine will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
7.1.2 
Non-investigational Products 
Not applicable.   


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7.1.3 
Medical Devices 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
Heart rate during the 6MWT will be measured by an HR monitor at specified time points 
(see Table 2-1 for 6MWT schedules).  An accelerometer will also be used throughout the 
study.  Any adverse events associated with the accelerometer (eg, allergic reaction to 
components of the instrument) will be captured in the Events CRF as a procedure-
related event.  Data collected from the accelerometer will not be available nor reviewed 
until after the end of the study (ie, last subject, last visit). 
7.1.4 
Other Protocol-required Therapies 
Not applicable.   
7.1.5 
Other Treatment Procedures 
There are no other treatment procedures in this study.  
7.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s), device, or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
For devices not provided by Amgen, refer to the device manual for product complaint 
procedures. 


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7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Other investigational procedures and products while participating in this study are 
prohibited. 
Strong CYP3A4 inhibitors are contraindicated.  Concomitant use of diltiazem and 
verapamil and CYP3A4 inducers is discouraged per label.  QT-prolonging medications 
are prohibited.  Consumption of grapefruit juice is not recommended. 
7.2 
Method of Treatment Assignment 
All subjects will receive open-label ivabradine.   
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment CRF. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
7.4 
Dose Modification 
Refer to Table 5-1 for dose titration according to HR and/or signs/symptoms of 
bradycardia. 
7.4.1 
Hepatotoxicity Stopping Rules 
Refer to Appendix 7 for details regarding drug-induced liver injury (DILI) guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.   
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.2.1 
Amgen Investigational Product:  Ivabradine 
Ivabradine will be initiated at a 5 mg BID dosing (with option to reduce initial dosing to 
2.5 mg BID based on investigator discretion as per Corlanor® (ivabradine) US 
Prescribing Information).  On day 15, subjects will be reassessed as to tolerability and 
clinical status as well as resting HR. Dose of study drug will be up-titrated to 7.5 mg BID 
(maximum dose), remain at 5 mg BID or down-titrated to 2.5 mg BID based on guidance 
in Table 5-1 and the investigator’s clinical judgment.  If the subject does not tolerate the 
lowest dose of ivabradine 2.5 mg BID, or continues to experience symptomatic 
bradycardia (eg, dizziness, fatigue, or hypotension), or has a resting HR of < 50 bpm on 
that dose, the study drug will be discontinued. 


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Discontinuation of study drug at any time during the study will be left up to the discretion 
of the investigator. 
The reason for dose change of ivabradine is to be recorded on each subject’s CRF. 
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM. 
7.6 
Treatment Compliance 
Subjects should be informed to return to the study site all bottles with all remaining 
tablets at each study visit.  To monitor dosage compliance, a manual tablet count will be 
performed by the site at the time of drug return to calculate the number of expected 
tablets that should have been taken versus the amount of remaining tablets.  Subjects 
should be re-educated on the importance of adhering to the study drug administration 
schedule (BID, every 12 hours ± 4 hours) if inventory of remaining tablets indicates 
medication non-compliance. 
7.7 
Treatment of Overdose 
Overdose of ivabradine may lead to severe and prolonged bradycardia.  In the event of 
bradycardia with poor hemodynamic tolerance, temporary cardiac pacing may be 
required.  Supportive treatment, including IV fluids, atropine, and IV beta-stimulating 
agents such as isoproterenol, may be considered.   
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies that were being taken/used from 30 days prior to the screening period 
through the end of the screening period will be collected.  For prior therapies, therapy 
name, indication, dose, unit, frequency, route, start date, and stop date will be collected. 
7.8.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7. 
Concomitant therapies (including but not limited to β-blocker, ACEi, and angiotensin II 
receptor blocker) are to be collected from day 1 through the end of the safety follow-up 
period at day 87 or 30 days after the last administration of investigational product, 
whichever is later.  Subjects should avoid concomitant use of moderate CYP3A4 


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inhibitors when using ivabradine.  Examples of moderate CYP3A4 inhibitors include 
diltiazem, verapamil, and grapefruit juice. 
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study.   
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
Decision by Sponsor 
• 
Lost to follow-up 
• 
Death 
• 
Ineligibility determined 
• 
Protocol deviation 
• 
Non-compliance  
• 
Adverse event  
• 
Subject request 
• 
Pregnancy 
If this occurs, the investigator is to discuss with the subject the appropriate processes for 
discontinuation from investigational product or other protocol-required therapies and 
must discuss with the subject the possibilities for continuation of the Schedule of 
Activities (see Table 2-1) including different options of follow-up (eg, in person, by 
phone/mail, through family/friends, in correspondence/communication with other treating 
physicians, from the review of medical records) and collection of data, including 
endpoints, adverse events, disease-related events, and must document this decision in 


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the subject’s medical records.  Subjects who have discontinued investigational product 
and/or other protocol-required therapies or procedures should not be automatically 
removed from the study.  Whenever safe and feasible, it is imperative that subjects 
remain on-study to ensure safety surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with Appendix 3. 
8.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Appendix 6 for further details).  Refer to the Schedule of Activities for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable.   
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
Decision by sponsor 
• 
Withdrawal of consent from study 
• 
Death 
• 
Lost to follow-up 
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  


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The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
is able to continue in the study. 
• 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts are 
to be documented in the subject’s medical record. 
• 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
• 
For subjects who are lost to follow-up, the investigator can search publically 
available records (where permitted) to ascertain survival status.  This ensures 
that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible. 
9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities (Table 2-1), is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject manually and screen 
the subject in order to assess eligibility for participation.  The screening window is 
7 days. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 1 time.  
Rescreened subjects must first be registered as screen failures and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 7-day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 
after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated. 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1).  On-study visits may be 
completed within ± 2 days for days 1, 15, and 29 and to be completed within ± 5 days for 
day 57.  The date of the first dose of ivabradine is defined as day 1.  All subsequent 
doses and study visits will be scheduled based on the day 1 date.  Administration of 
ivabradine is to be administered during each visit according to the Schedule of Activities 
(Table 2-1). 
9.1.3 
Safety Follow-up 
A safety follow-up period (phone contact) will be conducted at the study clinic at day 87 
or 30 days after the last dose of ivabradine.   
9.1.4 
Early Termination 
If a subject discontinues study drug administration before the day 57 visit, the subject will 
return to the study clinic in 30 days after study discontinuation and return the 
accelerometer and investigational product.  Subjects ending investigational product early 
will be asked to complete the early termination visit procedures outlined per the 
Schedule of Activities (Table 2-1). 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB approved informed consent before any study-specific procedures are performed. 


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9.2.1.2 
Demographics 
Demographics data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.   
9.2.1.3 
Medical History 
The Investigator or designee will collect targeted medical cardiovascular disease history 
along with the functional NYHA class history that started within 5 years prior to 
enrollment through screening.  Medical history will include information on the subject's 
concurrent medical conditions.  Record all findings on the medical history CRF.   
9.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded (eg, medical history, event). 
9.2.1.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes. 
9.2.1.6 
Substance Abuse History  
Obtain a detailed history of prior and/or concurrent use of alcohol, tobacco, caffeine. 
9.2.2 
Efficacy Assessments 
9.2.2.1 
Electrocardiogram 
Change in HR will be assessed by ECG.  Refer to Section 9.2.3.3 for further details. 
9.2.2.2 
6-Minute Walk Test 
The 6MWT will be conducted at baseline (day 1) and at the end of treatment period 
(day 57).  The 6MWT will be recorded by standard methods (see Appendix 8 for 6MWT 
instructions and Appendix 9 for 6MWT for recording form).  Heart rate (HR) during the 
6MWT will be recorded by an HR monitor. 
9.2.2.3 
Accelerometer 
An accelerometer will be provided to each subject at screening.  A 7-day screening visit 
with the accelerometer is required before day 1 dosing.  The subjects will be instructed 
to wear the accelerometer every day continuously, except to be recharged.  The 
accelerometer is to be worn daily from screening through the end of treatment period 
(day 57).  The accelerometer will record the subject’s physical activity.  Refer to the 
accelerometer manual for further details. 


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Data collected from wearable devices will not be available nor reviewed until after the 
end of the study (ie, last subject, last visit). 
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Table 2-1. 
9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Disease-related Events 
Disease-related events are defined in Appendix 4. 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
product(s)/study treatment/protocol-required therapies through the end of study/safety 
follow-up visit or 30 days after the last administration of investigational product, 
whichever is later, are collected/recorded/reported using the Event CRF.   
Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational product(s)/study treatment/protocol-required 
therapies, and determined to be serious, must be reported on the Event CRF as serious 
adverse events. 
In this study, subjects will have HF and left ventricular systolic dysfunction.  Therefore, 
disease-related events potentially include manifestation and complications of HF and left 
ventricular systolic dysfunction such as:  left ventricular dilatation, cardiopulmonary 
failure, cardiomyopathy, decreased cardiac output, low cardiac output syndrome, 
ejection fraction decreased, pulmonary edema, orthopnea, nocturnal dyspnea, 
peripheral edema, and testing suggesting progression of HF.  
• 
Disease-related events that would qualify as an adverse event or serious 
adverse event: 
o In case of an event based on the underlying disease that is worse than 
expected as assessed by the investigator for the subject’s condition or if 
the investigator believes there is a causal relationship between the 
investigational product(s)/study treatment/protocol-required therapies and 
disease worsening, this must be reported as an adverse event or serious 
adverse event. 


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• 
Disease-related events that do not qualify as adverse events or serious adverse 
events:  
o An event which is part of the normal course of disease under study 
(eg, disease progression in HF or hospitalization due to disease 
progression) is to be reported as a disease-related event. 
9.2.3.1.1.2 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0 and is described in 
Appendix 4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of investigational 
product through the end of study/safety follow-up visit or 30 days after the last 
administration of investigational product, whichever is latest, are reported using the 
Event CRF. 
All adverse events observed by the investigator or reported by the subject that are 
related to study procedures/study activities will be reported from signing the informed 
consent form through end of study/safety follow-up visit or 30 days after last dose of 
investigational product administration, whichever is later, are to be 
collected/recorded/reported using the Event CRF. 
9.2.3.1.1.3 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the end of study/safety follow-up visit or 30 days after the last 
administration of investigational product, whichever is later, are reported using the Event 
CRF. 
All serious adverse events will be collected, recorded, and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the (CTCAE), version 4.0 grading scale differs from the 
regulatory criteria for serious adverse events.  It is left to the investigator’s judgment to 
report these grade 4 abnormalities as serious adverse events. 


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9.2.3.1.1.4 
Serious Adverse Events After the Protocol-required Reporting 
Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 
after end of study.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
The method of recording, evaluating, and assessing causality of adverse events, 
disease-related events, and serious adverse events and the procedures for completing 
and transmitting serious adverse event reports are provided in Appendix 4. 
9.2.3.1.1.5 
Serious Adverse Events That are not to be Reported by the Sponsor 
to Regulatory Agencies in an Expedited Manner 
Serious adverse events (eg, population-related events) that are not planned to be 
reported individually in an expedited manner as they are anticipated to occur in the study 
population at some frequency independent of the protocol-required therapies are as 
follows:   
Hospitalizations and deaths due to chronic heart failure complications are anticipated to 
occur in the enrolled population.  The Amgen safety and medical team will review 
accumulating events on a regular basis. 
9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Appendix 4. 


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All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB, if appropriate according to local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and in female partners of 
male subjects will be collected after the start of study treatment and until 14 days after 
the last dose of study drug. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in Appendix 5.  
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 


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Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 
9.2.3.2 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, HR, 
respiratory rate, and temperature.  Subject should preferably be in a supine position in a 
rested and calm state for at least 5 minutes before blood pressure assessments are 
conducted.  If the subject is not in the supine position, the subject should be in the most 
recumbent position as possible.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF.  The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 
9.2.3.3 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in the most recumbent position as possible.  The ECG 
must include the following measurements: HR, QRS, QT, QTc, and PR intervals.  The 
primary investigator will review all ECGs.  Once signed, the original ECG tracing will be 
retained with the subject's source documents.  At the request of the sponsor, a copy of 
the original ECG will be made available to Amgen. 
9.2.3.4 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
9.2.3.5 
Suicidal Risk Monitoring 
Not applicable.  
9.2.4 
Clinical Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities Table 2-1, for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 


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must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 2-1).   
9.2.4.1 
Pregnancy Testing 
A high sensitive urine pregnancy test should be completed at screening and within 
7 days of initiation of investigational product for females of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Appendix 5 for contraceptive requirements.  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.4.2 
Prespecified Biomarker Assessments 
Not applicable.  
9.2.5 
Pharmacokinetic Assessments 
Not applicable. 
9.2.6 
Pharmacodynamic Assessments 
Not applicable.  
9.2.7 
Pharmacogenetic Assessments 
Not applicable. 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
The primary endpoint is HR reduction from baseline at day 57 greater than 5 bpm.  
Based on HR reduction results observed in the overall placebo-treated subjects of the 
SHIFT study as well as in the placebo-treated subjects of the subgroup analysis of 


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non-African-American/Black subjects enrolled in the SHIFT study, the mean change HR 
in the ivabradine group was 13 bpm with a standard deviation of 10.4 bpm at end of 
28 days and maintained until end of study.  In addition, the mean change in the placebo 
group was 5 bpm observed at end of 28 days, so the hypothesis is to evaluate the HR 
reduction from baseline at day 57 greater than 5 bpm.  Based on a 2-sided, 1-sample 
t-test with significance level of 0.05, the planned sample size of 30 to 100 subjects will 
provide approximately 97% to >99% power.  The sample size considerations incorporate 
an assumption of a study drop out of 10%. 
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
10.2.1.1 
Full Analysis Set 
Efficacy analyses will be performed on the full analysis set (FAS), which includes all 
enrolled subjects.   
10.2.1.2 
Safety Analysis Set 
Safety analyses will be performed on the safety analysis set (SAS), which includes all 
enrolled subjects who receive at least 1 dose of investigational product on study. 
10.2.2 
Covariates 
Baseline covariates include, but are not limited to: 
• 
Age: < 65 years, ≥ 65 years  
• 
Sex  
10.2.3 
Subgroups 
Subgroups might include, but are not limited to: 
• 
Age: < 65 years, ≥ 65 years  
• 
Sex 
10.2.4 
Handling of Missing and Incomplete Data 
No missing data will be imputed for efficacy and safety endpoints.   
10.3 
Adaptive Design 
Not applicable.   
10.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the primary analysis will be conducted and reported following 
the end of study, as defined in Section 5.3.1. 


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10.4.1 
Planned Analyses 
10.4.1.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis will be conducted in this study. 
10.4.1.2 
Primary Analysis 
The primary analysis for this study will be performed when all subjects have completed 
all planned study procedures.  This primary analysis will evaluate whether the effect of 
ivabradine on HR reduction at day 57 in African-American/Black subjects overall (the 
primary endpoint) exceeds 5 bpm.  Descriptive statistics of the exploratory endpoints will 
be summarized.  Safety data will be tabulated.  
10.4.1.3 
Final Analysis 
Not applicable.   
10.4.2 
Methods of Analyses 
10.4.2.1 
General Considerations 
At the time of primary analysis, the database will be cleaned, processed and a snapshot 
will be taken.  Based on the snapshot, efficacy and safety analyses will be performed on 
the FAS and safety analysis set respectively.  
Efficacy analyses of the primary endpoint will test whether the mean reduction with 
ivabradine exceeds 5 bpm.  Summary statistics and least-square means along with 95% 
confidence interval, analyzed by the repeated-measures linear model, will be provided 
for the primary endpoint. 
Subject disposition, demographics, baseline characteristics, medical history, baseline 
concomitant medications, and exposure to investigational product will be summarized.  
Continuous variables will be summarized using descriptive statistics, including the 
number of observations (n), mean, standard deviation or standard error, median, the first 
quartile and third quartile, minimum, and maximum.  Categorical variables will be 
summarized using the number and percent of subjects. 
10.4.2.2 
Efficacy Analyses 
10.4.2.2.1 
Primary Endpoint 
• 
HR reduction from baseline to day 57 for the overall African-American/Black 
subjects. 
The repeated measures linear model will be used to evaluate ivabradine efficacy on HR 
reduction from baseline to day 57 for the overall African-American/Black subjects.  The 
model will include terms of scheduled visits and baseline HR measurement as 


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covariates and will test whether the mean reduction with ivabradine exceeds 5 bpm, 
which is the reduction assumed with placebo.  Missing values will not be imputed when 
the repeated measures linear model is used.  Based on the model, the least-square 
means along with 95% confidence interval will be provided.  In addition, descriptive 
statistics of HR reduction by scheduled visit will be summarized. 
10.4.2.2.2 
Secondary Endpoints 
Not applicable.  
10.4.2.2.3 
Exploratory Endpoints 
10.4.2.3 
Safety Analyses 
10.4.2.3.1 
Analyses of Primary Safety Endpoint 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Descriptive statistics  
 
10.4.2.3.2 
Adverse Events and Disease-related Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product and significant 
treatment emergent adverse events will also be provided.  Subject incidence of 
disease-related events and fatal disease-related events, if applicable, will be tabulated 
by system organ class and preferred term. 
10.4.2.3.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at baseline. 
10.4.2.3.4 
Vital Signs 
The analyses of vital signs including systolic blood pressure and diastolic blood 
pressure, and HR will be summarized using descriptive statistics at each scheduled visit.   


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10.4.2.3.5 
Physical Measurements 
The analyses of height and weight measurements will include summary statistics at 
baseline. 
10.4.2.3.6 
Electrocardiogram 
All ECG measurements will be summarized using descriptive statistics at each 
scheduled visit.  In addition, the change in HR from baseline will be summarized at each 
scheduled postbaseline visit (day 15 and 57). 
The ECG measurements from this clinical study will be performed as per standard of 
care for routine safety monitoring, rather than for purposes of assessment of potential 
QTc effect.  Since these evaluations may not necessarily be performed under the 
rigorous conditions expected to lead to meaningful evaluation of QTc data, summaries 
and statistical analyses of ECG measurements are not planned, and these data would 
not be expected to be useful for meta-analysis with data from other studies. 
10.4.2.3.7 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by visit. 
10.4.2.3.8 
Exposure to Concomitant Medication 
Information regarding concomitant medications of interest, including but not limited to 
β-blockers, ACEi, and angiotensin II receptor blockers, will be summarized. 


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11. 
References 
Flannery G, Gehrig-Mills R, Billah B, et al. Analysis of randomized controlled trials on the 
effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic 
chronic failure receiving beta-blockers.  Am J Cardiol.  2008;101:865-869. 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation,  
July 2009. 
Go AS, Mozaffarian D, Roger VL, et al.  Heart disease and stroke statistics—2013 
update: a report from the American Heart Association.  Circulation. 2013;127:e6-e245. 
Jessup M, Brozena S. Heart failure.  N Engl J Med. 2003;348:2007-2018. 
Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with 
bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation.  
2001;103:1428-1433. 
Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et al. A polymorphism within a conserved 
beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in 
human heart failure. Proc Natl Acad Sci U S A. 2006;103:11288–11293. 
Liggett SB, Cresci S, Kelly RJ, et al. A GRK5 polymorphism that inhibits β-adrenergic 
receptor signaling is protective in heart failure. Nat Med. 2008;14:510–517. 
Maggioni AP, Dahlström U, Filippatos G, et al. Heart Failure Association of the ESC 
(HFA). EURObeservational Research Programme: the Heart Failure Pilot Survey 
(ESC-HF Pilot). Eur J Heart Fail 2010;12:1076-1084. 
Maggioni AP, EURObservational Research Programme: the Heart Failure Pilot Survey 
(ESC-HF Pilot). Complementary analyses from the ESC-HF Pilot database according to 
heart rate threshold in patients with chronic heart failure. With permission of the ESC 
EORP Executive Committee. 2012. 
McAlister FA, Wiebe N, Ezekowitz JA, et al. Meta-analysis: β-blocker dose, heart rate 
reduction, and death in patients with heart failure. Ann Intern Med. 2009;150:784-794. 
McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of 
Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the 
ESC. Eur Heart J. 2012;33:1787-1847. 
Moore JD, Mason DA, Green SA, Hsu J, Liggett SB. Racial differences in the 
frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G 
and c1165G>C. Hum Mutat. 1999;14:271. 
Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart 
failure (SHIFT): a randomised placebo-controlled study. Lancet.  2010;376:875-885. 
Webster G, Zhang J, Rosenthal D. Comparison of the epidemiology and co-morbidities 
of heart failure in the pediatric and adult populations: a retrospective, cross-sectional 
study. BMC Cardiovasc Disord. 2006; 25:6-23. 
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management 
of heart failure: a report of the American College of Cardiology Foundation/American 
Heart Association Task Force on practice guidelines. Circulation. 2013;128:e240-327. 


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12. 
Appendices 


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12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
6MWT 
6-minute walk test 
ACEi 
angiotensin-converting-enzyme inhibitors 
ANC 
absolute neutrophil count 
BID 
twice daily 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug induced liver injury  
DLRT 
dose level review team 
DMC 
data monitoring committee 
DRE 
device-related event 
DRT 
data review team 
ECG 
electrocardiogram 
EDC 
electronic data collection 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Study  
The end of study date is defined as the date when the last 
subject at the site is assessed or receives an intervention for 
evaluation in the study (ie, last subject last visit)  
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
Enrolled 
A subject is considered enrolled when the investigator decides 
that the subject has met all eligibility criteria.   
FAS 
Full analysis set 
GRK5 
G-protein receptor kinase 5 
Page 1 of 2 


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Abbreviation or Term 
Definition/Explanation 
HF 
heart failure 
HFrEF 
heart failure and reduced ejection fraction 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormonal replacement therapy 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB 
institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormonal-releasing system 
IV 
Intravenous 
LVEF 
left ventricular ejection fraction 
NASH 
Nonalcoholic fatty liver disease including steatohepatitis 
NYHA 
New York Heart Association 
SAS 
Safety analysis set 
SNP 
single-nucleotide polymorphisms 
SOC 
standard of care 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Enrollment Randomization 
identification, and Stratification Value. 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
SUSAR 
suspected unexpected serious adverse reactions 
ULN 
upper limit of normal 
Page 2 of 2 


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12.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the local laboratory.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 6.1 to Section 6.2. 
Additional tests may be performed at any time during the study as deemed necessary by 
the investigator or required by local regulations. 
Table 12-1.  Analyte Listing 
Local Laboratory 
Chemistry  
Local Laboratory 
Hematology 
Local Laboratory Other Labs 
Carbon dioxide (Bicarbonate) RBC 
Urine pregnancy test   
Chloride 
Hemoglobin 
BNP 
Potassium 
Hematocrit 
 
Sodium 
Platelets  
WBC 
 
BUN 
 
 
Creatinine  
eGFR 
 
 
total protein 
 
albumin 
 
total bilirubin 
 
ALT 
AST 
 
 
HbA1c 
 
 
Glucose 
 
 
 
 
Abbreviations; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; 
BNP = b-type natriuretic peptide; RBC = red blood count; WBC = white blood count 


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12.3 
Appendix 3.  Study Governance Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an IRB by the investigator and reviewed and approved by the IRB.  A copy of the written 
approval of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB for all subsequent protocol amendments and 
changes to the informed consent document.  The investigator must send a copy of the 
approval letter from the IRB and amended protocol Investigator’s Signature page to 
Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
• 
Obtaining annual IRB approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB continuance of approval must be 
sent to Amgen 
• 
Notifying the IRB of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance 
with local procedures 
• 
Overall conduct of the study at the site and adherence to requirements of Title 21 
of the US Code of Federal Regulations (CFR), ICH guidelines, the IRB, and all 
other applicable local regulations 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 


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The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  


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The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 30 days from the previous informed consent form signature 
date. 
The informed consent will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each subject the objectives of the exploratory 
research.  Subjects will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate signature will be required to document a subject’s agreement to allow any 
remaining specimens to be used for exploratory research.  Subjects who decline to 
participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the CRF demographics page, in addition to the unique subject identification number, 
include the age at time of enrollment. 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 


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In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB direct access to review the subject’s original medical 
records for verification of study-related procedures and data.  Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, the investigator will obtain input and 
assistance from Amgen staff as appropriate. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors (ICMJE) Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above. 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
All persons designated as authors must qualify for authorship, and all those who qualify 
are to be listed. 
Each author must have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 


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All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
A recognized expert in the therapeutic area 
• 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 


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The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents 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 study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 


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Elements to include: 
• 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the (IRB) 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts 
(POR), Investigational Product Accountability Record(s), Return of Investigational 
Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable 
• 
Non-investigational product(s), and/or medical device(s) or combination 
product(s) documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB in writing of the study’s completion or early termination and send a copy of 
the notification to Amgen. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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12.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Disease-related Event 
Disease-related Event Definition 
• 
Disease-related events are events (serious or non-serious) anticipated to occur in the study 
population due to the underlying disease.  See Section 9.2.3.1.1.1 for the list of disease-
related events.   
• 
Disease-related events that would qualify as an adverse event or serious adverse event: 
o 
An event based on the underlying disease that is worse than expected as assessed by 
the investigator for the subject’s condition or if the investigator believes there is a 
causal relationship between the investigational product(s)/study treatment/protocol-
required therapies and disease worsening, this must be reported as an adverse event 
or serious adverse event. 
• 
Disease-related events that do not qualify as adverse events or serious adverse events:  
o 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be reported 
as a disease-related event.   
Definition of Adverse Event 
Adverse Event Definition 
• 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
• 
Note:  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, medical device or procedure. 
Events Meeting the Adverse Event Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram [ECG], radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related to 
progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported regardless of 
sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an adverse event or serious adverse event.  Such instances will be captured in the 
efficacy assessments.  However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as adverse event or serious adverse event if they fulfill 
the definition of an adverse event or serious adverse event.  


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Events NOT Meeting the Adverse Event Definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to 
the procedure is the adverse event. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, meets at 
least 1 of the following serious criteria: 
• 
Results in death (fatal) 
• 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at risk of death at the time of the event.  It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are an adverse event.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in doubt 
as to whether “hospitalization” occurred or was necessary, the adverse event is to be 
considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an adverse event. 
• 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle) which may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect 
• 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse event 
reporting is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require medical or surgical intervention to prevent 1 of the other outcomes listed in the 
above definition.  These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 


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Recording Adverse Events, Disease-related Events (if applicable), and Serious 
Adverse Events 
Adverse Event, Disease-related Event (if applicable) and Serious Adverse Event 
Recording 
• 
When an adverse event, disease-related event or serious adverse event occurs, it is the 
responsibility of the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant adverse event/disease-related event/serious 
adverse event information in the Event CRF. 
o 
Additionally, the investigator is required to report a fatal disease-related event on the 
Event CRF. 
• 
The investigator must assign the following adverse event attributes: 
o 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
o 
Dates of onset and resolution (if resolved); 
o 
Severity (or toxicity defined below); 
o 
Assessment of relatedness to investigational product:  ivabradine, and/or other 
protocol‑required therapies and/or study‑mandated procedure/study mandated activity. 
o 
Action taken. 
o 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record a single event for each level of severity on the Event CRF. 
 
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical records 
to the sponsor in lieu of completion of the Event CRF page. 
• 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records.  In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to the sponsor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious adverse 
event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and serious 
adverse event reported during the study.  The assessment of severity will be based on:  
The Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 which is available 
at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 


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Assessment of Causality 
• 
The investigator is obligated to assess the relationship between investigational product, 
protocol-required therapies, and/or study-mandated procedures and each occurrence of 
each adverse event/serious adverse event. 
• 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each adverse event/serious adverse event, the investigator must document in the 
medical notes that he/she has reviewed the adverse event/serious adverse event and has 
provided an assessment of causality. 
• 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the serious adverse event data. 
• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment. 
• 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of Adverse Event and Serious Adverse Event 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully 
as possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a subject is permanently withdrawn from protocol-required therapies because of a serious 
adverse event, this information must be submitted to Amgen. 
• 
If a subject dies during participation in the study or during a recognized follow-up period, 
the investigator will provide the sponsor with a copy of any post-mortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed Event CRF. 
• 
The investigator will submit any updated serious adverse event data to Amgen within 24 
hours of receipt of the information. 


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Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
• 
The primary mechanism for reporting serious adverse event will be the electronic data 
collection (EDC) system via the Safety Report Form.  
• 
If the EDC system is unavailable for more than 24 hours, then the site will report the 
information to Amgen using an electronic Serious Adverse Event (eSAE) Contingency 
Report Form (paper based form see Figure 12-1) within 24 hours of the investigator’s 
knowledge of the event. 
• 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
• 
After the study is completed at a given site, the EDC system will be taken off-line to prevent 
the entry of new data or changes to existing data. 
• 
If a site receives a report of a new serious adverse event from a study subject or receives 
updated data on a previously reported serious adverse event after the EDC has been taken 
off-line, then the site can report this information on a paper Serious Adverse Event Report 
Form (eg, Serious Adverse Event Contingency Report Form, see Figure 12-1). 


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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
 


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12.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for female of childbearing potential are 
outlined in Section 6.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
14 days after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception for an increased length of time.  In addition, male subjects may 
also be required to use contraception.  The investigator must discuss these 
contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
• 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or  
3) subject’s medical history interview. 
• 
Premenarchal female 
• 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state 
in women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 


Product:  Ivabradine 
Protocol Number:  20160231 
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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note: Failure rate of < 1% per year when used consistently and correctly. 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormonal-releasing system (IUS) 
• 
Bilateral tubal ligation/occlusion 
• 
Vasectomized partner (provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success) 
• 
Sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and 
the preferred and usual lifestyle of the subject) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical studies include: 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus) 
• 
Spermicides only 
• 
Lactational amenorrhea method 
• 
Barrier methods (condoms, diaphragm, cervical cap, or sponge) 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
Collection of Pregnancy Information 
Female Subjects who Become Pregnant 
• 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 14 days. 
• 
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 12-2).  The worksheet must be submitted to Amgen Global Patient Safety 
within 24 hours of learning of a subject’s pregnancy.   


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• 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female subject 
who becomes pregnant while taking protocol-required therapies through 2 weeks of 
the study drug.  This information will be forwarded to Amgen Global Patient Safety.  
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 
• 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
• 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
• 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
• 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Appendix 4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
• 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 8.1 for details). 
Male Subjects with Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
• 
In the event a male subject fathers a child during treatment, and for an additional 
14 days after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet.  The worksheet (see 
Figure 12-2) must be submitted to Amgen Global Patient Safety within 24 hours of 
the site’s awareness of the pregnancy.   
• 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female partner to 
obtain additional pregnancy information. 
• 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 


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• 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
• 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
• 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 14 days. 
• 
Information will be recorded on the Lactation Notification Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
• 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 223. 
• 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 14 days after discontinuing 
protocol-required therapies. 


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Figure 12-2.  Sample Pregnancy and Lactation Notification Worksheets 
 


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12.6 
Appendix 6.  Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Activities (Table 2-1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
heart failure and left ventricular systolic dysfunction in African-American/Black Subjects, 
the dose response and/or prediction of response to ivabradine, and characterize aspects 
of the molecule (eg, mechanism of action/target, metabolites).  Results from this analysis 
are to be documented and maintained, but are not necessarily reported as part of this 
study.  Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetics, or other exploratory studies are not 
placed in the subject’s medical record and are not to be made available to the subject, 
members of the family, the personal physician, or other third parties, except as specified 
in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
sample types (eg, blood, tumor) samples and any other components from the cells can 
be located and destroyed.  Samples will be destroyed once all protocol-defined 
procedures are completed.  However, information collected from samples prior to the 
request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 


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appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample (See 
Appendix 3 for subject confidentiality). 


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12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments  
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR, and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
• 
Hepatobiliary tract disease 
• 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
• 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
• 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
• 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
• 
Alpha-one antitrypsin deficiency 
• 
Alcoholic hepatitis 
• 
Autoimmune hepatitis 
• 
Wilson’s disease and hemochromatosis 
• 
Nonalcoholic fatty liver disease including steatohepatitis (NASH) 
• 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible DILI 
according to recommendations in the last section of this appendix.  


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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product is to be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Table 12-2) are never to be rechallenged. 


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Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Appendix 4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 12-2 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
• 
Complete blood count (CBC) with differential to assess for eosinophilia 
• 
Serum total immunoglobulin IgG, anti-nuclear antibody (ANA), anti smooth muscle 
antibody, and liver kidney microsomal antibody -1 (LKM1) to assess for autoimmune 
hepatitis 
• 
Serum acetaminophen (paracetamol) levels 


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• 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
• 
Viral serologies 
• 
Creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
• 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
• 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  


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12.8 
Appendix 8.  Six Minute Walk Test Instructions 
 


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12.9 
Appendix 9.  Six Minute Walk Test Recording Form 
 
 


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Amendment 2 
Protocol Title:  Open-label, Single-arm Study Assessing the Efficacy and Safety of 
Ivabradine (Corlanor) in African-American/Black Subjects With Heart Failure and 
Left Ventricular Systolic Dysfunction 
 
Amgen Protocol Number Ivabradine 20160231 
 
Amendment Date: 
14 February 2019 
 
Rationale: 
This protocol is being amended to: 
• 


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Description of Changes  
Section:  Global 
Change:  Updated document date to 14 February 2019. 
Section:  Global 
Change:  Editorial changes (including typographical, grammatical, and formatting) have 
been made throughout the document. 
Section:  Title Page, Key Sponsor Contact 
Replace: 
Name: 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 91320, 
USA 
Telephone Number: 
Email Address: 
With: 
Name: 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 91320, 
USA 
Telephone Number: 
Email Address: 
Section:  Title Page 
Add: 
Amendment 2 
14 February 2019 
Section:  1 Protocol Synopsis, Rationale 
Delete: 
The goal of this study is to determine the impact of adding ivabradine therapy to the 
standard of care (SOC) in African-American/Black subjects with HF and reduced ejection 
fraction (HFrEF) on changes in heart rate (HR) from baseline (SOC alone).  Changes in 
HR from baseline will be correlated with 
 
, as well as with the changes from 


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baseline in activity level of the subjects, as measured by both a standard 6-minute walk 
distance and an accelerometer device. 
Section:  3.1 Study Rationale 
Delete: 
Changes in HR from baseline will be correlated with 
 
, as well as with the 
changes from baseline in activity level of the subjects, as measured by both a standard 
6-minute walk distance and an accelerometer device. 
Section:  4.1 Objectives and Endpoints, Exploratory Endpoints 
Delete: 
Exploratory 
Section:  5.1 Overall Design, Paragraph 4 
Delete: 


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Section:  9.2.1.3 Medical History 
Delete: 
The Investigator or designee will collect targeted medical cardiovascular disease history, 
genetic history (if available), along with the functional NYHA class history that started 
within 5 years prior to enrollment through screening.   
Section:  10.4.2.2.3 Exploratory Endpoints, Paragraph 1, Bullets 4-5 
Delete: 
Section:  10.4.2.2.3 Exploratory Endpoints, Paragraph 3 
Delete: 
Section:  10.4.2.4 Other Analyses  
Delete: 
10.4.2.4 
Other Analyses 
The exploratory endpoints will be summarized descriptively. 
Section:  Appendix 1, List of Abbreviations and Definitions of Terms 
Add: 
Abbreviation or Term 
Definition/Explanation 
EDC 
electronic data collection 


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Section:  Appendix 3, Data Quality Assurance, Paragraph 10 
Delete: 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the CRF Standard Instructions 
and the CRF Specific Instructions, both of these will be available through the electronic 
data capture (EDC) system.  Examples of obvious data errors that may be corrected by 
Amgen (or designee) include deletion of obvious duplicate data (ie, the same results 
sent twice with the same date with different visit) and updating a specific response if the 
confirming datum is provided in the “other, specify” field (eg, for race, reason for ending 
study). 


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Amendment 1 
Protocol Title:  Open-label, Single-arm Study Assessing the Efficacy and Safety of 
Ivabradine (Corlanor) in African-American/Black Subjects With Heart Failure and 
Left Ventricular Systolic Dysfunction 
 
Amgen Protocol Number 20160231 
 
Amendment Date: 
02 April 2018 
Rationale: 
This protocol is being amended to: 
• 
Change the secondary objective to an exploratory objective 
• 
Clarify that the study will be conducted at 1 to 3 sites 
• 
Clarify that between 30 to 100 subjects will be enrolled in the study 
• 
Update informed consent inclusion criteria 
• 
Clarify genetic background will be collected for a subset of subjects in the studied 
population 
• 
Update the Schedule of Activities table to clarify that 12-lead electrocardiogram will 
be collected during screening 
• 
Clarify that only urine pregnancy test will be utilized 
• 
Clarify that heart rate will be measured during the 6-minute walk test 
• 
Update the clinical laboratory tests that will be performed during the study 
• 
Align end of study definitions with the protocol template language 
• 
Clarify that a subject’s treatment assignment date should be entered on enrollment 
case report form 
• 
Recategorize the accelerometer as a medical device (instead of “other treatment 
procedure”) per protocol template instructions 
• 
Correct typographical and formatting errors throughout the document 


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Description of Changes: 
Section:  Global 
Change:  Replace the date 18 May 2017 to 02 April 2018 
Section:  Global 
Change:  Make administrative updates and editorial corrections (including typographical, 
grammatical, and formatting errors) throughout the document. 
Section:  Global (Title) 
Delete: 
Open-label, Single-arm, Single Center Study Assessing the Efficacy and Safety of 
Ivabradine (Corlanor) in African-American/Black Subjects With Heart Failure and Left 
Ventricular Systolic Dysfunction 
Section:  Title Page 
Add: 
Protocol Date: 
Document Version 
Date 
Original 
18 May 2017 
Amendment 1 
02 April 2018 
Section:  Protocol Synopsis, Rationale 
Add: 
Changes in HR from baseline will be correlated with the genetic background of a subset 
of subjects with available genetic data in the studied population, as well as with the 
changes from baseline in activity level of the subjects, as measured by both a standard 
6-minute walk distance and an accelerometer device. 


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Section:  Protocol Synopsis, Objective(s)/Endpoint(s), Secondary 
Delete: 
Secondary 
• 
Assess association of proportion of 
genetic heritage background in 
African-American/Black subjects with 
HR lowering 
• 
Change in HR from baseline to day 57 
among African-American/Black 
subjects associated with proportion of 
genetic heritage background 
• 
Change in HR from baseline to day 57 
among African-American/Black 
subjects with 85% proportion of 
genetic background and 
African-American/Black subjects with 
< 85% proportion of genetic 
background 
Section:  Protocol Synopsis, Overall Design 
Delete: 
This study is a prospective, single-site, open-label, single-arm intervention study in 
African-American/Black subjects with HFrEF nested in the Henry Ford Heart Failure 
Pharmacogenomics Registry, and will be conducted at the Henry Ford Health System in 
Detroit, MI. 
Section:  Protocol Synopsis, Number of Subjects 
Add: 
Approximately 30 to 100 subjects 
Section:  Protocol Synopsis, Treatments 
Add: 
The starting dose of ivabradine is 5 mg twice daily (BID).  In subjects with a history of 
conduction defects, or in subjects in whom bradycardia could lead to hemodynamic 
compromise, therapy is to be initiated at 2.5 mg BID based on investigator discretion.   
Section:  Protocol Synopsis, Statistical Considerations, Paragraph 1 
Delete: 
This primary analysis will evaluate the effect of ivabradine on HR reduction at day 57 in 
African-American/Black subjects overall (the primary endpoint) as well as within each 
genetic background (secondary endpoints). 


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Section:  Protocol Synopsis, Statistical Considerations, Paragraph 4 
Delete: 
Efficacy analyses of the primary endpoint will test whether the mean reduction with 
ivabradine exceeds 5 bpm, which is the reduction that would be assumed with placebo.  
Summary statistics and least-square means along with 95% confidence interval, 
analyzed by the repeated-measures linear model, will be provided for the primary 
endpoint.  Correlation analyses will be provided between HR reduction and genetic 
background as determined by the proportion of African-American heritage (1 of the 
secondary endpoints).  Summary statistics and least-square means along with 
95% confidence interval, based on the repeated-measures linear model, will be 
summarized for the subgroups based on the proportion of African-American heritage 
with 85% as the cut-off (the other secondary endpoint). 


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Section:  2.2 Schedule of Activities, Table 2-1 and footnotes 
Add: 
Procedure 
Screening 
Period 
Treatment Period (Days) 
Safety Follow-Up Period/ 
Early Termination Visita 
(Phone Contact for  
Safety Follow-up only) 
Screening 
(7 days) 
Day 1 
± 2 days 
Day 15  
± 2 days 
(dose titration 
begins) 
Day 29 
± 2 days 
Day 57 
± 5 
days 
Day 87 or 30 days after the 
last dose of open-label IP 
12-lead ECG 
X 
X 
X 
 
X 
 
6-Minute walk test (6MWT) 
 
X 
 
 
X 
 
Abbreviations:  6MWT = 6-Minute walk test; ECG = electrocardiogram; IP = investigational product 
Section:  2.2 Schedule of Activities, Table 2-1 
Delete: 
Procedure 
Screening 
Period 
Treatment Period (Days) 
Safety Follow-Up Period/ 
Early Termination Visita 
(Phone Contact for  
Safety Follow-up only) 
Screening 
(7 days) 
Day 1 
± 2 days 
Day 15  
± 2 days 
(dose titration 
begins) 
Day 29 
± 2 days 
Day 57 
± 5 
days 
Day 87 or 30 days after the 
last dose of open-label IP 
Investigational producth 
 
X 
X 
X 
X  
Xj 
 


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Section:  3.1 Study Rationale 
Add: 
Changes in HR from baseline will be correlated with the genetic background of a subset 
of subjects with available genetic data in the studied population, as well as with the 
changes from baseline in activity level of the subjects, as measured by both a standard 
6-minute walk distance and an accelerometer device. 
Section:  3.2.2 Amgen Investigational Product Background:  Ivabradine, Paragraph 3 
Replace: 
A detailed description of the chemistry, pharmacology, efficacy, and safety of ivabradine 
is provided in the package insert. 
With: 
A detailed description of the chemistry, pharmacology, efficacy, and safety of ivabradine 
is provided in the Corlanor® (ivabradine) US Prescribing Information. 
Section:  4.1 Objectives and Endpoints, Secondary 
Delete: 
Secondary 
• 
Assess association of proportion of 
genetic heritage background in 
African-American/Black subjects with 
HR lowering 
• 
Change in HR from baseline to day 57 
among African-American/Black 
subjects associated with proportion of 
genetic heritage background 
• 
Change in HR from baseline to day 57 
among African-American/Black 
subjects with 85% proportion of 
genetic background and 
African-American/Black subjects with 
< 85% proportion of genetic 
background 
Section:  4.1 Objectives and Endpoints, Exploratory, Bullet 2 
Replace: 


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With: 
Section:  4.1 Objectives and Endpoints, Exploratory, Bullet 4 
Add: 
Section:  4.1 Objectives and Endpoints, Safety 
Add: 
• 
Evaluate the safety and tolerability of 
ivabradine in African-American/Black 
subjects with HFrEF 
• 
Subject incidence of 
treatment-emergent adverse events 
• 
Vital signs at each scheduled 
assessment 
Section:  5.1 Overall Design, Paragraph 4 
Replace: 
A secondary objective will be to correlate the HR response to ivabradine in this 
population with the proportion of the specific genetic background characteristic of 
African-American/Black subjects. 
With: 
An exploratory objective in a 
 
 
 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  02 April 2018 
Page 8 of 15 
CONFIDENTIAL 
 
 
Section:  5.1 Overall Design, Paragraph 5 
Delete: 
This study is a prospective, single-site, open-label, single-arm intervention study in 
African-American/Black subjects with HFrEF nested in the Henry Ford Heart Failure 
Pharmacogenomics Registry, and will be conducted at the Henry Ford Health System in 
Detroit, MI. 
Section:  5.1 Overall Design, Paragraph 5 
Add: 
Approximately 30 to 100 subjects will be enrolled to receive ivabradine in an open-label 
design. 
Section:  5.1 Overall Design, Paragraph 7 
Add: 
In subjects with a history of conduction defects, or in subjects in whom bradycardia could 
lead to hemodynamic compromise, therapy is to be initiated at 2.5 mg BID, based on 
investigator discretion. 
Section:  5.2.2 Number of Sites 
Replace: 
One investigative site in the US will be included in the study. 
With: 
One to 3 investigative sites in the US will be included in the study. 
Section:  5.3.1 End of Study Definition, Paragraphs 1 and 2 
Replace: 
Primary Completion:  The primary completion date is the same as the end of study date 
and is the date when the last subject has completed the study (ie, last subject last visit). 
With: 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for 
the primary endpoint(s), for the purposes of conducting the primary analysis, 
whether the study concluded as planned in the protocol or was terminated early. 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  02 April 2018 
Page 9 of 15 
CONFIDENTIAL 
 
 
The primary completion date is the date when the last subject has completed the 
assessments for day 57. 
Section:  5.3.1 End of Study Definition, Paragraph 4 
Replace: 
End of Study:  The end of study date is defined as the date when the last subject at the 
site is assessed or receives an intervention for evaluation in the study (ie, last subject 
last visit). 
With: 
End of Study:  The end of study date is defined as the date when the last subject across 
all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, safety follow-up), 
as applicable. 
Section:  5.4 Justification for Investigational Product Dose 
Replace: 
Ivabradine will be initiated at 5 mg BID daily dosing (with option to reduce initial dosing 
to 2.5 mg BID based on investigator discretion), and the dose titration will follow the US 
package insert, as indicated in Table 5-1. 
With: 
Ivabradine will be initiated at 5 mg BID daily dosing (with option to reduce initial dosing 
to 2.5 mg BID based on investigator discretion), and the dose titration will follow the 
Corlanor® (ivabradine) US Prescribing Information, as indicated in Table 5-1. 
Section:  6.1 Inclusion Criteria, Criterion 101 
Replace: 
101 
Subject’s legally acceptable representative has provided informed consent prior 
to any study-specific activities/procedures being initiated when the subject has any kind 
of condition that, in the opinion of the Investigator, may compromise the ability of the 
subject to give written informed consent. 
With: 
101 
Subject has provided informed consent/assent prior to initiation of any 
study-specific activities/procedures. 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  02 April 2018 
Page 10 of 15 
CONFIDENTIAL 
 
 
Section:  7.1.1 Investigational Products, Table 7-1 
Replace: 
After 14 days, tolerability to be assessed as well as resting HR with dose adjustment, as 
recommended in the US package insert. 
With: 
After 14 days, tolerability to be assessed as well as resting HR with dose adjustment, as 
recommended in the Corlanor® (ivabradine) US Prescribing Information. 
Section:  7.1.3 Medical Device, Paragraph 3 (moved original language from 
Section 7.1.5) 
Add: 
Heart rate (HR) during the 6MWT will be measured by an HR monitor at specified time 
points (see Table 2-1 for 6MWT schedules).  An accelerometer will also be used 
throughout the study.  Any adverse events associated with the accelerometer 
(eg, allergic reaction to components of the instrument) will be captured in the Events 
CRF as a procedure-related event.  Data collected from the accelerometer will not be 
available nor reviewed until after the end of the study (ie, last subject, last visit). 
Section:  7.1.5 Other Treatment Procedures 
Replace: 
Heart rate (HR) will be measured by an HR monitor at specified time points (see 
Table 2-1).  An accelerometer will also be used throughout the study.  Note that the 
accelerometer is not considered a medical device and is not manufactured by Amgen.  
Any events associated with the accelerometer (eg, allergic reaction to components of the 
instrument) will be captured as procedure-related events (see Section 9.2.3.1.1.2). 
With: 
There are no other treatment procedures in this study. 
Section:  7.2 Method of Treatment Assignment, Paragraph 2 
Add: 
The treatment assignment date is to be documented in the subject’s medical 
record and on the enrollment CRF. 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  02 April 2018 
Page 11 of 15 
CONFIDENTIAL 
 
 
Section:  7.4.2.1 Amgen Investigational Product:  Ivabradine 
Replace: 
Ivabradine will be initiated at a 5 mg BID dosing (with option to reduce initial dosing to 
2.5 mg BID based on investigator discretion as per US package insert. 
With: 
Ivabradine will be initiated at a 5 mg BID dosing (with option to reduce initial dosing to 
2.5 mg BID based on investigator discretion as per Corlanor® (ivabradine) US 
Prescribing Information. 
Section:  9.2.1.3 Medical History 
Add: 
The Investigator or designee will collect targeted medical cardiovascular disease history, 
genetic history (if available), along with the functional NYHA class history that started 
within 5 years prior to enrollment through screening. 
Section:  9.2.2.3 Accelerometer, Paragraph 2 
Add: 
Data collected from wearable devices will not be available nor reviewed until after 
the end of the study (ie, last subject, last visit). 
Section:  9.2.3.1 Adverse Events 
Delete: 
All adverse events observed by the investigator or reported by the subject that occur 
after first dose of investigational product(s) through the end of study/safety follow-up visit 
or 30 days after the last administration of investigational product are to be 
collected/reported. 
All adverse events related to any study procedures/activities will be collected/ 
recorded/reported after signing the informed consent form through the end of 
study/safety follow-up visit or 30 days after last dose of investigational product 
administration. 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  02 April 2018 
Page 12 of 15 
CONFIDENTIAL 
 
 
Section:  9.2.3.1.1.1 Disease-related Events, Paragraph 2 
Replace: 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
product(s)/study treatment/protocol-required therapies through the end of study/safety 
follow-up visit of 30 days after the last administration of investigational product, are 
reported using the Event CRF.   
With: 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
product(s)/study treatment/protocol-required therapies through the end of study/safety 
follow-up visit or 30 days after the last administration of investigational product, 
whichever is later, are collected/recorded/reported using the Event CRF.   
Section:  9.2.3.1.1.2 Adverse Events, Paragraph 3 
Add: 
All adverse events observed by the investigator or reported by the subject that are 
related to study procedures/study activities will be reported from signing the informed 
consent form through end of study/safety follow-up visit or 30 days after last dose of 
investigational product administration, whichever is later, are to be 
collected/recorded/reported using the Event CRF. 
Section:  9.2.3.1.1.3 Serious Adverse Events, Paragraph 1 
Add: 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the end of study/safety follow-up visit or 30 days after the last 
administration of investigational product, whichever is later, are reported using the 
Event CRF. 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  02 April 2018 
Page 13 of 15 
CONFIDENTIAL 
 
 
Section:  9.2.3.1.1.3 Serious Adverse Events, Paragraph 5 
Delete: 
Hospitalizations and deaths due to chronic heart failure complications are anticipated to 
occur in the enrolled subject population.  The Amgen safety and medical team will 
review accumulating events on a regular basis. 
Section:  9.2.3.1.1.5 Serious Adverse Events, Paragraph 1 (moved from existing 
Section 9.2.3.1.1.3) 
Add: 
Serious adverse events (eg, population-related events) that are not planned to be 
reported individually in an expedited manner as they are anticipated to occur in the study 
population at some frequency independent of the protocol-required therapies are as 
follows:   
Section:  9.2.4.1 Pregnancy Testing, Paragraph 1 
Delete: 
A high sensitive (urine or serum) pregnancy test should be completed at screening and 
within 7 days of initiation of investigational product for females of childbearing potential. 
Section:  10.4.1.2 Primary Analysis 
Delete: 
This primary analysis will evaluate whether the effect of ivabradine on HR reduction at 
day 57 in African-American/Black subjects overall (the primary endpoint) exceeds 
5 bpm, as well as HR reduction at day 57 within each of the genetic background groups 
(secondary endpoints). 
Section:  10.4.2.1 General Considerations, Paragraph 2 
Delete: 
Efficacy analyses of the primary endpoint will test whether the mean reduction with 
ivabradine exceeds 5 bpm, which is the reduction that would be assumed with placebo.  
Summary statistics and least-square means along with 95% confidence interval, 
analyzed by the repeated-measures linear model, will be provided for the primary 
endpoint.  Correlation analyses will be provided between HR reduction and genetic 
background as determined by the proportion of African-American heritage (1 of the 
secondary endpoints).  Summary statistics and least-square means along with 95% 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  02 April 2018 
Page 14 of 15 
CONFIDENTIAL 
 
 
confidence interval, based on the repeated-measures linear model will be summarized 
for the subgroups based on the proportion of African-American heritage with 85% as the 
cut-off (the other secondary endpoint). 
Section:  10.4.2.2.2 Secondary Endpoints 
Replace: 
• 
Change in HR from baseline to day 57 among African-American/Black subjects 
associated with proportion of genetic heritage background 
Correlation analyses will be provided between change in HR from baseline to 
day 57 and proportion of genetic heritage background among African-American/Black 
subjects. 
• 
Change in HR from baseline to day 57 among African-American/Black subjects with 
≥ 85% proportion of genetic background and African-American/Black subjects with 
< 85% proportion of genetic background 
The repeated measures linear model will be used to evaluate ivabradine efficacy on HR 
reduction from baseline to day 57 for subgroups based on the proportion of 
African/American heritage with 85% as the cut-off.  The model will include terms of 
scheduled visits, subgroups based on the proportion of African/American heritage with 
85% as the cut-off, baseline HR measurement, and the interaction of subgroups with 
scheduled visits.  Missing values will not be imputed when the repeated measures linear 
model is used.  Based on the model, the least-square means along with 95% confidence 
interval for each subgroup based on the proportion of African/American heritage with 
85% as the cut-off will be provided.  In addition, descriptive statistics of HR reduction by 
scheduled visit by each subgroup based on the proportion of African/American heritage 
with 85% as the cut-off will be summarized. 
With: 
Not applicable. 
Section:  10.4.2.2.3 Exploratory Endpoints, Bullet 3 
Replace: 
With: 


Product:  Ivabradine 
Protocol Number:  20160231 
Date:  02 April 2018 
Page 15 of 15 
CONFIDENTIAL 
 
 
Section:  10.4.2.2.3 Exploratory Endpoints, Bullet 5 
Add: 
Section:  10.4.2.2.3 Exploratory Endpoints, Paragraph 3 
Add: 
Section:  Appendix 2 Clinical Laboratory Tests, Table 12-1 
Add: 
Local Laboratory Chemistry  
total bilirubin 
Section:  Appendix 2 Clinical Laboratory Tests, Table 12-1 and Footnotes 
Delete: 
Local Laboratory Other Labs 
Urine pregnancy test   
NT-proBNP 
NT-proBNP = N-terminal pro b-type natriuretic peptide 
Section:  Appendix 4 Safety Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting, Recording Adverse Events, Disease-related 
Events (if applicable), and Serious Adverse Events, Bullet point 3, Sub-bullet 4 
Add: 
o Assessment of relatedness to investigational product:  ivabradine, and/or other 
protocol‑required therapies and/or study‑mandated procedure/study mandated 
activity. 

SAP_001.pdf: 
Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 1 of 26 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
Open-label, Single-arm Study Assessing the 
Efficacy and Safety of Ivabradine (Corlanor) in 
African-American/Black Subjects With Heart Failure 
and Left Ventricular Systolic Dysfunction  
Short Protocol Title: 
A Phase 4 Study of Ivabradine in 
African-American/Black Subjects with Heart Failure 
and Left Ventricular Systolic Dysfunction 
Protocol Number: 
20160231 
Authors: 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
SAP Date: 
Document Version 
Original (v[1.0]) 
Date 
26 September 2018 
Amendment 1 (v[2.0]) 
19 April 2019 
NCT Number: NCT03456856 
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 2 of 26 
CONFIDENTIAL 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes, including 
rationale for changes 
Original (v1.0) 
26 September 2018 
 
[Amendment 1 (v2.0)] 
19 April 2019 
• 
Section: Title page 
• 
Update document date to  
19 April 2019. 
• 
Add new study statistician Da 
Geng in the author section.  
• 
Section: Global 
• 
Editorial changes (including 
typographical, grammatical, 
and formatting) have been 
made throughout the 
document. 
• 
Section: 2.1 Objectives and 
Endpoints 
• 
Remove two genetic related 
exploratory endpoints to be 
consistent with protocol. 
• 
Section: 5 Definitions 
• 
Make the following changes 
for the definitions to reflect the 
changes of the activity count 
analysis: 
Remove:  
Baseline activity counts 
Total Number of Minutes 
Spent in Activity Category  
Proportion of Time Spent in 
Activity Category 
Add: 
Total Number of Minutes 
Spent in Sedentary Activity 
Category  
Total Number of Minutes 
Spent in Light Activity 
Category 
Total Number of Minutes 
Spent in Moderate to Very 
Vigorous Activity Category 
Proportion of Time Spent in 
Sedentary Activity Category 
Proportion of Time Spent in 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 3 of 26 
CONFIDENTIAL 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes, including 
rationale for changes 
Proportion of Time Spent in 
Light Activity Category  
Proportion of Time Spent in 
Moderate to Very Vigorous 
Activity Category 
• 
Add the definition of HR for 
6MWT to define how to 
calculate HR for 6 minute walk 
test. 
• 
Section: 8.3 Handling of Missing 
and Incomplete Data  
• 
Add below text and Table 8-1 
to describe imputation rules for 
incomplete dates.  
Add:  
“Adverse event and 
concomitant medication 
with completely or partially 
missing start dates will be 
queried. After the issue is 
queried, if the date is still 
incomplete with year only or 
year and month only, the 
start date will be imputed as 
described in Table 2 below.”   
• 
Section: 9.5.2 Sensitivity Analysis of 
Primary Endpoint(s)  
Adding detailed information for multiple 
imputation in sensitivity analysis: 
• 
Change “A sensitivity 
analysis will be performed 
using multiple imputation to 
impute missing primary 
endpoint.” to “A sensitivity 
analysis will be performed 
using multiple imputation.” 
• 
Add:   
“A sensitivity analysis will 
be performed using multiple 
imputation to impute 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 4 of 26 
CONFIDENTIAL 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes, including 
rationale for changes 
missing primary endpoint. 
The primary analysis model 
will be repeated using FAS 
with missing values 
imputed. Missing values 
from patients who 
discontinued IP will be 
imputed using non-missing 
data from subjects who 
discontinued IP while 
missing values from 
patients who completed IP 
will be imputed using non-
missing data from subjects 
who completed IP, provided 
that there is a sufficient 
number of subjects with 
non-missing endpoint data 
in both groups.” 
• 
Section: 9.5.4 Analyses of 
Exploratory Efficacy Endpoint(s) 
Make the following changes to be 
consistent with protocol: 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 5 of 26 
CONFIDENTIAL 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes, including 
rationale for changes 
• 
Section: 9.5.4 Analyses of 
Exploratory Efficacy Endpoint(s) 
Make the following changes to reflect the 
changes of the activity count analysis: 
• 
Section: 9.5.4 Analyses of 
Exploratory Efficacy Endpoint(s) 
Add detail dose profile groups: 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 6 of 26 
CONFIDENTIAL 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes, including 
rationale for changes 
• 
Section: 10 Changes from 
Protocol-specified Analyses 
• 
Replace “There are no 
changes to the protocol 
specified analyses” with “For 
the endpoint of change in 
activity counts measured 
with an accelerometer from 
baseline to day 57, activity 
counts will not be 
summarized. Instead the 
weekly total number of 
minutes spent and weekly 
proportion of time spent in 
activity categories will be 
summarized, since time 
spent by activity categories 
represent clinical 
meaningful interpretation.” 
• 
Section: Appendix A 
Remove content related to the 
Accelerometer data as it is already defined 
in section 5. 
• 
Change “Analytical Study 
Week Assignments” to 
“Analytical Study Day 
Assignments” 
• 
Change “Handling multiple 
records assigned to an 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 7 of 26 
CONFIDENTIAL 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes, including 
rationale for changes 
analytical study week” to 
“Handling multiple records 
assigned to an analytical 
study day” 
• 
Remove: 
• 
Remove: “For accelerometer, 
the analytical record for the 
scheduled visit is defined as 
the average 7 days prior/on 
the target study day.” 
• 
Section:  Appendix C 
• 
Remove Appendix C.  
Accelerometer (8, 15] 
(22, 29] (50,57] 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 8 of 26 
CONFIDENTIAL 
 
Table of Contents 
Table of Contents ............................................................................................................ 8 
1. 
Introduction ........................................................................................................... 11 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 11 
2.1 
Objectives and Endpoints .......................................................................... 11 
2.2 
Hypotheses and/or Estimations ................................................................. 11 
3. 
Study Overview .................................................................................................... 12 
3.1 
Study Design ............................................................................................. 12 
3.2 
Sample Size .............................................................................................. 13 
4. 
Covariates and Subgroups ................................................................................... 13 
4.1 
Planned Covariates ................................................................................... 13 
4.2 
Subgroups ................................................................................................. 13 
5. 
Definitions ............................................................................................................. 14 
6. 
Analysis Sets ........................................................................................................ 17 
6.1 
Full Analysis Set........................................................................................ 17 
6.2 
Safety Analysis Set ................................................................................... 17 
7. 
Planned Analyses ................................................................................................. 17 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 17 
7.2 
Primary Analysis ....................................................................................... 17 
7.3 
Final Analysis ............................................................................................ 17 
8. 
Data Screening and Acceptance ........................................................................... 17 
8.1 
General Principles ..................................................................................... 17 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 17 
8.3 
Handling of Missing and Incomplete Data ................................................. 17 
8.4 
Detection of Bias ....................................................................................... 18 
8.5 
Outliers ..................................................................................................... 18 
8.6 
Distributional Characteristics ..................................................................... 18 
8.7 
Validation of Statistical Analyses ............................................................... 18 
9. 
Statistical Methods of Analysis.............................................................................. 19 
9.1 
General Considerations ............................................................................. 19 
9.2 
Subject Accountability ............................................................................... 19 
9.3 
Important Protocol Deviations ................................................................... 19 
9.4 
Demographic and Baseline Characteristics ............................................... 20 
9.5 
Efficacy Analyses ...................................................................................... 20 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 20 
9.5.2 
Sensitivity Analysis of Primary Endpoint(s) ................................ 20 
9.5.3 
Analyses of Secondary Efficacy Endpoint(s).............................. 20 
9.5.4 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 20 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 9 of 26 
CONFIDENTIAL 
 
9.6 
Safety Analyses ........................................................................................ 21 
9.6.1 
Analyses of Safety Endpoint(s) .................................................. 21 
9.6.2 
Adverse Events and Disease-related Events ............................. 21 
9.6.3 
Laboratory Test Results ............................................................ 21 
9.6.4 
Vital Signs ................................................................................. 21 
9.6.5 
Physical Measurements ............................................................ 21 
9.6.6 
Electrocardiogram ..................................................................... 22 
9.6.7 
Exposure to Investigational Product .......................................... 22 
9.6.8 
Exposure to Other Protocol-specified Treatment ....................... 22 
9.6.9 
Exposure to Concomitant Medication ........................................ 22 
9.7 
Other Analyses ......................................................................................... 22 
10. 
Changes from Protocol-specified Analyses ........................................................... 22 
11. 
Literature Citations / References ........................................................................... 23 
12. 
Appendices ........................................................................................................... 24 
Appendix A.  Analytical Study Day Assignments ........................................................... 25 
Appendix B.  Common Terminology Criteria for AEs (CTCAE) ...................................... 26 
 
List of Tables 
Table 3-1.  Ivabradine Dose Titration at Day 15 Based on Heart Rate From 
Electrocardiogram .................................................................................. 12 
Table 8-1.  Imputation Rules for Incomplete Dates ........................................................ 18 
 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 10 of 26 
CONFIDENTIAL 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
6MWT 
6-minute walk test 
ACEi 
angiotensin-converting-enzyme inhibitors 
BID 
twice daily 
bpm 
beats per minute 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
End of Study 
The end of study date is defined as the date when the last 
subject at the site is assessed or receives an intervention for 
evaluation in the study (ie, last subject last visit) 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
Enrolled 
A subject is considered enrolled when the investigator decides 
that the subject has met all eligibility criteria 
FAS 
Full analysis set 
HF 
heart failure 
HFrEF 
heart failure and reduced ejection fraction 
HR 
heart rate 
LVEF 
left ventricular ejection fraction 
NYHA 
New York Heart Association 
SAS 
Safety analysis set 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to 
the subject 
 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 11 of 26 
CONFIDENTIAL 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20160231, Ivabradine 
dated 14 February 2019. The scope of this plan includes the primary analysis that is 
planned and will be executed by the Amgen Global Biostatistical Science department 
unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Determine whether ivabradine 
effectively reduces heart rate 
(HR) from baseline to day 57 in 
African-American/Black subjects 
• 
Change in HR from baseline to 
day 57 
 
Exploratory 
Safety 
• 
Evaluate the safety and tolerability 
of ivabradine in 
African-American/Black subjects 
with HFrEF 
• 
Subjects incidence of treatment 
emergent adverse events 
• 
Vital signs at each scheduled 
assessment 
 
2.2 
Hypotheses and/or Estimations 
The primary hypothesis is that ivabradine effectively reduces HR between baseline and 
day 57 in African-American/Black subjects. Because mean reductions of approximately 
5 beat per minute (bpm) have been observed in the overall placebo-treated subjects in 
the SHIFT study as well as in the placebo-treated subjects of the subgroup analysis of 
non-African-American/Black subjects enrolled in the SHIFT study, we will test whether 
the mean reduction with ivabradine exceeds 5 bpm, and estimate the degree to which 
the mean reduction with ivabradine exceeds 5 bpm. 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 12 of 26 
CONFIDENTIAL 
 
3. 
Study Overview 
3.1 
Study Design 
This study is a prospective, open-label, single-arm intervention study in 
African-American/Black subjects with HfrEF. Approximately 30 to 100 subjects will be 
enrolled to receive ivabradine in an open-label design. 
Eligible subjects will include African-American/Black subjects with chronic HFrEF, New 
York Heart Association (NYHA) classes II to IV, with baseline HR ≥ 70 bpm in sinus 
rhythm and an left ventricular ejection fraction (LVEF) ≤ 35% who are on stable 
(≥ 4 weeks) optimal HF therapy, including maximally tolerated dose of β-blockers. 
After signing the informed consent form, subjects will enter a 7-day screening period that 
will allow accurate measurement of baseline activity as measured by the accelerometer 
(which is a non-Amgen, medical device). On day 1, eligible subjects with confirmed sinus 
rhythm and HR ≥ 70 bpm will be enrolled into a 57-day open-label treatment period. The 
starting dose of ivabradine is 5 mg twice daily (BID). In subjects with a history of 
conduction defects, or in subjects in whom bradycardia could lead to hemodynamic 
compromise, therapy is to be initiated at 2.5 mg BID, based on investigator discretion. 
On day 15, the dose will be titrated according to HR as defined in Table 3-1. Ivabradine 
dose levels can be adapted to HR at any clinical visit if necessary. 
Table 3-1.  Ivabradine Dose Titration at Day 15 Based on Heart Rate From 
Electrocardiogram 
 
Initial Dose: 5 mg BID 
Initial Dose: 2.5 mg BID 
HR ≥ 60 bpm 
7.5 mg BID 
5.0 mg BID 
HR ≥ 50 bpm, < 60 bpm 
5.0 mg BID 
2.5 mg BID 
HR < 50 bpm and/or signs or 
symptoms of bradycardia 
2.5 mg BID 
Discontinue therapy 
Abbreviations: BID = twice daily; bpm = beats per minute; HR = heart rate 
The primary efficacy measurement for this study is HR and will be measured at 
Screening, Day 1, Day 15 and Day 57. This study includes the collection of the 
continuous daytime physical activity counts measured by a wearable device 
(accelerometer) from baseline (7-day screening period prior to initiation of ivabradine) 
until the end of the course of the interventional treatment. This device will record 
continuous parameters of physical activity, which will be used for analysis. These data 
will be compared to those obtained by a standard 6MWT (performed at baseline and end 


Product: Ivabradine  
Protocol Number:  20160231 
Date:  19 April 2019 
Page 13 of 26 
CONFIDENTIAL 
 
of treatment). Heart rate response to the standard 6MWT between baseline and end of 
treatment will also be compared with an HR monitor. 
A safety follow-up will be conducted at day 87 or 30 days after the last administration of 
the investigational product. 
3.2 
Sample Size 
A minimum of 30 subjects with up to approximately 100 subjects with HFrEF will be 
enrolled in the study.  
The primary endpoint is HR reduction from baseline at day 57 greater than 5 bpm. 
Based on HR reduction results observed in the overall placebo-treated subjects of the 
SHIFT study as well as in the placebo-treated subjects of the subgroup analysis of 
non-African-American/Black subjects enrolled in the SHIFT study, the mean change HR 
in the ivabradine group was 13 bpm with a standard deviation of 10.4 bpm at end of 
28 days and maintained until end of study. In addition, the mean change in the placebo 
group was 5 bpm observed at end of 28 days, so the hypothesis is to evaluate the HR 
reduction from baseline at day 57 greater than 5 bpm. Based on a 2-sided, 1-sample 
t-test with significance level of 0.05, the planned sample size of 30 to 100 subjects will 
provide approximately 97% to >99% power. The sample size considerations incorporate 
an assumption of a study drop out of 10%. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
• 
Age 
• 
Sex 
• 
Baseline HR 
4.2 
Subgroups 
• 
Age: < 65 years, ≥ 65 years 
• 
Sex 
• 
Baseline HR (< 77 bpm, >= 77 bpm) 
A subgroup variable will be eliminated if one of the two subgroups levels is <10% of 
overall group. 


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5. 
Definitions 
Treatment Emergent Disease-Related Event 
Events categorized as Disease-related Events (DREs) starting on or after first dose of 
investigational product as determined by the flag indicating if the event started prior to 
the first dose on the Events eCRF and up to the EOS/Safety Follow-up visit or 30 days 
after the last administration of investigational product (IP), whichever is earlier. 
Treatment Emergent Adverse Event 
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by the flag indicating if the event started prior to 
the first dose on the Events eCRF and up to the EOS/Safety Follow-up visit or 30 days 
after the last administration of IP, whichever is earlier. 
Treatment Emergent Serious Adverse Event 
Treatment emergent adverse events (as defined above) that are indicated as serious on 
the Events eCRF. 
End of Investigational Product (EOIP) Date  
For each subject, the end of investigational product date is defined as the date recorded 
in the EOIP administration form,   
Last Dose Date  
For each subject, the last dose date is defined as the stop date on the last record of 
administration of IP page.  
End of Study (EOS) Date  
For each subject, the End of Study Date is the date recorded on the End of Study eCRF.  
Baseline 
For all variables, the baseline value is defined as the last non-missing value collected 
prior to or on Study Day 1. 
Change from Baseline 
The arithmetic difference between a post-baseline value and the baseline value:  
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value) 


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Percent change from Baseline 
Percent Change from Baseline = [(Post-baseline Value – Baseline Value) / Baseline 
Value] x 100  
Enrollment Date  
Enrollment Date is defined as the date collected on the Subject Enrollment eCRF.  
Investigational Product (IP) 
The term investigational product is used in reference to Ivabradine. 
Study Day 1 
Day 1 is defined as the day that IP is first administered to the subject. If a subject 
enrolled but never received IP, Study Day 1 is defined as the enrollment day. 
Study Day 
For each subject, and for a given date of interest, Study Day is defined as the number of 
days since Study Day 1:  
Study Day = (date of interest - date of Study Day 1) +1  
If the date of interest is prior to the Study Day 1:  
Study Day = (date of interest – date of Study Day 1), so the day of the first IP dose is 
Study Day 1 and the day prior to the Study Day 1 is Study Day -1. 
IP Exposure in Months  
IP Exposure in Months = [min (last IP dose date + 2 days, EOS Date) – study day 1 + 1]/ 
365.25 ×12 
Study Exposure in Months 
Study Exposure in Months = (EOS date – Enrollment Date + 1)/ 365.25 ×12 


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6. 
Analysis Sets 
6.1 
Full Analysis Set 
Efficacy analyses will be performed on the full analysis set (FAS), which includes all 
enrolled subjects.  
6.2 
Safety Analysis Set 
Safety analyses will be performed on the safety analysis set (SAS), which includes all 
enrolled subjects who receive at least 1 dose of investigational product on study. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis will be conducted in this study. 
7.2 
Primary Analysis 
The primary analysis for this study will be performed when all subjects have either early 
terminated from the study or completed all planned study procedures. At that time, the 
database will be cleaned, processed, locked, and a snapshot will be taken. Based on the 
snapshot of the locked database, efficacy and safety analyses will be performed. 
7.3 
Final Analysis 
Not applicable. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
For efficacy endpoints, where the analysis method is repeated measures linear model 
then missing heart rate measurements will not be imputed. For the sensitivity analysis 
of efficacy HR endpoints, the multiple imputation will be used to impute Day 15 and 
Day 57 missing heart rate measurements.    
Adverse event and concomitant medication with completely or partially missing 
start dates will be queried. After the issue is queried, if the date is still incomplete 


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with year only or year and month only, the start date will be imputed as described 
in Table 8-1 below. 
Table 8-1.  Imputation Rules for Incomplete Dates 
Start date (AE 
and 
concomitant 
medication) 
Missing 
Imputation 
Exception 
Day 
1 
Default to Study Day 1 if an event starts 
the same year and month as Study Day 1 
Day / Month 
1-Jan 
Default to Study Day 1 if an event started 
the same year as Study Day 1 
Missing data will not be imputed for safety endpoints. 
8.4 
Detection of Bias 
Factors that may bias the results of the study are major protocol deviations likely to 
impact the analysis and interpretation of the endpoints.  Important protocol deviations 
likely to impact the analysis and interpretation of the endpoints will be tabulated in the 
Clinical Study Report (CSR).   
If any sensitivity analyses are required to evaluate potential biases in the study’s 
conclusions, the sources of the potential biases and results of the sensitivity analyses 
will be documented in the CSR. 
8.5 
Outliers 
Various methods, including univariate summaries, histograms, scatter plots, box plots, 
and line graphs, may be used to identify outliers in key variables. The primary analysis 
will include outliers in the data. Sensitivity analyses may be undertaken if extreme 
outliers for a variable are observed. 
8.6 
Distributional Characteristics 
If the distributional assumptions are not met, then alternative methods will be utilized. 
The use of alternative methods will be fully justified in the CSR. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  Tables, figures, and listings will be 
produced with validated standard macro programs where standard macros can produce 
the specified outputs.   


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The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
For efficacy endpoints, where the analysis method is repeated measures linear effects 
model then missing heart rate measurements will not be imputed. For the sensitivity 
analysis of efficacy HR endpoints, multiple imputation will be used to impute Day 15 and 
Day 57 missing heart rate measurements.  
Missing data will not be imputed for safety endpoints. 
Subject disposition, demographics, baseline characteristics, medical history, baseline 
concomitant medications, and exposure to investigational product will be summarized. 
Continuous variables will be summarized with descriptive statistics, including the number 
of subjects (n), mean, standard deviation or standard error, median, the first quartile and 
third quartile, minimum, and maximum. Frequency and percentage will be given for 
categorical variables. 
9.2 
Subject Accountability 
The number and percent of subjects enrolled who received, completed and discontinued 
from IP (including reasons for discontinuing), completed and discontinued the study 
(including reasons for discontinuing) will be summarized.  
The number of subjects included in and excluded from each analysis set will be 
summarized. 
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 


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9.4 
Demographic and Baseline Characteristics 
Demographics data including sex, age, race, and ethnicity, baseline characteristics, 
medical history, and baseline concomitant medications will be summarized. 
9.5 
Efficacy Analyses 
HR reduction from baseline to day 57 will be estimated from a repeated measures linear 
model. Summary statistics will be provided for exploratory endpoints. 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
The repeated measures linear model will be used to evaluate ivabradine efficacy on HR 
reduction from baseline to day 57 for subjects in FAS regardless of treatment 
adherence. The model will include terms of scheduled visits and baseline HR 
measurement as covariates and test whether the mean reduction with ivabradine 
exceeds 5 bpm, a reduction assumed with placebo. Missing values will not be imputed 
when the repeated measures linear model is used. Based on the model, the 
least-square means along with 95% confidence interval will be provided. Descriptive 
statistics of HR reduction by scheduled visit will also be summarized. 
In addition, the primary endpoint will be analyzed within each of the subgroups (indicated 
in Section 4.2) using the same methodology as the primary endpoint based on the FAS 
of the treatment period.  
9.5.2 
Sensitivity Analysis of Primary Endpoint(s) 
To evaluate the robustness of the analysis results, sensitivity analyses will be performed 
as follows:   
• 
A sensitivity analysis will be performed using multiple imputation. The primary 
analysis model will be repeated using FAS with missing values imputed. 
Missing values from patients who discontinued IP will be imputed using 
non-missing data from subjects who discontinued IP while missing values 
from patients who completed IP will be imputed using non-missing data 
from subjects who completed IP, provided that there is a sufficient number 
of subjects with non-missing endpoint data in both groups. 
• 
Analysis of covariance (ANCOVA) will be performed for day 57 data using 
covariates (described in Section 4.1) in the same model 
9.5.3 
Analyses of Secondary Efficacy Endpoint(s) 
Not applicable. 
9.5.4 
Analyses of Exploratory Efficacy Endpoint(s) 


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9.6 
Safety Analyses 
9.6.1 
Analyses of Safety Endpoint(s) 
Treatment emergent adverse events and disease-related events will be summarized. 
9.6.2 
Adverse Events and Disease-related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or later will be 
used to code all events categorized as adverse events and disease-related events to a 
system organ class and a preferred term. 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0 or later. 
Subject incidence of all treatment emergent adverse events will be tabulated by system 
organ class and preferred term. Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product will be provided.  
Significant treatment emergent adverse events (if applicable) will also be provided.  
Subject incidence of treatment emergent disease-related events and fatal 
disease-related events will also be tabulated by system organ class and preferred term. 
9.6.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at baseline. 
9.6.4 
Vital Signs 
The analyses of vital signs including systolic blood pressure and diastolic blood 
pressure, and HR will be summarized using descriptive statistics at each scheduled visit. 
9.6.5 
Physical Measurements 
The analyses of height and weight measurements will include summary statistics at 
baseline. 


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9.6.6 
Electrocardiogram 
All ECG measurements will be summarized using descriptive statistics at each 
scheduled visit. In addition, the change in HR from baseline will be summarized at each 
scheduled post-baseline visit (day 15 and 57). 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QT interval corrected (QTc) effect.  Because these evaluations 
may not necessarily be performed under the rigorous conditions expected to lead to 
meaningful evaluation of QTc data; neither summaries nor statistical analyses will be 
provided, and these data would not be expected to be useful for meta-analysis with data 
from other trials.  
9.6.7 
Exposure to Investigational Product 
Descriptive statistics will be provided to describe the exposure to investigational product 
by visit. Dosage adjustments will also be summarized.   
9.6.8 
Exposure to Other Protocol-specified Treatment 
Not applicable.  
9.6.9 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving medication of interest, including but not 
limited to β-blockers, ACEi, and angiotensin II receptor blockers, will be summarized by 
preferred term or category as coded by the World Health Organization Drug (WHO 
DRUG) dictionary (version March 1, 2017 or later). 
9.7 
Other Analyses 
Not applicable. 
10. 
Changes from Protocol-specified Analyses 
For the endpoint of change in activity counts measured with an accelerometer 
from baseline to day 57, activity counts will not be summarized. Instead the 
weekly total number of minutes spent and weekly proportion of time spent in 
activity categories will be summarized, since time spent by activity categories 
represent clinical meaningful interpretation. 


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11. 
Literature Citations / References 
Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart 
failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885. 
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management 
of heart failure: a report of the American College of Cardiology Foundation/American 
Heart Association Task Force on practice guidelines. Circulation. 2013;128:e240-327. 


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12. 
Appendices 


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Appendix A.  Analytical Study Day Assignments 
Selected endpoints will be summarized by scheduled study visits in descriptive analyses. 
Since the actual visits may not exactly coincide with their scheduled visit day, the actual 
visit day is mapped to the study visit generally by non-overlapping consecutive intervals 
covering the entire time continuum. The mapping intervals for all distinct schedules are 
summarized in the following table. 
Handling multiple records assigned to an analytical study day: 
Scheduled Visit Day 
Day 15  
Day 29  
Day 57  
Target Study Day 
15 
29 
57 
Vital signs 
(1, 22] 
(22, 43] 
>43 
12-lead ECG 
(1, 36] 
 
>36 
6-Minute walk test 
 
 
>1 
If there is more than one record in a given analytical window, the analytical record for 
that scheduled visit will be defined as the record closest to target study day for that 
scheduled visit. If two records are equidistant from the scheduled visit day, then the 
earlier record will be chosen. If there are multiple records on the same day, the last 
record will be used.  


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Appendix B.  Common Terminology Criteria for AEs (CTCAE) 
Refer to the NCI Common Terminology Criteria for AEs (CTCAE) Version 5.0, published: 
November 27, 2017 for AE and lab shift grading and information.  The CTCAE is 
available at the following link: http://evs.nci.nih.gov/ftp1/CTCAE/About.html