Clinical trial NCT02827500
Conditions: Heart Failure
Sponsor: Duke University
Start date: 2016-07-01; Completion date: 2018-10-15
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The PRIME-HF study is a multi-center, patient-level, randomized, open-label study of approximately 450 patients with reduced (left ventricular ejection fraction) LVEF of ≤ 35% and heart-rate ≥70 beats per minute (bpm) who are being discharged from the hospital following stabilization from acute heart failure (HF)(primary or secondary) and will be randomized to a treatment strategy of predischarge initiation of ivabradine or usual care.

All participants should have a follow-up visit within 7-14 days of hospital discharge. Heart rate and systolic blood pressure will be assessed at this clinical visit. For participants randomized to predischarge initiation of ivabradine and on ivabradine 5mg BID, the heart rate may be used to adjust the dose the dose to 2.5mg BID or 7.5mg BID. For participants randomized to usual care, ivabradine may be initiated at the provider's discretion. All participants will have a second follow-up study visit 6 weeks (42 +/- 14 days) post-discharge. Heart rate, systolic blood pressure and quality of life (KCCQ and PGA) will be assessed. For participants already taking ivabradine in either treatment group, the heart rate may again be used to adjust the dose of ivabradine. For participants not yet receiving ivabradine, it may be initiated at the provider's discretion. All participants will receive a 90 (+/-7) day post-discharge phone call by site to assess for event status and tolerability of ivabradine. All participants will have a final study visit at 180 (+/-14) days post-discharge. Heart rate, systolic blood pressure and quality of life (Kansas City Cardiomyopathy Questionnaire and Patient Global Assessment) will be assessed. The attending physician may initiate ivabradine per usual care clinical practice.

The primary hypothesis of the PRIME-HF study is that, compared with usual care, a treatment strategy of initiation of ivabradine prior to discharge for a hospitalization with acute HF will be associated with a greater proportion of participants using ivabradine at 180 days. Secondary objectives are to assess the impact of predischarge initiation of ivabradine on:Heart Rate (Change in heart rate from baseline to 180 days and Median heart rate at 180 days) and Patient-Centered Outcomes (Kansas City Cardiomyopathy Questionnaire (KCCQ) and Patient Global Assessment (PGA)). Tertiary objectives will be to explore the impact of predischarge initiation of ivabradine on other assessments of evidence-based implementation of ivabradine and beta-blockers at 180 days. Evaluations will incorporate data based on whether or not indication status was retained and whether or not an ivabradine prescription was provided. Tolerability of ivabradine and adverse events during study follow-up.

Detailed description:
* Purpose of the study The primary hypothesis of the PRIME-HF study is that, compared with usual care, a treatment strategy of initiation of ivabradine prior to discharge for a hospitalization with acute HF (primary or secondary) will be associated with a greater proportion of participants using ivabradine at 180 days. Secondary objectives are to assess the impact of predischarge initiation of ivabradine on:Heart Rate (Change in heart rate from baseline to 180 days and Median heart rate at 180 days) and Patient-Centered Outcomes (Kansas City Cardiomyopathy Questionnaire (KCCQ) and Patient Global Assessment (PGA)). Tertiary objectives will be to explore the impact of predischarge initiation of ivabradine on other assessments of evidence-based implementation of ivabradine and beta-blockers at 180 days. Evaluations will incorporate data based on whether or not indication status was retained and whether or not an ivabradine prescription was provided. Tolerability of ivabradine and adverse events during study follow-up will be assessed. Barriers to acquisition of ivabradine will be explored.
* Background \& significance Heart failure is a major public health issue. More than 5 million Americans have HF and the prevalence is expected to increase as the population ages and survival from coronary, hypertensive, and valvular heart disease improves. Data from randomized clinical trials have established the efficacy of a number of medical and device therapies for patients with chronic Heart failure with reduced ejection fraction (HFrEF), but patient outcomes remain poor, especially after a hospitalization for heart failure. The 1-year mortality rate after a HF hospitalization is 20-30%, and this number has been relatively unchanged over the past decade. These data suggest that there is an unmet need for novel treatment strategies and supports the assessment of new approaches in the post-acute HF setting.

There is also wide variation in the implementation of clinical trial evidence into routine practice. Previous data highlight a multi-year gap between the generation of new evidence through clinical trials and the adoption of the data into routine clinical practice. This gap in care translates into many unnecessary deaths and hospitalizations each year for patients with HFrEF. While there are multiple reasons for this quality gap, clinical inertia has most often been noted as a major barrier. Ivabradine have been approved for use in Europe for several years for patients with symptomatic chronic HFrEF (LVEF \<35%) and a heart rate \>75 bpm on guideline-directed medical therapy (or intolerance/contra-indication to beta-blocker use). Ivabradine was recently approved for use in the United States. However, no US data exist regarding the potential adoption of ivabradine into routine clinical care.

Since ivabradine is a newly approved drug, this study also serves as a strategy trial to challenge study sites to explore drug acquisition for a drug that has been proven efficacious to the heart failure population and has been added to 2016 ACC/AHA/HFSA guidelines, however, has not been adopted rapidly into clinical practice. Ivabradine is not being provided for this study. Data are being captured to assess the number of subjects who were able to obtain ivabradine pre and post discharge as well as the barriers to acquisition.

Previous data for patients with HFrEF suggest that the hospital setting may provide a unique opportunity for patients to initiate guideline-directed medical therapy. In the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in HF (IMPACT-HF) study, patients with an LVEF\<40% hospitalized for HF that were started on carvedilol prior to hospital discharge were more likely to be on a beta-blocker at 60 days post-randomization compared to those receiving usual care. These improvements in care were achieved without increasing side effects or index hospitalization length of stay. Similar to beta-blockers and other medical therapies for HF, ivabradine was initially studied in patients with chronic HF. The initiation of ivabradine specifically in patients following stabilization for acute HF has not been evaluated.

• Design \& procedures The PRIME-HF study is a multi-center, patient-level, randomized, open-label study of approximately 450 patients with reduced LVEF of ≤35% and heart-rate ≥70 bpm who are being discharged from the hospital following stabilization from acute HF and will be randomized to a treatment strategy of predischarge initiation of ivabradine or usual care.

All participants should have a follow-up visit within 7-14 days of hospital discharge. Heart rate and systolic blood pressure will be assessed at this clinical visit. For participants randomized to predischarge initiation of ivabradine and on ivabradine 5mg BID, the heart rate may be used to adjust the dose the dose to 2.5mg BID or 7.5mg BID. For participants randomized to usual care, ivabradine may be initiated at the provider's discretion. All participants will have a second follow-up study visit 6 weeks (42 +/- 14 days) post-discharge. Heart rate, systolic blood pressure and quality of life (KCCQ and PGA) will be assessed. For participants already taking ivabradine in either treatment group, the heart rate may again be used to adjust the dose of ivabradine. For participants not yet receiving ivabradine, it may be initiated at the provider's discretion. All participants will receive a 90 (+/-7) day post-discharge phone call by site to assess for event status and tolerability of ivabradine. All participants will have a final study visit at 180 (+/-14) days post-discharge. Heart rate, systolic blood pressure and quality of life (KCCQ and PGA) will be assessed. The attending physician may initiate ivabradine per usual care clinical practice.

Arms: arm 1: Active Comparator: ivabradine arm 2: Placebo Comparator: usual care
Interventions: intervention 1: ivabradine intervention 2: Usual Care
Intervention descriptions: intervention 1: Active Comparator: ivabradine intervention 2: Placebo Comparator: usual care

Protocol documents:
Prot_000.pdf: 
Amgen Proprietary - Confidential
PRIME-HF 
Confidential 
Version 3 – July 19, 2017 
1
PredischaRge Initiation of Ivabradine in the Management of 
Heart Failure (PRIME-HF)  
Date: July 19, 2017 
Version: 3 
NCT02827500
Principal Investigator: Robert J. Mentz, MD 
Duke Clinical Research Institute 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the property or under control of DUKE CLINICAL 
RESEARCH INSTITUTE (DCRI) and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Institutional Review Board or 
Independent Ethics Committee.  The information is only to be used by you in connection with the clinical 


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study described in the protocol.  You will not disclose any of the information to others without written 
authorization from DCRI. 
 
 
 
 
Protocol Version and Amendment Tracking 
Version Number/Amendment 
Approval Date 
 
 
Version 1  
May 2, 2016 
Version 2 
June 29, 2016 
Version 3 
July 19, 2017 
 
 
 
 
 


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Protocol Synopsis 
Name of Study Sponsor 
Dr. Robert Mentz, Duke Clinical Research Institute 
Product 
Ivabradine 
Protocol Title 
Predischarge Initiation of Ivabradine in the Management of 
Heart Failure 
Main Criteria for Inclusion 
Acute HF hospitalization 
Study Objective 
To test the primary hypothesis that, compared with usual care, 
a treatment strategy of initiation of ivabradine prior to 
discharge for a hospitalization for acute HF will result in a 
greater proportion of participants using ivabradine at 180 days. 
To explore barriers to acquisition of new HF therapies in 
routine clinical practice.   
Study Design 
A multi-center, patient-level, randomized, open-label study of 
180 days duration following index hospitalization in 
approximately 450 patients.  
Treatment Regimen 
Pre-discharge initiation of twice-daily oral ivabradine (starting 
at 5mg BID with encouraged dose titration to 7.5mg BID) 
versus usual care (i.e., post-discharge initiation of ivabradine at 
discretion of routine physician) for 180 days. Patients 
randomized to pre-discharge ivabradine who are not able to 
afford medication will enter a registry of ivabradine-eligible 
paitents with documentation of medication acquisition 
challenges. 
Duration of Study Participation 
180 days 
Number of Subjects 
Approximately 450 
Number of Sites 
Approximately 50 US 
Primary Endpoint 
Proportion of participants taking ivabradine at 180 days 
Secondary Endpoints 
Heart Rate Assessments: change in heart rate from baseline to 
180 days; heart rate at 180 days; and proportion of patients 
with heart rate < 70 bpm at 180 days 


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Name of Study Sponsor 
Dr. Robert Mentz, Duke Clinical Research Institute 
Product 
Ivabradine 
Changes in symptoms and quality of life from baseline to 180 
days by KCCQ and PGA 
 
 
 


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Table of Contents 
 
Protocol Version and Amendment Tracking ...................................................................2 
Protocol Synopsis..........................................................................................................3 
Table of Contents ..........................................................................................................5 
Abbreviations................................................................................................................9 
Executive Summary .................................................................................................... 10 
1 
Introduction ..................................................................................................... 16 
1.1 
Background .......................................................................................... 16 
1.2 
Prior data.............................................................................................. 17 
1.3 
Rationale .............................................................................................. 18 
2 
Objectives........................................................................................................ 19 
2.1 
Primary Objective ................................................................................. 19 
2.2 
Secondary Objectives............................................................................ 19 
2.3 
Tertiary Objectives ............................................................................... 19 
3 
Subject Selection ............................................................................................. 21 
3.1 
Study Population .................................................................................. 21 
3.2 
Inclusion Criteria .................................................................................. 21 
3.3 
Exclusion Criteria ................................................................................. 22 
4 
Study Design ................................................................................................... 24 
4.1 
Overview of Study ................................................................................ 24 
4.2 
Screening Phase.................................................................................... 24 
4.3 
Clinical Evaluation Prior to Randomization ........................................... 24 


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4.4 
Randomization ..................................................................................... 25 
Figure 1. Study Flow Diagram ..................................................................................... 26 
 
26 
Figure 2. Schematic of Study Design ........................................................................... 27 
4.5 
Treatment Arms.................................................................................... 27 
4.6 
Patient Safety and Concomitant Medical Therapy .................................. 27 
5 
Study Procedures ............................................................................................. 29 
5.1 
Screening and Prerandomization Procedures .......................................... 29 
5.2 
Baseline Evaluations ............................................................................. 29 
5.3 
Treatment Intervention.......................................................................... 29 
5.4 
Follow-up Evaluations .......................................................................... 30 
5.4.1 
Clinical Follow-up Visit (Study Visit 1) .................................. 30 
Table 1. Recommended Dose Adjustments for Patients Taking Ivabradine  .................... 30 
5.4.2 
Clinical Follow-up Visit (Study Visit 2) .................................. 30 
5.4.3 
Phone Call.............................................................................. 31 
5.4.4 
Final Study Visit (Study Visit 3) ............................................. 31 
5.5 
Schedule of Assessments ...................................................................... 33 
6 
Enrollment and Randomization......................................................................... 34 
6.1 
Enrollment............................................................................................ 34 
6.2 
Randomization ..................................................................................... 34 
7 
Participant safety ............................................................................................. 35 
7.1 
Patient Safety and Concomitant Therapies ............................................. 35 
7.2 
Institutional Review Boards .................................................................. 35 
7.3 
Informed Consent ................................................................................. 35 
7.4 
Study Discontinuation........................................................................... 35 


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8 
Adverse Event Reporting and Follow-up........................................................... 37 
8.1 
Safety ................................................................................................... 37 
8.2 
Definitions............................................................................................ 37 
8.2.1 
Events of Interest.................................................................... 37 
8.3 
Protocol Specific Exceptions to SAE Reporting ..................................... 38 
8.3.1 
Suspected Adverse Reaction ................................................... 38 
8.4 
Assessment of Adverse Event Severity .................................................. 39 
8.5 
Assessment of Causal Relationship........................................................ 39 
8.6 
Expectedness ........................................................................................ 40 
8.7 
Adverse Event Reporting ...................................................................... 40 
8.8 
Serious Adverse Events......................................................................... 40 
8.9 
Pregnancy............................................................................................. 41 
8.10 
Withdrawal of Subjects from Study ....................................................... 41 
9 
Summary of clinical events .............................................................................. 42 
10 
Statistical Analysis Plan and Determination of Sample Size............................... 43 
10.1 
Overview.............................................................................................. 43 
10.2 
Sample Size Justification ...................................................................... 43 
10.3 
Analysis of the Primary Endpoint .......................................................... 44 
10.4 
Analysis of Secondary and Tertiary Endpoints ....................................... 44 
10.5 
Interim Analyses................................................................................... 45 
11 
Data Monitoring and Quality Control................................................................ 46 
11.1 
Required Data....................................................................................... 46 
11.2 
Data Collection and Tracking ................................................................ 46 
12 
Study Responsibilities ...................................................................................... 48 
12.1 
Investigator Responsibility/Performance................................................ 48 
12.2 
Study Data Reporting and Processing .................................................... 48 
12.3 
Training ............................................................................................... 48 


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12.4 
Monitoring the Investigational Sites ...................................................... 49 
12.5 
Study Documentation............................................................................ 50 
12.6 
Source Documentation .......................................................................... 50 
12.7 
Protocol Deviations .............................................................................. 52 
12.8 
Data Transmittal and Record Retention ................................................. 52 
12.9 
Study Closeout ..................................................................................... 53 
12.10 Audit/Inspections.................................................................................. 53 
12.11 Publication Policies .............................................................................. 53 
13 
Ethical Considerations...................................................................................... 54 
13.1 
Informed Consent ................................................................................. 54 
13.2 
Confidentiality of Subjects .................................................................... 54 
13.3 
Authorization for Use and Disclosure of Protected Health Information 
(HIPAA) .............................................................................................. 55 
13.4 
Human Subject Protections ................................................................... 55 
13.4.1 
Research Subject Selection and Justification of Exclusions ...... 55 
13.4.2 
Risks/Discomforts of Study Participation ................................ 55 
13.5 
Institutional Review Board/Ethics Committee Review ........................... 55 
13.6 
Steering Committee .............................................................................. 56 
13.7 
Data and Safety Monitoring Board ........................................................ 56 
14 
Appendices ...................................................................................................... 57 
Appendix A. Safety Considerations.............................................................................. 57 
Appendix B. Cardiomyopathy Questionnaire and Patient Global Assessment ................ 58 
References .................................................................................................................. 59 
 
 
 


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Abbreviations 
bpm 
Beats per minute 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
HF 
Heart Failure 
HFrEF 
Heart failure with reduced ejection fraction 
IRB 
Institutional Review Board 
IV 
Intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LVEF 
Left Ventricular ejection fraction 
NYHA 
New York Heart Association 
PGA 
Patient Global Assessment 
 
 
 
 
 
 
 


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Executive Summary 
Title 
PredischaRge initiation of Ivabradine in ManagEment of Heart Failure (PRIME-
HF) 
Patient 
Population 
Post-Acute Heart Failure Syndrome with left ventricular ejection fraction (LVEF) 
<35%, New York Heart Association (NYHA) class II-IV symptoms despite 
guideline-directed medical therapy, documented clinical stability, and sinus rhythm 
with a resting heart rate of >70 beats per minute (bpm).  
Location 
Approximately 50 clinical centers in the United States 
Brief Rationale 
Heart failure (HF) affects over 5 million adults in the United States alone and the 
prevalence is expected to increase.1 Despite promising advances in the treatment of 
chronic heart failure with reduced ejection fraction (HFrEF),2 patient outcomes 
remain poor, especially after a hospitalization for HF, and there is an unmet need for 
novel treatment strategies. Previous data also suggest that the hospital setting may 
provide a unique opportunity for patients with HF to initiate guideline-directed 
medical therapy.3 
Ivabradine is an orally available, specific inhibitor of the If current in the sinoatrial 
node recently approved for use for patients with HFrEF by the Food and Drug 
Administration. A double-blind, randomized, placebo-controlled trial demonstrated 
that heart-rate reduction with ivabradine improves clinical outcomes for patients with 
chronic, symptomatic HF.4 The initiation of ivabradine specifically in patients 
following stabilization for acute HF has not been evaluated. 
Since ivabradine was FDA approved relatively recently, this study also serves as a 
strategy trial to explore drug acquisition for a drug that has been proven efficacious 
to the heart failure population and has been added to 2016 ACC/AHA/HFSA 


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guidelines, however, has not been adopted broadly into clinical practice. Ivabradine 
is not being provided for this study. Data are being captured to assess the number of 
subjects able to obtain ivabradine pre and post discharge as well as the barriers to 
obtaining ivabradine and reasons for non-initiation. 
Study Design 
A multi-center, patient-level, randomized, open-label study of 180 days duration 
following index hospitalization in approximately 450 patients. Given barriers to 
adoption of relatively novel therapeutics into clinical practice, those patients who are 
randomized to pre-discharge ivabradine but are not able to afford medication will 
enter a registry of ivabradine-eligible patients with documentation of the medication 
acquisition challenges experienced by the patient and provider. 
Treatment 
Pre-discharge initiation of twice-daily oral ivabradine (starting at 5mg BID with 
encouraged dose titration to 7.5mg BID) versus usual care (i.e., post-discharge 
initiation of ivabradine at discretion of routine physician) for 180 days.  
Primary 
Objective 
To test the primary hypothesis that, compared with usual care, a treatment strategy of 
initiation of ivabradine prior to discharge for a hospitalization for acute HF will be 
associated with a greater proportion of participants using ivabradine at 180 days.  
Secondary 
Objectives 
To assess the impact of predischarge initiation of ivabradine on: 
1) Heart Rate 
a) Change in heart rate from baseline to 180 days 
b) Median heart rate at 180 days 
2) Patient-Centered Outcomes  
a) Kansas City Cardiomyopathy Questionnaire  (KCCQ) 
b) Patient Global Assessment (PGA) 
Tertiary 
Objectives 
To explore the impact of predischarge initiation of ivabradine on: 
1) Evidence-Based Implementation 
a) Assessments of beta-blocker use at 180 days (e.g., proportion on beta-
blocker, proportion on target dose, mean change in dose) 


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b) Other assessments of ivabradine use at 180 days (e.g., mean dose, proportion 
with any initiation, proportion on maximum dose) 
i) Evaluations will incorporate data based on whether or not indication 
status was retained and whether or not an ivabradine prescription was 
provided. 
2) Tolerability of ivabradine and events of interest 
a) Symptomatic bradycardia 
b) Symptomatic hypotension 
c) Other symptoms leading to ivabradine discontinuation 
To explore barriers to ivabradine acquisition in routine clinical practice. 
Summary of 
Clinical Events 
1) Worsening HF defined as hospital admission for worsening signs and/or 
symptoms of HF or receiving unplanned intravenous (IV) diuretics for HF as an 
outpatient 
2) All-cause mortality 
Primary 
Endpoint 
Proportion of participants taking ivabradine at 180 days. 
Secondary 
Endpoints 
1) Heart Rate Assessments 
a) Change in heart rate from baseline to 180 days 
b) Heart rate at 180 days 
c) Proportion of patients with heart rate <70bpm at 180 days 
2) Changes in symptoms and quality of life from baseline to 180 days as assessed 
by: 
a) KCCQ 
b) PGA 
Tertiary 
Endpoints 
1) Beta-blocker use at 180 days as assessed by the (a) proportion of participants on 
a beta-blocker at 180-days, (b) proportion on target dose, (c) the proportion 


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discontinuing beta-blockers at 180 days and (d) the mean change in beta-blocker 
dose from discharge to 180 days 
2) Ivabradine use at 180 days as assessed by the (a) proportion of appropriate 
participants with any initiation of ivabradine at 180 days, (b) the proportion of 
appropriate participants at the maximum dose of ivabradine at 180 day (i.e., 7.5 
mg twice daily), and (c) the mean dose of ivabradine achieved at 180 days 
3) Tolerability of ivabradine and events of interest: 
a) Symptomatic bradycardia 
b) Symptomatic hypotension 
c) Other symptoms leading to ivabradine discontinuation  
4) Summary of barriers to acquisition of ivabradine. 
Summary of 
Clinical Events 
1) Worsening HF defined as hospital admission for worsening signs and/or 
symptoms of HF or receiving unplanned intravenous (IV) diuretics for HF as an 
outpatient 
2) All-cause mortality 
Abbreviated 
Study Flow 
1) Patients with a reduced LVEF (<35%) will be identified during a hospitalization 
with acute HF. Patients will be screened throughout the hospital stay though 
heart rate will specifically be assessed following stabilization. 
2) Prior to discharge, clinical stability will be assessed including blood pressure and 
heart rate criteria. Patients with a pre-discharge blood pressure of >90/50 mm Hg 
and heart rate > 70 bpm will be eligible and consent will be obtained. Subject 
should not have a planned/scheduled up-titration of beta-blocker in the following 
4 weeks. However, adjustments of background therapy can be made at any point 
during the study period at the discretion of the treating physician. Patients can be 
consented and randomized prior to the day of discharge as long as they meet 
entry criteria. 


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3) Consented patients will undergo baseline examination, KCCQ, and PGA. 
Baseline heart rate will be assessed on at least one 12-lead ECG (screening ECG 
may be used). 
4) Participants will then be randomized to predischarge initiation of ivabradine or 
usual care. Randomization will be stratified by clinical site.  
5) Participants randomized to predischarge initiation of ivabradine should receive at 
least the initial dose of 5mg BID prior to discharge from the hospital if possible. 
6) If the patient is randomized to pre-discharge initiation, the study team and/or 
inpatient care team (e.g., providers and care coordinator) should initiate the 
process to acquire outpatient medication, explore patient costs and consider 
support options for the patient. If the patient is not able to pay for the medication, 
they will continue in the study and will enter a registry of ivabradine-eligible 
patients with documentation of the medication acquisition challenges 
experienced by the patient and provider. 
7) Consistent with current HF guidelines,2 all participants should have a follow-up 
visit within 7-14 days of hospital discharge. Heart rate and systolic blood 
pressure will be assessed at this clinical visit. For participants randomized to 
predischarge initiation of ivabradine and on ivabradine 5mg BID,  the heart rate 
may be used to adjust the dose the dose to 2.5mg BID or 7.5mg BID. For 
participants randomized to usual care, ivabradine may be initiated at the 
provider’s discretion. 
8) All participants will have a second follow-up study visit 6 weeks (42 +/- 14 days) 
post-discharge. Heart rate, systolic blood pressure and quality of life (KCCQ and 
PGA) will be assessed. For participants already taking ivabradine in either 
treatment group, the heart rate may again be used to adjust the dose of 
ivabradine. For participants not yet receiving ivabradine, it may be initiated at the 
provider’s discretion.  
9) All participants will receive a 90 (+/-7) day post-discharge phone call by site to 
assess for event status and tolerability of ivabradine. 


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10) All participants will have a final study visit at 180 (+/-14) days post-discharge. 
Heart rate (on exam and 1 ECG), systolic blood pressure and quality of life 
(KCCQ and PGA) will be assessed. The treating physician may initiate 
ivabradine per usual care clinical practice.  


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1 
INTRODUCTION 
1.1 
Background 
Heart failure is a major public health issue. More than 5 million Americans have HF and 
the prevalence is expected to increase as the population ages and survival from coronary, 
hypertensive, and valvular heart disease improves.1,5 Data from randomized clinical trials 
have established the efficacy of a number of medical and device therapies for patients 
with chronic HFrEF,2 but patient outcomes remain poor, especially after a hospitalization 
for heart failure. The 1-year mortality rate after a HF hospitalization is 20-30%, and this 
number has been relatively unchanged over the past decade.6,7 These data suggest that 
there is an unmet need for novel treatment strategies and supports the assessment of 
new approaches in the post-acute HF setting. 
There is also wide variation in the implementation of clinical trial evidence into 
routine practice. Previous data highlight a multi-year gap between the generation of new 
evidence through clinical trials and the adoption of the data into routine clinical 
practice.8,9 This gap in care translates into many unnecessary deaths and hospitalizations 
each year for patients with HFrEF.10 While there are multiple reasons for this quality gap, 
clinical inertia has most often been noted as a major barrier. Ivabradine have been 
approved for use in Europe for several years11 for patients with symptomatic chronic 
HFrEF (LVEF <35%) and a heart rate >75 bpm on guideline-directed medical therapy (or 
intolerance/contra-indication to beta-blocker use). Ivabradine was recently approved for 
use in the United States. However, no US data exist regarding the potential adoption of 
ivabradine into routine clinical care. 
Since ivabradine is a newly approved drug, this study also serves as a strategy 
trial to challenge study sites to explore drug acquisition for a drug that has been proven 
efficacious to the heart failure population and has been added to 2016 ACC/AHA/HFSA 
guidelines, however, has not been adopted rapidly into clinical practice. Ivabradine is not 
being provided for this study. Data are being captured to assess the number of subjects 


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who were able to obtain ivabradine pre and post discharge as well as the barriers to 
acquisition. 
Previous data for patients with HFrEF suggest that the hospital setting may 
provide a unique opportunity for patients to initiate guideline-directed medical therapy. 
In the Initiation Management Predischarge: Process for Assessment of Carvedilol 
Therapy in HF (IMPACT-HF) study, patients with an LVEF<40% hospitalized for HF 
that were started on carvedilol prior to hospital discharge were more likely to be on a 
beta-blocker at 60 days post-randomization compared to those receiving usual care.3 
These improvements in care were achieved without increasing side effects or index 
hospitalization length of stay. Similar to beta-blockers and other medical therapies for 
HF, ivabradine was initially studied in patients with chronic HF.4 The initiation of 
ivabradine specifically in patients following stabilization for acute HF has not been 
evaluated. 
1.2 
Prior data 
The Systolic Heart failure treatment with Ivabradine Trial (SHIFT) enrolled 6,558 
patients with chronic, symptomatic heart failure with reduced ejection fraction.4 In this 
double-blind, randomized, placebo-controlled trial, patients treated with ivabradine were 
less likely to experience the primary composite endpoint of cardiovascular death or 
hospitalization for HF (HR 0.82, 95% CI 0.75, 0.90). These results support that 
ivabradine represents a novel treatment strategy for patients with HFrEF already on 
optimal medical therapy including a beta-blocker. 
A prior study of data from the Organized Program to Initiate Lifesaving 
Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry suggest 
that a substantial proportion of patients hospitalized with HFrEF have an elevated heart 
rate at discharge.12 This study analyzed 10,696 hospitalizations of patients with acute HF 
from United States hospitals with a LVEF <40%. Patients with a history of atrial 
arrhythmia or with a pacemaker or cardiac resynchronization therapy were excluded. At 
the time of discharge, the median heart rate was 72 bpm (interquartile range, 65-80 bpm) 


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for patients on high-dose beta-blockers and increased to 80 bpm (interquartile range, 70-
89 bpm) for patients on no beta-blockers. Most patients, 7647 (71%), had a discharge 
heart rate of >70 bpm, including 1460 of 2301 patients (63%) discharged on >50% of 
target dose of beta-blocker therapy. 
1.3 
Rationale 
Outcomes for patients with HFrEF remain poor after a hospitalization for HF, and there is 
an unmet need for novel treatment strategies in HF. Previous data suggest that the 
hospital setting may provide a unique opportunity for patients with HF to initiate 
guideline-directed medical therapy.3 
A double-blind, randomized, placebo-controlled trial demonstrated that heart-rate 
reduction with ivabradine improves clinical outcomes for patients with chronic, 
symptomatic HF4,  but the initiation of ivabradine in patients following stabilization for 
acute HF has not been evaluated. 
 


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2 
OBJECTIVES 
The primary hypothesis of the PRIME-HF study is that, compared with usual care, a 
treatment strategy of initiation of ivabradine prior to discharge for a hospitalization for 
acute HF will be associated with a greater proportion of participants using ivabradine at 
180 days.  
2.1 
Primary Objective 
To test the primary hypothesis that, compared with usual care, a treatment strategy of 
initiation of ivabradine prior to discharge for a hospitalization for acute HF will be 
associated with a greater proportion of participants using ivabradine at 180 days.  
2.2 
Secondary Objectives 
To assess the impact of predischarge initiation of ivabradine on: 
1) Heart Rate 
a) Change in heart rate from baseline to 180 days 
b) Median heart rate at 180 days 
2) Patient-Centered Outcomes  
a) Kansas City Cardiomyopathy Questionnaire  (KCCQ) 
b) Patient Global Assessment (PGA) 
2.3 
Tertiary Objectives 
Tertiary objectives will be to explore the impact of predischarge initiation of ivabradine 
on: 
1) Other assessments of evidence-based implementation of ivabradine and beta-blockers 
at 180 days. Evaluations will incorporate data based on whether or not indication 
status was retained and whether or not an ivabradine prescription was provided. 
2) Tolerability of ivabradine based on  events of interest during study follow-up: 
a) Symptomatic bradycardia 


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b) Symptomatic hypotension 
c) Other symptoms leading to ivabradine discontinuation 
3) To explore barriers to the acquisition of ivabradine. 
 


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3 
SUBJECT SELECTION 
3.1 
Study Population 
Patients suitable for this protocol are individuals with chronic HF who are hospitalized 
with acute heart failure, have achieved clinical stability and have an LVEF<35% and 
heart-rate >70 bpm in normal sinus rhythm. Subjects should not have a 
planned/scheduled uptitration of beta-blocker in the following 4 weeks. Adjustments of 
background therapy can be made at any point during the study period at the discretion of 
the attending physician. 
3.2 
Inclusion Criteria 
To be eligible for the study subject must meet the inclusion criteria listed below: 
1) Hospitalized with acute HF  (primary or secondary diagnosis) based on clinician 
assessment  
2) A prior clinical diagnosis of HF (i.e., not a new diagnosis of heart failure during 
the current hospitalization) 
3) Most recent LVEF ≤ 35% and within 6 months of randomization or LVEF ≤ 25% 
within 12 months of randomization 
4) On optimal guideline-directed medical therapy for HFrEF (or previously deemed 
intolerant) as determined by the clinician including ACE-inhibitors or angiotensin 
receptor antagonists or neprilysin inhibition, aldosterone receptor antagonists, and 
maximally-tolerated doses of beta-blockers at the time of current evaluation 
(which may differ from long-term targets) 
 Maximally-tolerated doses of beta-blockers will be defined by the treating 
physician when considering aspects such as current dose relative to the target 
dose used in clinical trials, patient heart rate and blood pressure, and patient 
symptoms   
 Patients with intolerance or contraindication to beta-blocker use are eligible 
for enrollment (details will be documented in the case report form) 


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5) Age >18 years 
6) Willingness to provide informed consent from the subject (or at the discretion of 
the local IRB, the subject’s  guardian or legally authorized representative [LAR])   
7) On the day of planned randomization, all participants: 
 Must be in sinus rhythm with a resting heart rate >70 bpm as measured on  
ECG or a 10 second rhythm strip 
 Must have a blood pressure of >90/50 mm Hg 
3.3 
Exclusion Criteria 
If a subject meets any of the following criteria, he or she cannot be enrolled in the study: 
1) Documented plan for uptitration of beta-blocker in the following 4 weeks 
2) Permanent atrial fibrillation or atrial flutter 
3) Patients with recent atrial fibrillation or flutter defined by either precipitating the 
current HF hospitalization or occurring during the current HF hospitalization 
4) History of untreated sick sinus syndrome, sinoatrial block, or second and third 
degree atrio-ventricular block 
5) Pacemaker with atrial or ventricular pacing (except biventricular pacing) >40% of 
the time 
6) Family history or congenital long QT syndrome  
7) Recent myocardial infarction (<2 months prior to screening) [troponin elevation 
secondary to acute HF as determined by the clinician is not an exclusion] 
8) Acute or chronic severe liver disease as evidenced by any of the following: 
encephalopathy, variceal bleeding, INR > 1.7 in the absence of anticoagulation 
treatment  
9) Creatinine clearance <15 mL/min within 48 hours of screening that was not due to 
acute kidney injury that resolved 
10) Planned mechanical circulatory support within 180 days 


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11) Pregnant or breastfeeding women. Women of child-bearing potential should use 
effective contraception 
12) Medical conditions likely to lead to poor non-cardiac survival at 180 days (e.g., 
cancer) 
13) Inability to comply with planned study procedures  
14) If the following medications are needed at inclusion or during the study: 
a) Non-dihydropyridine calcium channel blockers (e.g., diltiazem and verapamil) 
b) Class I anti-arrhythmics (e.g., quinidine, procainamide, lidocaine, phenytoin) 
c) Strong inhibitors of cytochrome P450 3A4 (CYP3A4), including some 
macrolide antibiotics (e.g., clarithromycin, erythromycin), cyclosporine, 
antiretroviral drugs (e.g., ritonavir, nelfinavir), and systemic azole antifungal 
agents (e.g., ketoconazole, itraconazole), and nefazodone 
d) Inducers of cytochrome P450 3A4 (CYP3A4) including St. John’s wort, 
rifampicin, barbiturates, and phenytoin. 
e) Treatments known to be associated with significant prolongation of the QT 
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4 
STUDY DESIGN 
4.1 
Overview of Study 
The PRIME-HF study is a multi-center, patient-level, randomized, open-label study of 
approximately 450 patients with reduced LVEF of <35% and heart-rate >70 bpm who are 
being discharged from the hospital following stabilization from acute HF and will be 
randomized to a treatment strategy of predischarge initiation of ivabradine or usual care.  
4.2 
Screening Phase 
Patients admitted with acute HF will be screened for basic entry criteria. To be eligible, 
patients should be hospitalized with acute HF (primary or secondary diagnosis). Patients 
hospitalized with acute HF will be treated with standard therapy at the discretion of the 
treating physician including adjustment of guideline-directed medical therapies such as 
beta-blockers. Patients will be screened for potential eligibility during the index 
hospitalization but study inclusion criteria including clinical stability, heart rate, and 
blood pressure will be assessed once the patient is stable and approaching discharge. 
Patients can be consented and randomized prior to the day of discharge as long as they 
meet entry criteria. 
4.3 
 Clinical Evaluation Prior to Randomization 
When patients are approaching the time for discharge, final study eligibility will be 
determined. Prior to discharge, clinical stability will be assessed to ensure resolution of 
signs and symptoms of acute HF. Blood pressure and resting heart rate will be assessed. 
Patients with a pre-discharge blood pressure of >90/50 mm Hg and heart rate > 70 bpm 
will be eligible and approached for consent. Subjects should not have a 
planned/scheduled uptitration of beta-blocker in the following 4 weeks. Willing 
participants meeting entry criteria will provide written informed consent. Baseline heart 
rate must be ≥70bpm on ECG or a 10-second rhythm strip. 


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4.4 
 Randomization 
After signing the informed consent form, all subjects who fulfill all of the inclusion 
criteria and none of the exclusion criteria will be randomized. All patients will be 
randomized using an electronic system in a 1:1 allocation ratio to either predischarge 
initiation of ivabradine or usual care. Randomization will be stratified by clinical site.  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1. Study Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening  
 
LVEF<35% and hospitalized for acute HF (primary or secondary diagnosis) 
 
Treated with standard therapy at the discretion of the treating physician including beta-blockers 
Patient Deemed Eligible for Discharge 
 
Obtain informed consent 
 
BP > 90/50 mm hg and sinus rhythm with a resting heart rate >70 bpm on a 12-lead ECG or 10-second rhythm strip  
 
Obtain baseline exam, KCCQ, PGA (obtain ECG if not already completed in screening) 
Baseline/Randomization (Day 0) 
 
1:1 randomization to predischarge initiation of ivabradine or usual care 
Predischarge Initiation (n=225) 
Usual Care (n=225) 
In-Hospital Monitoring 
 
Patients randomized to predischarge initiation receive 1st dose of 
ivabradine 5mg BID prior to hospital discharge. Explore medication costs 
and options to support patient. 
Post-discharge Follow-up (7-14 days post-
discharge) (Follow up Visit 1) 
 
Assess current medication use/doses, heart 
rate, KCCQ, PGA, event status 
 
Dose titration of ivabradine 
Week 6 Follow-up Visit (42 ± 14 days) (Follow up Visit 2) 
 
Assess current medication use/doses, heart rate, KCCQ, PGA, event status 
 
If participant now on ivabradine: 
o 
If heart rate <50 or symptomatic bradycardia, decrease ivabradine dose  
o 
If heart rate 50-60, maintain ivabradine dose 
o 
If heart rate >60, increase ivabradine dose 
 
If participant not on ivabradine, it may be initiated at the provider’s discretion 
Day 90 Phone Call (± 7 days) (Follow up Phone Call) 
 
Assess current heart failure medication use/doses, event status and tolerability of ivabradine in all participants 
Day 180 Follow-up Visit (± 14 days) (Follow up Visit 3) 
 
Assess current medication use/doses, heart rate via ECG, KCCQ, PGA, event status, and the final dose of ivabradine prior to the visit  
Post-discharge Follow-up (7-14 days post-
discharge) (Follow up Visit 1) 
 
Assess current medication use/doses, heart 
rate, KCCQ, PGA, event status 
 
Ivabradine may be initiated at the 
provider’s discretion 


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Figure 2. Schematic of Study Design 
 
4.5 
Treatment Arms 
The treatment arms for this study are pre-discharge initiation of twice-daily oral 
ivabradine (starting at 5mg BID with encouraged dose titration to 7.5mg BID) versus 
usual care (i.e., post-discharge initiation of ivabradine at discretion of routine physician) 
for 180 days. 
4.6 
Patient Safety and Concomitant Medical Therapy 
Patients will receive standard medical therapy throughout the study. Adjustments of 
background therapy can be made at any point during the study period at the discretion of 
the attending physician. Therapy may include diuretics, ACE-inhibitors or ARBs, 
neprilysin inhibition, beta-blockers, and mineralocorticoid receptor antagonists. Patients 
may have adjustments of beta-blocker therapies up until 24 hours prior to 
randomization and still be eligible for the study. Subject should not have a 
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Sites will report  events of interest to include SAEs related to Ivabradine, Pregnancy, or 
lactation exposure.  Additional details are found in Section 8. 


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5 
STUDY PROCEDURES 
5.1 
Screening and Prerandomization Procedures 
Potentially eligible subjects will be identified from inpatient admissions and screened by 
interview. Interested subjects will be asked to give written informed consent and undergo 
a screening evaluation to include a complete history, physical examination, and laboratory 
tests. Study personnel will assess each subject against each inclusion and each exclusion 
criterion, and the investigator will determine the subject’s eligibility for study participation. 
The informed consent process and all assessments will be documented in the subject’s 
medical record.  
5.2 
Baseline Evaluations 
At the baseline visit and the time of randomization (prior to administration of ivabradine), 
all study participants will undergo the following: 
 History and physical examination 
 Baseline heart rate assessment via ECG (if ECG not already obtained in 
screening) 
 KCCQ and PGA 
5.3 
Treatment Intervention 
Participants randomized to predischarge initiation of ivabradine should receive the first 
dose of medication prior to discharge if possible. If ivabradine is administered and then 
discharge is delayed, participants should continue on open-label ivabradine until hospital 
discharge. Participants should then receive a prescription for outpatient ivabradine. Study 
drug will not be provided as part of the study. If the patient is randomized to pre-
discharge initiation, the study team and/or inpatient care team (e.g., providers and care 
coordinator) should initiate the process to acquire outpatient medication, explore patient 
costs and consider support options for the patient. If the patient is not able to pay for the 
medication, they will continue in the study and will enter a registry of ivabradine-eligible 


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patients with documentation of the medication acquisition challenges experienced by the 
patient and provider. All participants will be counseled on the signs and symptoms of 
bradycardia including lightheadedness, dizziness, and syncope. Participants will also be 
followed carefully for the remainder of the hospitalization and monitored for adverse 
events including bradycardia or recurrence of heart failure signs or symptoms.  
5.4 
Follow-up Evaluations 
5.4.1 Clinical Follow-up Visit (Study Visit 1) 
Consistent with current HF guidelines,2 all participants should have a follow-up study 
visit within 7-14 days of hospital discharge. The timing of this visit will be determined by 
treating physicians. Current medication use and doses, physical examination, heart rate, 
systolic blood pressure and quality of life (KCCQ and PGA) will be assessed at this 
clinical visit. For participants randomized to predischarge initiation of ivabradine and on 
5mg BID, the heart rate may be used to adjust the dose of ivabradine to 2.5mg BID or 
7.5mg BID (Table 1). For participants randomized to usual care, ivabradine may be 
initiated at the provider’s discretion. Participants not eligible for ivabradine at this visit 
will be documented and continue study follow-up.  
Table 1. Recommended Dose Adjustments for Patients Taking Ivabradine  
Heart Rate 
Dose Adjustment 
>60 bpm 
Increase dose by 2.5 mg (given twice daily) up to a maximum 
dose of 7.5mg twice daily 
50-60 bpm 
Maintain current dose 
<50 bpm or signs and 
symptoms of bradycardia 
Decrease dose by 2.5mg (given twice daily); if current dose is 
2.5 mg twice daily, then discontinue therapy 
5.4.2 Clinical Follow-up Visit (Study Visit 2) 
At 6 weeks (42 +/- 14 days) post-discharge, all participants will have follow-up study 
visit. The study visit will include an assessment of current medication use and doses, 


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physical examination,  heart rate, and systolic blood pressure. For participants on 
ivabradine, the heart rate may be used to adjust the dose (Table 1). For participants with a 
resting heart rate >60 bpm, the dose may be increased to either 5mg or 7.5mg BID. If the 
resting heart rate is <50 bpm or the participant is experiencing signs or symptoms related 
to bradycardia, then the dose may be reduced to 2.5mg BID or the study drug should be 
discontinued. If the heart rate is 50 to 60 bpm, then the dose may be maintained. For 
participants not yet taking ivabradine, then it may be initiated at the provider’s discretion. 
Participants not eligible for ivabradine at this visit will be documented and continue study 
follow-up. Study investigators or designee will assess quality of life (KCCQ and PGA).  
5.4.3  Phone Call 
At 90 (+/-7) days post-discharge, participants should be contacted by the site (phone call)  
to assess for event status, current medication use and doses, and tolerability of ivabradine, 
specifically 
 
 Symptomatic bradycardia 
 
Symptomatic hypotension 
 
Other symptoms leading to ivabradine discontinuation 
  
5.4.4  Final Study Visit (Study Visit 3) 
At 180 (+/- 14) days post discharge, all participants will have a routine clinic visit. The 
visit will include an assessment of current medication use and doses, physical 
examination including heart rate assessment (by exam and 1 ECG), and systolic blood 
pressure. The final dose of ivabradine prior to the visit will be recorded. Participants 
never initiated on or eligible for ivabradine will also be recorded. The study investigators 
or designee will assess quality of life (KCCQ and PGA).  
 
Using the  study schedule of assessments, provider-determined heart rate will be assessed 
at the following time points: baseline, post-discharge clinical follow-up visit (within 7-14 


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days of hospital discharge), week 6, and day 180. Patient quality of life assessment will 
be assessed at the following time points: baseline, post-discharge clinical follow-up visit 
(within 7-14 days of hospital discharge), week 6, and day 180. 


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5.5 
Schedule of Assessments 
 
 
 
 
 
 
 
 
 
Baseline 
Time (Day) 
Pre-discharge 
Day 7-14 
post 
discharge 
6 Weeks post-
discharge  
(42 +/- 14 
days) 
90 Days post-
discharge  
(+/-7 days) 
180 Days 
post-
discharge 
(+/- 14 days) 
 
 
 
 
 
 
Visit 
Baseline/Randomization FU Visit 
1 
FU Visit 2 
FU Phone 
Call 
FU Visit 3 
Subject consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical examination 
X 
X 
X 
 
X 
Vital signs (HR,BP) 
X 
X 
X 
 
X 
ECG  
X 
 
 
 
X 
KCCQ 
X 
X 
X 
 
X 
PGA 
X 
X 
X 
 
X 
Medication assessment 
X 
X 
X 
X 
X 
Events of interest assessment  
 
X 
X 
X 
X 


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6 
ENROLLMENT AND RANDOMIZATION 
6.1 
Enrollment 
Eligible subjects who have given written informed consent and meet all inclusion and no 
exclusion criteria will be randomized.  
6.2 
Randomization 
After signing the informed consent form, all subjects who fulfill all of the inclusion 
criteria and none of the exclusion criteria will be randomized. All patients will be 
randomized using an electronic system in a 1:1 allocation ratio to either predischarge 
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7 
PARTICIPANT SAFETY 
7.1 
Patient Safety and Concomitant Therapies 
This study will evaluate and compare pre-discharge initiation of ivabradine versus usual 
care in patients stabilized after an acute HF exacerbation requiring hospitalization. 
Although investigators are encouraged to follow the assigned treatment strategy, in all 
cases the patient’s safety based on the clinical judgment of the treating physician will 
take priority over the specific treatment assignment. Concomitant therapies will be at the 
discretion of the treating physician. All subjects will receive standard of care which can 
be adjusted by their usual care provider(s) during the study according to clinical need. 
Usual care providers will be encouraged to follow the most up to date guidelines for 
cardiovascular care based upon local and institutional practice patterns and relevant 
published practice guidelines. 
7.2 
Institutional Review Boards  
All sites will submit the study protocol, informed consent form, and other relevant study 
documents to their Institutional Review Board (IRB) for approval.  
7.3 
Informed Consent  
All patients will have the purpose of the study, the study interventions and evaluations, 
and the potential risks and benefits of participation explained to them and their questions 
answered. If they consent to participation in this study, they will review and sign the 
informed consent form. 
7.4 
Study Discontinuation  
Subjects may withdraw at any time during the study without prejudice or be discontinued 
from study treatment at the discretion of the investigator if medically necessary. In 
addition, a subject may be withdrawn by the investigator or the sponsor if the subject 
violates the study plan or for administrative and/or other safety reason.  


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The investigator or designee will document in the eCRF when a subject has been 
discontinued or withdrawn from study treatment because of an adverse experience. When 
a subject discontinues or is withdrawn from treatment before study completion, all 
applicable activities scheduled for the final study visit should be performed at the time of 
discontinuation. Any adverse experiences that are present at the time of 
discontinuation/withdrawal should be followed by the site PI until resolution. 


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8 
ADVERSE EVENT REPORTING AND FOLLOW-UP 
8.1 
Safety 
In this study, all medications and procedures commonly used or performed as a part of 
standard of care for the management of HF have well-defined safety profiles. For this 
trial, defined clinical endpoints and events of interest will be recorded in the eCRF. In 
addition, events that are Serious and Unexpected will be reported by a site investigator to 
the local IRB per the IRB’s instructions and will be the subject of a MedWatch report, 
based on local requirements. 
 
The investigator is responsible for monitoring the safety of subjects enrolled into the 
study at the study site. The investigator or qualified designee will enter the required 
initial and follow-up information regarding events into the appropriate module of the 
eCRF.  Investigators are to report serious adverse events in accordance with their local 
IRB requirements. Investigators should follow usual clinical practices at their institution 
for reporting to regulatory authorities serious, unexpected events related to standard of 
care medications and devices.  
8.2 
Definitions 
8.2.1 Events of Interest 
Sites will record in the eCRF Events of Interest which include 
1) Symptomatic bradycardia 
2) Symptomatic hypotension 
3) Other symptoms leading to ivabradine discontinuation 
4) Any Adverse Event that, in the opinion of the site investigator, is related to 
ivabradine and is:  
a) Serious, and  
b) Unexpected 


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8.3 
Protocol Specific Exceptions to SAE Reporting 
The following events will be collected in the CRF but are not the subject of a MedWatch 
report. These events will be captured on anticipated/disease related events pages, not on 
the SAE eCRF page.  Anticipated, disease related-event in patients with acute 
decompensated heart failure include: 
• 
Ventricular tachycardia  
• 
Atrial fibrillation  
• 
Myocardial infarction  
• 
Acute coronary syndrome  
• 
Acute renal failure  
• 
Worsening heart failure  
• 
Death  
 
With the exception of the events listed above, all serious adverse events the site PI 
determines to be related to ivabradine must be recorded in the Serious Adverse Event 
eCRF and  should be monitored until stabilization or resolution.  
 
Site investigators are responsible for knowing the local requirements for prompt reporting 
of an adverse event to the reviewing IRB/EC and for reporting an SAE to FDA via a 
MedWatch.  
An Independent Data and Safety Monitoring Board (DSMB) will review safety composite 
data at regular intervals throughout the study. The DSMB will be empowered to stop the 
study for evidence of harm but not for evidence of efficacy.  
8.3.1 Suspected Adverse Reaction 
In PRIME-HF a suspected adverse reaction (SAR) is any AE for which there is a 
reasonable possibility that ivabradine caused the event. “Reasonable possibility” suggests 
there is a causal relationship between the drug and the AE. “Suspected adverse reaction” 


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implies a lesser degree of certainty about causality than adverse reaction, which means 
any AE caused by a drug. 
8.4 
Assessment of Adverse Event Severity  
The determination of AE severity rests on medical judgment of a medically qualified 
investigator. The severity of AEs will be graded using the following definitions:  
 Mild: Awareness of sign, symptom, or event, but easily tolerated. 
 Moderate: Discomfort enough to cause interference with usual activity and 
may warrant intervention. 
 Severe: Incapacitating with inability to do usual activities or significantly 
affects clinical status and warrants intervention. 
8.5 
Assessment of Causal Relationship 
A medically qualified investigator must assess the relationship of any AE to the use of 
study drug, based on available information, using the following guidelines: 
 Not related: There is not a reasonable causal relationship between the 
investigational product and the AE.  
 Unlikely related: No temporal association or cause of the event has been 
identified, or the drug or biologic cannot be implicated. 
 Possibly related: There is reasonable evidence to suggest a causal 
relationship between the drug and AE. 
 Probably related: There is evidence to suggest a causal relationship between 
the drug and AE, and the influence of other factors is unlikely. 


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8.6 
Expectedness 
The Investigative site PI or designee will determine expectedness of an SAE according to 
the package insert for U.S. marketed ivabradine. Any SAE that is not identified in nature, 
severity, or specificity in the current study drug reference documents is considered 
unexpected. Events that are listed in the package insert as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but not specifically 
listed as occurring with the particular drug under investigation, are considered 
unexpected. As per the ivabradine package insert, the most common adverse reactions 
occurring in ≥ 1% of patients are bradycardia, hypertension, atrial fibrillation and 
luminous phenomena (phosphenes). 
8.7 
Adverse Event Reporting 
All SAEs obtained via direct subject reporting and/or clinical staff observation that the 
site PI determined to be related to ivabradine will be captured within the electronic case 
report form (eCRF). 
8.8 
Serious Adverse Events 
The investigator must record, via the EDC system, all SAEs that the site PI determined to 
be related to ivabradine occurring at visit 1 through visit 3 within 24 hours of knowledge 
of the event. If the eCRF system is temporarily unavailable, notify the sponsor or 
designee of the event, including investigator-determined causality assessment, via a paper 
back-up SAE form. Upon return of the availability of the EDC system, the SAE 
information must be entered into the eCRF. 
 
The investigator must record in the EDC system when important follow-up information 
(final diagnosis, outcome, results of specific investigations, etc.) becomes available after 
submission of the initial SAE information. Follow-up information should be submitted 
according to the same process used for reporting the initial event as described above (i.e., 


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within 24 hours of knowledge, via the EDC system). All SAEs will be followed until 
resolution, stabilization, until otherwise explained.  
 
Research sites are expected to follow local IRB policies and procedures for reporting 
AEs/SAEs.  
8.9 
Pregnancy 
During the course of the trial, if any female subject who is receiving ivabradine becomes 
pregnant, or if any person is exposed to ivabradine by a lactating female subject, this 
information will be recorded in the eCRF and reported via the pregnancy form.  While a 
subject’s pregnancy is not considered an SAE, it must be reported within the same 
timelines as an SAE (within 24 hours).  Any AEs or SAEs associated with ivabradine that 
occur to the female subject or fetus/child will be recorded in the eCRF on the AE or SAE 
form, as appropriate. 
8.10 Withdrawal of Subjects from Study 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to future medical care. In the case of subject withdrawal, the investigator will 
discuss with the subject the most appropriate way to terminate study participation to 
ensure the subject’s health. All efforts will be made to complete and report the 
observations as thoroughly as possible up to the date of study termination. All applicable 
activities scheduled for the final study visit should be preformed at the time of 
discontinuation. Randomized subjects who withdraw from the study will not be replaced.  
 
 
 


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9 
SUMMARY OF CLINICAL EVENTS 
Additional data on clinical events of interest will be collected. 
a. Worsening HF defined as either hospital admission for worsening signs and/or 
symptoms of HF or receiving unplanned intravenous (IV) diuretics for HF as 
an outpatient. 
b. All-cause mortality 
 
 


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10 STATISTICAL ANALYSIS PLAN AND DETERMINATION OF SAMPLE 
SIZE 
10.1 Overview 
All planned analyses will be prospectively defined for this study and approved by the 
Steering Committee. In addition, exploratory analyses will be performed to help explain 
and understand findings observed from the planned analyses. Statistical tests with a 2-
sided p-value <0.05 will be considered statistically significant, unless otherwise stated. 
Analyses will be performed using SAS software (SAS Institute, Inc, Cary, NC).  
The primary endpoint of the study is proportion of participants using ivabradine at 180 
days.  
10.2 Sample Size Justification 
We assumed that 35% of participants randomized to the usual care arm will be treated 
with ivabradine at 180 days, and the predischarge initiation of ivabradine would increase 
the use at 180 days to 50%. The usual care event rate is based on investigator estimates of 
clinical use in the first year following approval by the Food and Drug Administration. At 
a two-sided Type I error rate of 0.05, 450 participants would provide 85% power to 
detect a significant difference in the rate of ivabradine use between groups. This sample 
size estimate is based on a two-group continuity corrected chi-square test and assumes a 
1:1 allocation ratio between the predischarge initiation of ivabradine and usual care 
groups. This sample size estimate allows for 8% missing primary endpoint data. 
 
For the KCCQ overall summary endpoint we have made a conservative assumption of 16 
points for the standard deviation.  For this measure, the medium and large clinically 
meaningful differences are 5 and 10 points for the KCCQ overall summary measure, 
respectively. Allowing for approximately 8% missing data, the proposed sample size of 
450 participants provides approximately 90% power to detect a difference of 5 points 


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(medium clinically meaningful difference). The power calculations are based on the two 
sample t-test with a two-sided Type I error rate of 0.05.  
10.3 Analysis of the Primary Endpoint 
The primary analysis will be conducted on an intention-to-treat (ITT) basis including all 
randomized participants. A logistic regression model with ivabradine use at 180 days as 
the binary outcome variable and indicator variables for treatment group main effects and 
category of baseline beta-blocker use. The treatment effect for the ivabradine at discharge 
group will be summarized by the odds ratio and the associated 95% confidence interval.  
10.4 Analysis of Secondary and Tertiary Endpoints 
 Heart Rate Assessments 
o Change in heart rate from baseline to 180 days across treatment groups. 
Change will be calculated as follows: (Baseline heart rate – 180-day heart 
rate). Comparisons across treatment groups will be performed using a 
linear model with adjustment for the baseline heart rate and beta-blocker 
use.  Treatment groups will be included in the regression model as main 
effects. Multiple imputation will be used to impute 180-day missing HR 
observations if missing is > 10%. 
o Heart rate in bpm at 180 days will be compared in the predischarge 
ivabradine group compared across treatment groups. Comparisons across 
treatment groups will be performed using a linear model with adjustment 
for the baseline heart rate and beta-blocker use.  Treatment groups will be 
included in the regression model as main effects. Multiple imputation will 
be used to impute 180-day missing HR observations if missing is > 10%. 
 Changes in symptoms and quality-of-life from baseline to 180 days as assessed by 
KCCQ and PGA will be evaluated across treatment groups using a linear model 
with adjustment for the baseline quality-of-life and beta-blocker use. A multiple 
imputation approach will be used to account for possible missing data. The 


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differences between treatment groups will be estimated using point estimates and 
the associated two-sided 95% confidence intervals. 
 Beta-blocker use at 180 days as assessed by the (a) proportion of participants on a 
beta-blocker at 180-days, (b) proportion on target dose, (c) the proportion 
discontinuing beta-blockers at 180 days and (d) the mean change in beta-blocker 
dose from discharge to 180 days will be compared between treatment groups. 
 Ivabradine use at 180 days as assessed by the (a) proportion of appropriate 
participants with any initiation of ivabradine at 180 days, (b) the proportion of 
appropriate participants at the maximum dose of ivabradine at 180 day (i.e., 7.5 
mg twice daily), and (c) the mean dose of ivabradine achieved at 180 days will be 
compared between treatment groups. 
 The event counts and subject incidences for the following adverse events will be 
presented for the treatment groups: 
o Symptomatic bradycardia 
o Symptomatic hypotension 
 Barriers to the acquisition of ivabradine. Barriers will be documented in the case 
report form and reported in tabular format. 
10.5 Interim Analyses 
Interim data analysis for efficacy will not be conducted due to modest size and short 
duration of this study. Safety data will be periodically assessed by the DSMB. 


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11 DATA MONITORING AND QUALITY CONTROL 
11.1 Required Data 
The full study dataset will be collected for subjects who enter the randomization phase of 
the study. Limited data as available (i.e., demographics, serious adverse events related to 
ivabradine, selection criteria, and reason for discontinuation) will be collected for subjects 
who discontinue before the end of the protocol specified follow-up period. 
All required data for this study will be entered into the electronic case report form (eCRF). 
11.2 Data Collection and Tracking 
Qualified study staff at each site will perform primary data collection from source-
document reviews. The sponsor or designee will perform clinical monitoring, including 
review of eCRFs with verification to the source documentation. 
This study will use Web-based e-CRFs developed through a validated, electronic reporting-
electronic-signatures–compliant platform (21 Code of Federal Regulations Part 11). The 
investigator's site staff who will be entering data will receive training on the system, after 
which each person can set up their database account and request study access 
For security reasons, and in compliance with regulatory guidelines, it is imperative that 
only the persons who own the user IDs and passwords access the system using their own 
unique access codes. Access codes are nontransferable. Site personnel who have not 
undergone training may not use the system and will not be granted access to the clinical 
database until appropriate training is completed. 
During monitoring visits, the site will make their computer and/or high-speed Internet 
access available to the clinical research associate, so that he or she may verify the data 
entries with the source documentation. At the conclusion of the study, each enrolling site 
will be provided with a thumb drive containing PDF files of both the individual subject's 


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data and the audit trail (changes made to the database). This will be maintained at the site 
according to the requirements for records retention. 


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12 Study Responsibilities 
12.1 Investigator Responsibility/Performance 
The site principal investigator (PI) agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems to ensure that all work incidental 
to this protocol is conducted and data are generated, documented, and reported in 
compliance with: the protocol; accepted standards of Good Clinical Practice (GCP); and 
all applicable federal, state, and local laws, rules and regulations relating to the conduct of 
the clinical study. 
The PI will provide current copies of the study protocol to all subinvestigators or other site 
personnel responsible for study conduct. 
The PI will provide the sponsor or designee with copies of all institutional review board 
(IRB) actions regarding the study. 
12.2 Study Data Reporting and Processing 
Each page of the electronic case report form (eCRF) will be reviewed by PI at the site. The 
PI is required to sign the eCRF on the appropriate pages to verify that he or she has 
reviewed the recorded data. This review and sign-off may be delegated to a qualified 
physician appointed as a subinvestigator by the PI. The transfer of duties to a 
subinvestigator will be recorded on the delegation list, which is kept on file at the site. The 
investigator must ensure that all site staff involved in the conduct of the trial are familiar 
with the protocol and all study-specific procedures, and that they have appropriate 
knowledge of the study agents. 
12.3 Training 
The initial training of appropriate clinical site personnel will be the responsibility of  the 
sponsor or designee. The PI is responsible for ensuring that staff conduct the study 
according to the protocol. To ensure proper administration of study agents, uniform data 


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collection, and protocol compliance, the sponsor or designee will present a formal 
training session to study site personnel, to include instructions for study procedures, the 
investigational plan, instructions on in-hospital data collection, methods for soliciting 
data from alternative sources, schedules for follow-up with the study site coordinators, 
and regulatory requirements. Detailed feedback regarding completion of forms will be 
provided by the sponsor ot designee in the course of  monitoring. 
12.4 Monitoring the Investigational Sites 
As part of a concerted effort to follow the study in a detailed and orderly manner in 
accordance with established principles of GCP and applicable regulations, a study monitor 
from the sponsor or designee will visit the study sites as appropriate and will maintain 
frequent telephone and written communication. 
Periodic monitoring visits may be made at all active investigational sites throughout the 
clinical study as needed to assure that the investigator obligations are being fulfilled and 
all applicable regulations and guidelines are being followed. The goal of these visits are to 
assure the facilities are still acceptable, the protocol and investigational plan are being 
followed, the IRB/EC has been notified of approved protocol changes as required, 
complete records are being maintained, appropriate  reports have been made to the sponsor 
or designee and the IRB/EC, and the investigator is carrying out all agreed-upon activities. 
During monitoring visits, the monitor will perform a review of  inclusion/exclusion criteria, 
informed consent, HIPAA authorization, events of interest , as well as safety and efficacy 
endpoints. Additional review will be performed on a site-by-site basis, as warranted by the 
findings of previous monitoring visits. Key variables will be confirmed through review of 
source documents for a sampling of patients.  
Sites may be required to provide at a minimum the informed consent and discharge 
summary for subjects to the the sponsor or designee via a secure system.  


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Trends will be monitored and, if warranted, the frequency of onsite monitoring visits may 
be adjusted at sites.  Details will be described in the clinical monitoring plan. 
12.5 Study Documentation 
Study documentation includes all electronic  case report forms, source documents, 
monitoring logs and appointment schedules, sponsor-investigator correspondence, and 
regulatory documents (e.g., protocol and amendments, IRB or EC correspondence and 
approval, approved and signed subject consent forms,  clinical supplies receipts and 
distribution records). 
The site PI will prepare and maintain complete and accurate study documentation in 
compliance with GCP standards and applicable federal, state, and local laws, rules and 
regulations. For each subject participating in the study at the site, the investigator will 
promptly complete all eCRFs and such other reports as required by this protocol following 
completion or termination of the clinical study or as otherwise required pursuant to any 
agreement with the sponsor. 
The site PI acknowledges that, within legal and regulatory restrictions and institutional and 
ethical considerations, study documentation will be promptly and fully disclosed to the 
sponsor or designee by the investigator upon request and also shall be made available at 
the investigator’s site upon request for inspection, copying, review, and audit at reasonable 
times by representatives of the sponsor or responsible government agencies as required by 
law.  
The PI agrees to promptly take any reasonable steps that are requested by the sponsor or 
designee as a result of an audit to cure deficiencies in the study documentation and eCRFs. 
12.6 Source Documentation 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 


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study. Accordingly, source documents include, but are not limited to, laboratory reports, 
electrocardiogram (ECG) tracings, x-rays, radiologist reports, subject diaries, biopsy 
reports, ultrasound photographs, subject progress notes, hospital charts, pharmacy records, 
and any other similar reports or records of any procedure performed in accordance with the 
protocol. 
Whenever possible, the original recording of an observation should be retained as the 
source document; however, a photocopy is acceptable provided that it is a clear, legible, 
and exact duplication of the original document. 
The following information will be maintained and made available as required by the 
sponsor or designee and/or regulatory inspectors: 
1. Medical history/physical condition of the study subject before involvement in 
the study sufficient to verify protocol entry criteria. 
2. Documentation that informed consent was obtained for the subject’s 
participation in the study. 
3. Dated and signed notes for each subject visit, including results of 
examinations. 
4. Notations on abnormal laboratory results and their resolution. 
5. Dated printouts or reports of special assessments (e.g., ECG reports). 
6. Description of adverse events (AEs) and follow-up of the AEs (minimally, 
event description, severity, onset date, duration, relation to study drug, 
outcome, and treatment for AE). 
7. Notes regarding concomitant medications taken during the study (including 
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8. Subject’s condition upon completion of or withdrawal from the study. 
12.7 Protocol Deviations 
A protocol deviation is defined as an event where the investigator or site personnel did not 
conduct the study according to the investigational plan. Site investigators must also follow 
the policy of the reviewing IRB for reporting such deviations. to their reviewing IRB per 
local policy. 
The IRB/EC will be informed of all protocol changes by the sponsor or the investigator in 
accordance with applicable regulations and the IRB/EC’s established procedures. No 
deviations from the protocol of any type will be made without complying with the 
IRB/EC’s established procedures. 
Investigators will maintain documentation of the dates and reasons for each deviation from 
the protocol. 
12.8 Data Transmittal and Record Retention 
Required data will be entered in the eCRF at the time of or as soon as possible after the 
subject visit or the availability of test results 
The PI will maintain  final eCRFs, worksheets, and all other study-specific documentation 
(e.g., study file notebooks or source documentation) until notified by the sponsor that 
records may be destroyed. To avoid error, the investigator will contact the sponsor or 
designee before the destruction of any records pertaining to the study to ensure they no 
longer need to be retained. In addition, the sponsor or designee will be contacted if the PI 
plans to leave the institution so that arrangements can be made for the transfer of records. 
The site PI takes responsibility for maintaining adequate and accurate source documents of 
all observations and data generated during this study. Such documentation is subject to 
inspection by the sponsor or designee as well as by federal, state, and local regulatory 
agencies. 


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12.9 Study Closeout 
Upon completion of the study (defined as all subjects have completed all follow-up visits, 
all eCRFs are complete, and all queries have been resolved), the sponsor or designee will 
notify the site of closeout, and a study closeout visit will be performed. All unused study 
materials can be destroyed by the site when the study is completed. The sponsor or designee 
will ensure that the PI’s regulatory files are up-to-date and complete and that any 
outstanding issues from previous visits have been resolved. Other issues to be reviewed at 
the closeout visit include discussing retention of study files, possibility of site audits, 
publication policy, and notifying the IRB of study closure. 
12.10 Audit/Inspections 
As needed, quality assurance personnel from the sponsor or designee may conduct audits 
at the study sites at a reasonable time and in a reasonable manner. Audits will include, but 
not be limited to, audit trail of data handling and processes, standard operating procedures, 
presence of required documents, the informed consent process, and comparison of eCRFs 
with source documents. The site PI agrees to accommodate and participate in audits that 
are conducted. 
Regulatory authorities from the U.S. or abroad may inspect the site during or after the study 
at a reasonable time and in a reasonable manner. The PI should contact the sponsor 
immediately if contacted regarding an inspection. Site personnel are expected to cooperate 
with personnel from regulatory agencies (e.g., FDA) audits conducted  
12.11 Publication Policies 
Members of the Steering Committee will be primarily responsible for creation, review, and 
submission of publications and presentations relating to the major aspects of the study and 
approved ancillary analyses within a timely fashion after completion of the study. Details 
will be contained in the Publication Plan.  
 


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13 Ethical Considerations 
13.1 Informed Consent 
The PI has both ethical and legal responsibility to ensure that each subject being considered 
for inclusion in this study is given a full explanation of the study. Written informed consent 
will be obtained from all subjects (or, at the discretion of the local IRB, the subject’s 
guardian or legally authorized representative [LAR]) before any study-related procedures  
are performed or given.  
Written informed consent will be documented on an informed consent form (ICF) approved 
by the local IRB/EC responsible for approval of this protocol. The ICF will conform to the 
applicable requirements of 45 CFR 46, ICH E6 and institutional requirements for informed 
consent.  The site investigator agrees to obtain approval from the sponsor of any ICF 
intended for use in the study before submission of the ICF for IRB approval. 
The ICF will be reviewed with the prospective study subject (or LAR), and the investigator 
or qualified designee will be available to answer questions regarding procedures, risks, and 
alternatives.  
13.2 Confidentiality of Subjects 
Subject confidentiality will be maintained throughout the clinical study in a way that 
ensures that study data can always be tracked back to the source data.  
Subject information collected in this study will comply with the standards for protection of 
privacy of individually identifiable health information as promulgated by the U.S. Health 
Insurance Portability and Accountability Act (HIPAA). All records will be kept 
confidential, and the subject’s name will not be released to persons outside the study site. 
Subject records will not be released to anyone other than the sponsor or its designees and 
responsible regulatory authorities when requested. In all cases, caution will be exercised to 
assure the data are treated confidentially and that the subject’s privacy is guaranteed. 


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13.3 Authorization for Use and Disclosure of Protected Health Information 
(HIPAA) 
An authorization for use and disclosure of protected health information (PHI) under the 
HIPAA Privacy Rule will be obtained from every trial subject before enrollment. The 
investigator is responsible for obtaining subjects’ (or their LARs’) authorizations and 
signatures and for explaining the elements of the HIPAA authorization form, if necessary. 
The site PI will promptly inform the sponsor of any restrictions on the use or disclosure of 
any subject’s PHI. The site investigator will also promptly inform the sponsor of written 
revocation of any subject’s HIPAA authorization. 
13.4 Human Subject Protections 
13.4.1 Research Subject Selection and Justification of Exclusions 
There will be no exclusion from participation in the study on the basis of ethnicity or race. 
Subjects younger than 18 years of age will be excluded from the study, as the target 
population is adults. Women of childbearing potential will have serum-hCG testing before 
randomization to avoid potential fetal exposure to ivabradine.  
13.4.2 Risks/Discomforts of Study Participation 
This study will evaluate the safety and efficacy of ivabradine following stabilization for 
acute HF. Oral ivabradine was found to be safe and efficacious in chronic HF patients in 
the SHIFT trial over a median follow-up of 22.9 mos. In SHIFT, the overall rate of SAEs 
was similar between the ivabradine and placebo arms; ivabradine was not associated with 
any evidence of harm over this follow-up period.  
13.5 Institutional Review Board/Ethics Committee Review 
The appropriate IRB/EC must approve the protocol and informed consent documents, 
agree to monitor the conduct of the study, and agree to review study progress periodically, 


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at intervals not to exceed 1 year. The investigator will provide the sponsor or designee with 
documentation that the IRB/EC has approved the study before the study may begin. 
In addition, the investigator must provide the following documentation to DCRI: 
1. IRB/EC annual reapproval of the protocol,. 
2. IRB/EC approval of revisions to the informed consent documents or any 
amendments to the protocol. The investigator will provide the sponsor or 
designee with documentation of all approvals. 
13.6 Steering Committee 
The Steering Committee will be the primary decision making body of the study and is 
responsible for its successful completion. The Steering Committee will be comprised of 
the study principal investigators, the project leader, and selected other investigators with 
expertise in heart failure and clinical trials.  
13.7 Data and Safety Monitoring Board 
A data and safety monitoring board (DSMB) will be appointed for the PRIME-HF trial, 
which will include individuals with pertinent expertise in heart failure and clinical trials. 
The DSMB will advise the Steering Committee regarding  safety concerns for current 
participants and those yet to be recruited.  
 
 


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14 Appendices 
Appendix A. Safety Considerations 
Similar to the SHIFT study, the following treatments are not allowed at inclusion or 
during the study: 
 
Non-dihydropyridine calcium channel blockers (e.g., diltiazem and verapamil) 
 
Class I anti-arrhythmics (e.g., quinidine, procainamide, lidocaine, phenytoin) 
 
Strong inhibitors of cytochrome P450 3A4 (CYP3A4), including some macrolide 
antibiotics (e.g., clarithromycin, erythromycin), cyclosporine, antiretroviral drugs 
(e.g., ritonavir, nelfinavir), and systemic azole antifungal agents (e.g., 
ketoconazole, itraconazole)  
 
Inducers of cytochrome P450 3A4 (CYP3A4) including St. John’s Wort, 
rifampicin, barbiturates, and phenytoin 
 
Treatments known to be associated with significant prolongation of the QT 
interval, including sotalol 
  
 
 


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Appendix B. Cardiomyopathy Questionnaire and Patient Global Assessment  
Kansas City Cardiomyopathy Questionnaire  
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a self-administered, 23-item 
questionnaire developed to provide a better description of health-related quality of life 
(QOL) in patients with heart failure. It quantifies physical limitation, symptoms, QOL, 
social interference and self-efficacy. The survey requires 4-6 minutes to complete, and is 
scored by assigning each response an ordinal value, beginning with 1 for the response 
that implies the lowest level of functioning and summing items within each domain. 
Scale scores are transformed to a 0 to 100 range by subtracting the lowest possible scale 
score, dividing by the range of the scale and multiplying by 100. A clinical summary 
score will be calculated by combining the functional status with the quality of life and 
social limitation domains.  
 
Patient Global Assessment  
A seven category global assessment of clinical status that is completed by the participant 
will be utilized in the assessment of the composite score. This Patient Global Assessment 
(PGA) tool consists of the categories of: markedly improved, moderately improved, 
mildly improved, no change, slightly worse, moderately worse and markedly worse.  
Participants will be asked to define their status using this tool at specified times during 
the protocol by marking their current status, relative to the baseline condition. The Patient 
Global Assessment tool will be prepared in a manner which is simple to read (large print) 
and will be retained as a source document. 
 


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References  
1. 
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics—
2015 Update: A Report From the American Heart Association. Circulation. 
2015;131(4):e29-e322. 
2. 
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(16):e240-e327. 
3. 
Gattis WA, O'Connor CM, Gallup DS, Hasselblad V, Gheorghiade M. 
Predischarge initiation of carvedilol in patients hospitalized for decompensated heart 
failure: results of the Initiation Management Predischarge: Process for Assessment of 
Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. Journal of the American 
College of Cardiology. 2004;43(9):1534-1541. 
4. 
Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic 
heart failure (SHIFT): a randomised placebo-controlled study. The 
Lancet.376(9744):875-885. 
5. 
Braunwald E. Heart failure. JACC: Heart Failure. 2013;1(1):1-20. 
6. 
Chen J, Normand SL, Wang Y, Krumholz HM. National and regional trends in 
heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998-2008. 
JAMA : the journal of the American Medical Association. 2011;306(15):1669-1678. 
7. 
Loehr LR, Rosamond WD, Chang PP, Folsom AR, Chambless LE. Heart Failure 
Incidence and Survival (from the Atherosclerosis Risk in Communities Study). The 
American journal of cardiology. 2008;101(7):1016-1022. 
8. 
Fonarow GC, Yancy CW, Heywood JT. Adherence to heart failure quality-of-care 
indicators in US hospitals: analysis of the ADHERE Registry. Arch Intern Med. 
2005;165(13):1469-1477. 
9. 
Peterson PN, Chan PS, Spertus JA, et al. Practice-level Variation in Use of 
Recommended Medications Among Outpatients With Heart Failure: Insights From the 
NCDR PINNACLE Program. Circulation: Heart Failure. 2013. 


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10. 
Fonarow GC, Yancy CW, Hernandez AF, Peterson ED, Spertus JA, Heidenreich 
PA. Potential impact of optimal implementation of evidence-based heart failure therapies 
on mortality. American heart journal. 2011;161(6):1024-1030.e1023. 
11. 
Members ATF, McMurray JJV, Adamopoulos S, 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. European Heart Journal. 2012;33(14):1787-1847. 

SAP_001.pdf: 
PredischaRge Initiation of Ivabradine in the Management 
of Heart Failure (PRIME-HF) 
NCT02827500
Statistical Analysis Plan (SAP) 
Version 2.0 
Status:  Final, 11 January 2019 


 
Table of contents 
 
Abbreviations ................................................................................................................................................ 3 
1 
Purpose .................................................................................................................................................. 4 
2 
Study Overview .................................................................................................................................... 4 
 
Study Design ................................................................................................................................. 4 
 
Study Objectives ........................................................................................................................... 5 
2.2.2 
Secondary Objectives ................................................................................................................ 5 
2.2.3 
Tertiary Objectives .................................................................................................................... 5 
 
Sample Size Determination ........................................................................................................... 6 
 
Study Populations ......................................................................................................................... 6 
 
Study Endpoints ............................................................................................................................ 7 
2.5.1 Primary Endpoint ......................................................................................................................... 7 
2.5.2 Secondary Endpoints.................................................................................................................... 7 
2.5.3 Tertiary endpoints ........................................................................................................................ 8 
3 
Data Sources ......................................................................................................................................... 9 
4 
Participant Disposition .......................................................................................................................... 9 
5 
Demographics and Baseline Characteristics ......................................................................................... 9 
 
Demographics and Baseline Characteristics ................................................................................. 9 
 
Vital Signs and NYHA Class ........................................................................................................ 9 
 
Medical History .......................................................................................................................... 10 
 
Clinical Laboratory Results ........................................................................................................ 10 
6 
Medications ......................................................................................................................................... 11 
7 
Protocol Deviations ............................................................................................................................. 11 
8 
Safety Assessments ............................................................................................................................. 11 
 
12-Lead ECG .............................................................................................................................. 11 
 
Adverse Events ........................................................................................................................... 12 
9 
Endpoint Analyses .............................................................................................................................. 12 
 
Primary Analysis ......................................................................................................................... 12 
 
Secondary Analyses .................................................................................................................... 13 
 
Tertiary Analyses ........................................................................................................................ 16 
10 
Clinical Events ................................................................................................................................ 18 
11 
Competing risk analysis of death .................................................................................................... 19 


12 
Sub-group analyses ......................................................................................................................... 19 
13 
Statistical Considerations ................................................................................................................ 20 
 
Data Collection Windows and Conventions ............................................................................... 20 
 
General Analysis Conventions/Rules .......................................................................................... 21 
 
Documentation Conventions ....................................................................................................... 21 
 
Verification of SAS® Codes ....................................................................................................... 22 
 
Handling of Missing Data ........................................................................................................... 22 
 
Exploratory Analyses .................................................................................................................. 23 
 
Multiple Comparisons ................................................................................................................. 23 
14 
References ....................................................................................................................................... 23 
15 
Appendices ...................................................................................................................................... 25 
Table shells ................................................................................................. Error! Bookmark not defined. 
  
 
 
 


 
Abbreviations 
BB 
Beta-blocker 
bpm 
Beats per minute 
ECG 
Electrocardiogram 
HF 
Heart Failure 
HR 
Heart Rate 
IV 
Intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LVEF 
Left Ventricular ejection fraction 
NYHA 
New York Heart Association 
PGA 
Patient Global Assessment 
 
 
 


 
1 
PURPOSE  
This statistical analysis plan (SAP) reviews the study design and objectives, outlines the types of 
analyses and data presentations that address study objectives, and describes in detail the 
statistical methods for safety and efficacy analyses specified in the study protocol (PRIME-HF 
version 3, of July 19, 2017).  Any additional analyses or deviations from the planned statistical 
analysis will be described in a supplement to this SAP for non-substantive changes,  and in an 
SAP amendment, if the changes are substantive  (CT Stats SOP ST-S-005, 5.0, 31Jan2017, V.L).     
 
2 
 STUDY OVERVIEW 
This section summarizes the study objectives and design.   
 
Study Design 
The PRIME-HF study is a multi-center, patient-level, randomized, open-label study with a target 
of enrolling approximately 450 participants (patients) with reduced LVEF of <35% and heart-
rate >70 bpm who are being discharged from the hospital following stabilization from acute HF 
and will be randomized to a treatment strategy of pre-discharge initiation of ivabradine or usual 
care, involving post discharge initiation of ivabradine.   
  


 
Study Objectives 
The primary hypothesis of the PRIME-HF study is that, compared with usual care, a treatment 
strategy of initiation of ivabradine prior to discharge for a hospitalization for acute HF will be 
associated with a greater proportion of participants using ivabradine at 180 days.  
 
2.2.1 Primary Objectives 
 To test the primary hypothesis that, compared with usual care, a treatment strategy of initiation 
of ivabradine prior to discharge for a hospitalization for acute HF will be associated with a 
greater proportion of participants using ivabradine at 180 days. 
2.2.2 Secondary Objectives 
To assess the impact of pre-discharge initiation of ivabradine on: 
1) Heart rate 
a) Change in heart rate from baseline to 180 days 
b) Median heart rate at 180 days 
2) Patient-centered outcomes  
a) Kansas City Cardiomyopathy Questionnaire ( KCCQ) 
b) Patient Global Assessment (PGA) 
2.2.3 Tertiary Objectives 
Tertiary objectives will be to explore the impact of pre-discharge initiation of ivabradine on: 


1) Other assessments of evidence-based implementation of ivabradine and beta-blockers at 180 
days. Evaluations will incorporate data based on whether or not indication status was retained 
and whether or not an ivabradine prescription was provided. 
2) Tolerability of ivabradine based on  events of interest during study follow-up: 
a) Symptomatic bradycardia 
b) Symptomatic hypotension 
c) Other symptoms leading to ivabradine discontinuation 
3) To explore barriers to the acquisition of ivabradine. 
 
Sample Size Determination 
For sample size determination, it was assumed that 35% of participants randomized to the usual 
care arm would be treated with ivabradine at 180 days, and the pre-discharge initiation of 
ivabradine would increase the use at 180 days to 50%. The usual care event rate is based on 
investigator estimates of clinical use in the first year following approval by the Food and Drug 
Administration. At a two-sided Type I error rate of 0.05, 450 participants would provide 85% 
power to detect a significant difference in the rate of ivabradine use between groups. The original 
plan was to randomize 450 participants in the study. However, due to enrollment challenges 
faced in the study, enrollment was stopped after enrolling a total of 104 participants. 
 
Study Populations 
Participants suitable for this protocol are individuals with chronic HF who are hospitalized with 
acute heart failure, have achieved clinical stability and have an LVEF<35% and heart-rate >70 
bpm in normal sinus rhythm. Participants should not have a planned/scheduled up titration of 


beta-blocker in the following 4 weeks. Adjustments of background therapy can be made at any 
point during the study period at the discretion of the attending physician. 
All participants randomized to the study constitute the intent to treat (ITT) population. 
Participants that receive ivabradine at the week 6 visit constitute the treated population.  The 
primary efficacy endpoint will be evaluated based on the ITT population. As a sensitivity 
analysis, the primary and key secondary endpoints will be evaluated on the treated population. 
 
Study Endpoints 
  2.5.1 Primary Endpoint  
The study protocol (in section 10.1) states that the primary endpoint of the study is the 
proportion of participants using ivabradine at 180 days. The endpoint for each participant will be 
determined from ivabradine use at 180 days evaluated as a binary outcome. 
2.5.2 Secondary Endpoints 
The secondary endpoints are: 
1) Heart rate assessments 
a)  Change in heart rate from baseline to 180 days  
b) Heart rate at 180 days 
c) Proportion of participants with heart rate < 70 bpm at 180 days 
2)  Change in symptoms and quality of life from baseline to 180 days as assessed by: 
          a)  KCCQ 
          b)  PGA 


 2.5.3 Tertiary endpoints 
Tertiary endpoints are 
1)  Beta-blocker use at 180 days as assessed by the: 
a)  Proportion of participants on beta-blocker at 180 days 
b)  Proportion on target dose1 
c) Proportion discontinuing beta-blockers at 180 days and 
d.)  Mean change in beta-blocker dose from discharge to 180 days. 
2). Ivabradine use at 180 days as assessed by the: 
     a) Proportion of appropriate2 participants with any initiation3 of ivabradine at 180 days 
     b)  Proportion of appropriate participants at the maximum dose of ivabradine at 180 day. 
     c) Mean dose of ivabradine achieved at 180 days. 
3). Tolerability of ivabradine and events of interest: 
     a) Symptomatic bradycardia 
    b) Symptomatic hypotension 
    c) Other symptoms leading to ivabradine discontinuation 
4). Summary of barriers to acquisition of ivabradine 
                                                          
1 Beta-blocker target dose is defined as participants who receive Carvedilol equivalent total daily dose of 50 mg 
2Appropriate participants are defined as participants who have a sinus rhythm (participants excluding those with AF) 
and heart rate of ≥70 bpm. For participants missing 180 day ECG, results from the baseline ECG are used to 
determine appropriateness. 
3 Receiving ivabradine at any time point during the study. 


3 
DATA SOURCES 
Clinical data are collected within the IBM Clinical Development (IBM CD, formerly eCOS) 
database. Protocol deviation data are collected within the Clinical Trial Management System 
(CTMS) database. 
4 
PARTICIPANT DISPOSITION 
The number of participants randomized, the number who dropped out early and the number that 
completed4 the study will be summarized by randomization arm and overall. 
 
 
5 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
 
Demographics and Baseline Characteristics   
Participant demographics will be summarized by randomization arm using descriptive statistics 
(mean, SD, median, inter-quartile range, min and max) for continuous and counts (percentages) 
for categorical variables. Demographics will include age, sex, race and ethnicity. Baseline 
characteristics will include BMI, LVEF and number of prior HF hospitalization, medical history 
and baseline medications.   
 
Vital Signs and NYHA Class 
Participant vital signs will be summarized by randomization arm over time and analyzed with a 
mixed model approach, described in Appendix 2.  Statistical test for the treatment and the 
                                                          
4 Completers are participants who had an in-person day 180 visit. 


treatment * time interaction will be done.   The vital signs   summarized include heart rate5, 
systolic blood pressure, diastolic blood pressure and weight. NYHA class will be summarized by 
randomization arm in shift tables from baseline to worst post-baseline and baseline to 180 days. 
Improvement (worsening) will be evaluated using the Chi-Square test. Improvement is defined 
as moving from a higher NYHA class to a lower class from baseline. Worsening is defined as 
moving from a lower class to a higher class from baseline.   A data listing of vital signs and 
NYHA class will be presented.  
 
Medical History 
Detailed information from the relevant medical history is reviewed during screening for each 
body system. Incidences of medical diagnostic conditions found during assessment will be 
tabulated by randomization arm.  
 
Clinical Laboratory Results 
 Descriptive summary of lab results of BNP and NT-proBNP6 will be presented by 
randomization arm over time. Moreover, summary change from baseline to 180 days will be 
presented by randomization arm. The data will be analyzed using the mixed model approach 
described in Appendix 2 after log transformation to correct the highly skewed nature of the data. 
A data listing of the lab measures BNP and NT-proBNP will be presented. 
                                                          
5 The primary source of heart rate (at baseline and 180 days) is ECG assessment, if ECG assessment was not done at 
the 180 day visit, heart rate from vital signs assessment is used. 
6 BNP and NT-proBNP labs are deemed most relevant for this presentation. 


6 
MEDICATIONS 
A summary of medication usage will be presented by randomization arm over time. The 
summary will show the frequencies and percentages of participants using the medications.  Beta-
blocker and Ivabradine doses taken will be summarized by randomization arm. Beta-blocker 
dose descriptive summary will be will be presented in Carvedilol equivalent unit.  Reasons for 
not taking beta-blocker will be summarized as frequencies and percentages by randomization 
arm over time. Dose data will be analyzed using the mixed model approach described in 
Appendix 2.  A data listing of the medications will be presented. 
7 
PROTOCOL DEVIATIONS 
Protocol deviations will be summarized as frequencies and percentages by deviation type on a 
participant basis. A data listing of protocol deviations will also be presented. 
8 
SAFETY ASSESSMENTS 
 
12-Lead ECG 
Summary of ECG findings will be presented by randomization arm by assessment time point. 
Specifically, frequencies and percentages of rhythm, and descriptive summaries of QRS duration 
and QTc interval will be presented at baseline and 180 days post-discharge. ECG data will be 
analyzed using the Wilcoxon rank sum test.  A data listing of ECG findings will be presented. 
      


 
Adverse Events 
Adverse events (AEs) will be summarized for each randomization arm by body system and 
preferred term using MedDRA. The adverse events include events of interest, serious and 
unexpected events, and events which are related to ivabradine use in the opinion of site 
investigators. The summaries will show participant level and event level counts.  Events will be 
sorted alphabetically by body systems and preferred terms. A data listing of adverse events will 
be presented. 
  
9 
ENDPOINT ANALYSES 
 
Primary Analysis 
The primary analysis will be performed on an intention-to-treat (ITT) basis including all 
randomized participants. Participant who are not assessed at the 180 day visit due to death or 
other reasons of early termination, and otherwise medication data not being collected will be 
coded as failures (ivabradine use=0). The primary analysis will be based on the imputed data. 
For sensitivity analysis, observed ivabradine use will be used. Given that death is a competing 
risk of ivabradine use, a competing risk analysis will be performed (see section 11). 
The primary analysis will be performed with a logistic regression model, with ivabradine use7 at 
180 days as the binary outcome variable and indicator variables for treatment group main effects 
                                                          
7 Ivabradine use will be determined from the Ivabradine use pane and will be coded as a “0/1” (no/yes) variable. 


and category (0/1) of baseline beta-blocker (BB) use8. The treatment effect for the ivabradine at 
discharge group will be summarized by the odds ratio and associated 95% confidence interval.  
Ivabradine use in the ivabradine arm at 180 days is expected to be higher than in the usual care 
arm. 
Model (logistic): 
Ivabradine use at 180 days= Intercept+ β1* treatment + β2* baseline beta-blocker use     
Hypothesis: 
 
H0: β1=0 
 
H1: β1≠0. 
 
The null hypothesis will be rejected if the p-value of the treatment effect is <0.05. 
 
 
Secondary Analyses 
  
1.  Heart Rate Assessments 
a. Change in heart rate from baseline to 180 days will be compared across 
randomization groups. Change will be calculated as follows: (Baseline heart rate 
– 180 day heart rate)9. Comparisons across randomization groups will be 
performed using a linear model with adjustment for baseline heart rate and beta-
blocker use.  Randomization groups will be included in the regression model as 
main effect.  
                                                          
8 Baseline beta-blocker use will be coded as a “0/1” variable with participants who received beta-blocker coded as 
“1” and those who did not receive beta-blocker as “0”. 
9 All change from baseline results presented are calculated similarly. 


 Heart rate is expected to be lower in the ivabradine arm than the usual care arm. 
Thus, change from baseline is expected to be higher in the ivabradine arm. 
 
Model (linear): 
Change in Heart Rate (HR) at 180 days = Intercept + β1* treatment + β2* baseline HR + β3* 
baseline BB use    
   
Hypothesis: 
 
H0: β1=0 
 
H1: β1≠0. 
 
The null hypothesis will be rejected if the p-value of the treatment effect is <0.05 
b. Heart rate in bpm at 180 days in the pre-discharge ivabradine group will be 
compared to the usual care group. Comparisons across randomization groups 
will be performed using a linear model with adjustment for the baseline heart 
rate and beta-blocker use.  Treatment groups will be included in the regression 
model as main effects. 
Model (linear): 
HR at 180 days = Intercept +β1*treatment + β2* baseline HR +β3* baseline BB use    
Hypothesis: 
 
H0: β1=0 
 
H1: β1≠0. 
 
The null hypothesis will be rejected if the p-value of the treatment effect is <0.05 


c. The proportion of participants with heart rate < 70 bpm at 180 days will be 
evaluated. Differences between the randomization arms will be evaluated using 
the Chi-square test10.   
2. Changes in symptoms and quality-of-life from baseline to 180 days as assessed by KCCQ 
and PGA will be evaluated across randomization groups using a linear model with 
adjustment for the baseline quality-of-life and beta-blocker use.  The differences between 
the randomization arms  will be estimated using point estimates and the associated two-
sided 95% confidence intervals 
Model (linear): 
Change in KCCQ at 180 days= Intercept + β1*treatment + β2* baseline KCCQ + β3* 
baseline BB use   
Hypothesis: 
 
H0: β1=0 
 
H1: β1≠0. 
 
The null hypothesis will be rejected if the p-value of the treatment effect is <0.05 
Change in PGA at 180 days = Intercept + β1*treatment + β2* baseline PGA + β3* baseline 
BB use    
Hypothesis: 
 
H0: β1=0 
 
H1: β1≠0. 
 
The null hypothesis will be rejected if the p-value of the treatment effect is <0.05 
Missing values of 180 day heart rate, KCCQ and PGA will be imputed if missing values  
                                                          
10  If events are rare, p-value from the Fisher’s exact test will be reported. 


exceed 10% of the observations (see section 12.5).   
 
Tertiary Analyses 
1. Beta-blocker use at 180 days as assessed by the (a) proportion of participants on a 
beta-blocker at 180-days, (b) proportion on target dose, (c) proportion of 
participants who are at ≥50% target dose (d) the proportion discontinuing beta-
blockers at 180 days and (e) the mean change11 in beta-blocker dose from 
discharge to 180 days will be compared between the randomization arms.   The 
mean change of beta-blocker dose will be calculated for participants who provide 
data at baseline and at 180 days post-discharge visits.   
 
 The proportions of participants on beta-blocker, the proportions on target dose, the 
proportion on at least 50% of the target dose, and the proportions discontinuing beta-
blocker at 180 days will be summarized by randomization arms and tested using the Chi-
square test.  The change in beta-blocker dose from discharge to 180 days will be 
summarized and compared using the Wilcoxon rank sum test. 
 
2. Ivabradine use at 180 days as assessed by the (a) proportion of appropriate 
participants with any initiation of ivabradine at 180 days, (b) the proportion of 
appropriate participants at the maximum dose of ivabradine at 180 day (i.e., 7.5 mg 
                                                          
11  Comparing the mean change in beta-blocker dose is interpreted as comparing the distribution of dose changes 
between the randomization arms. 


twice daily), and (c) the mean dose of ivabradine achieved at 180 days will be 
compared between  the randomization arms.  
Participants who do not provide the 180 day visit data will be coded as failures 
(ivabradine=0 and dosage=0.0). The mean dose of ivabradine achieved will be 
calculated for participants who provide data at 180 days post-discharge visit and 
using imputed values for the participants who do not provide 180 day visit data. As a 
sensitivity analysis, data will also be analyzed on observed data without imputing 
missing values.  In addition, ivabradine dosage will be summarized for participants on 
ivabradine at the 180 day visit. 
The proportions of appropriate participants with any initiation of ivabradine and the 
proportion of appropriate participants at the maximum dose of ivabradine at 180 days 
will be summarized as incidences by the randomization arms and tested using the 
Chi-Square test.  The dose of ivabradine achieved at 180 days will be summarized 
and compared using the Wilcoxon rank sum test. 
3. The event incidences for the following adverse events will be summarized by the 
randomization arms. 
a. Symptomatic bradycardia 
b. Symptomatic hypotension 
c. Other symptoms leading to ivabradine discontinuation 
 Other symptoms leading to ivabradine discontinuation will be determined using data collected in 
the AE CRF panel.  . 
Differences between the randomization arms of the events will be tested using the Chi-square 
test. 


 
4. Barriers to acquisition of ivabradine. 
Reasons for not obtaining ivabradine will be summarized by randomization arm over time as 
classified in the case report form. Frequencies and percentages of the classified reasons will be 
presented for each visit and overall. Results will be presented as descriptive summaries.   
  
10 CLINICAL EVENTS  
The following clinical events occurring within 180 + 14 days will be summarized by 
randomization arm.  The summaries will be presented as incidences and rates. 
The clinical events include:  
1) Worsening HF defined as hospital admission for worsening signs and/or symptoms of HF or 
receiving unplanned intravenous (IV) diuretics for HF as an outpatient. 
2) HF hospitalization 
3) All-cause hospitalization 
4) All-cause mortality 
5) Composite of all-cause mortality and HF hospitalization 
  
Incidences of the events will be tabulated by randomization arm and differences between the 
randomization arms will be tested using the Chi-square test. 


11 COMPETING RISK ANALYSIS OF DEATH 
Participants are at risk of dying before the final visit, and thus death is a competing risk to 
ivabradine use. In order to account for participants who die prior to the 180 day visit, a 
competing risk analysis of time to ivabradine discontinuation will be conducted. Participants 
who die during the study will be coded separately from those who discontinue ivabradine use. 
The analysis will be performed using the cumulative incidence function (CIF) method with death 
as an additional censoring variable12. The Gray’s test (Gray, 1988) will be used to evaluate 
hypothesis of equality of the cumulative incidence functions. 
12 SUB-GROUP ANALYSES 
To evaluate differences in ivabradine use among participant sub-groups, pre-specified sub-group 
analysis will be performed.  For each subgroup, the analysis specified for the primary endpoint in 
section 9.1 will be performed. Accordingly, ivabradine use rates will be summarized by 
randomization arm, odds ratio with their 95% CI and p-value of the treatment effect will be 
presented.  Also, a forest plot of ivabradine use will be presented. 
The sub-groups are:  
Variable 
 
  
  
   Criteria 
Age (years)                              
<75 vs. >=75  
Sex:                                
 
Male vs. female  
Baseline beta-blocker use  
 
Yes vs. No 
Race    
 
 
 
White vs. Non-white  
                                                          
12 Participants who did not receive any ivabradine dose will be censored at time 0. 


EF    
 
 
 
 
<25 vs. ≥25 
NYHA class    
 
 
I and II   vs.  III and IV 
Systolic blood pressure   
 
<120   vs. ≥120     
GFR    
 
 
 
< 60 vs. ≥ 60 
Diabetes  
 
 
 
  Yes vs. No 
Etiology of HF  
 
 
  Ischemic vs. Non-ischemic 
 
13 STATISTICAL CONSIDERATIONS 
 Data Collection Windows and Conventions 
Data will be presented according to the schedule of assessments in the study protocol. The 
possible visits and windows are baseline, Day 7-14 post discharge, 6 weeks post-discharge 
(42±14 days), 90 days post-discharge (±7 days), and 180 days post-discharge (±14 days). If 
participants missed their scheduled window, data collected from clinic visits and entered in the 
EDC system will be used if clinic visits occurred within 60 days of the assessment window.  
Heart rate obtained from ECG assessment is the primary data source. If, however, ECG 
assessment was not performed, heart rate results from vital signs collected during the scheduled 
visit or clinical visit close to the visit window will be used.   
For participants who are lost to follow-up, the latest date available is used as date of last contact 
for the purpose of determining their vital status. Lost to follow-up participants whose survival 
status are ascertained beyond the study period will be censored at 194 days (180 +14). Those 
whose last contact date falls within the study period will be censored at their date of last contact 
for any time to event analysis. 


 General Analysis Conventions/Rules  
All analyzed continuous variables will be summarized using descriptive statistics including 
number of observations,  mean, standard deviation, minimum, 25th percentile, median, 75th 
percentile, and maximum.  All analyzed categorical variables will be summarized using 
frequency counts and percentages. Percentages are calculated out of non-missing values unless 
stated otherwise. Comparisons of continuous (or discrete ordered) variables between 
randomization groups will generally be tested using the Wilcoxon rank sum test. For the 
secondary endpoint (change from baseline of the measures), analyses will be conducted using the 
general linear model approach.  For comparisons over more than 2 time points, when 
appropriate, mixed effects models13 will be used to account for correlation within participant 
observations and assess time-by-treatment interactions (see Appendix 2 for details).Tests of 
binomial outcomes between randomization groups will generally be done with a Chi-square 
statistic.  Tests of treatment effects will generally be 2-sided, with type I error = 0.05.  
Interaction tests will generally be done at the 0.10.  Statistical significance is determined at a ≤ 
0.05 alpha level.  
. 
 Documentation Conventions 
Statistical analyses will be performed using SAS, version 9.4 or higher (SAS Institute, Cary, 
NC).  Additional statistical software may be used as needed. Where applicable, all the tables and 
listings will be presented by study randomization arm and overall. 
                                                          
13 See Appendix 2 for details 


 Verification of SAS® Codes 
All tables, listings, and graphs will be verified and reviewed before being considered final. The 
verification process will ensure that the numbers are produced by a statistically valid method and 
that the execution of the computations is correct.  Suitably qualified personnel who have not 
been previously involved in the production of the original SAS code will perform the 
verification procedures.  Methods of verification will include independent programming of all 
analysis datasets and comparison to data listings as specified in the verification plan.  Tables will 
be reviewed for accuracy, consistency with this analysis plan, consistency within tables, and 
consistency with corresponding output.  Once verification is complete, all documentation of the 
verification process will be filed in a statistical programming documentation as required by the 
Statistical Standard Operations Procedure (CT Stats SOP ST-S-010, 11.0, 31Jan2017, V.E) of 
the Duke Clinical Research Institute (DCRI).   
 Handling of Missing Data   
All efforts will be made to make sure all data needed for the analyses outlined in the SAP are complete. 
However, it is possible that some data will be missing. Missing data is a common problem in clinical 
research. It reduces statistical power (the probability that the test will reject the null hypothesis when it is 
false) and results in biased parameter estimates (Kang, 2013). Outcomes for participants who do not 
provide data during the 180 day visit will be imputed as failures. Missing heart rate, PGA and KCCQ 
values will be imputed for the final (180 day) visit using multiple imputation technique if more than 10% 
of the measures are missing.   
It is expected that missing 180 day visit values constitute > 10% of the secondary endpoints (Heart rate, 
KCCQ and PGA). Thus, multiple imputation (MI) will be performed and presented for the ITT and 
Treated populations, respectively. 


Imputation will be conducted using PROC MI and imputed data analyzed with PROC MIANALYZE in 
SAS 9.4. 
The following variables shall be used in the imputation: 
AGE, SEX, RACE, ETHNICITY, WEIGHT, NYHA class, LVEF, and baseline value of the imputed 
variable) – For NYHA class, WEIGHT and LVEF, baseline values will be used. 
 RACE shall be recoded to: White, Black and Others (combining American Indian, other, and mixed - as 
they are of very low frequency) 
Results of the imputation shall be presented as the primary result of the secondary endpoints. A total of 25 
imputations will conducted for each imputed value. 
 Sensitivity analyses will be conducted by analyzing these endpoints with and without imputation.   
 Exploratory Analyses 
All analyses that are not specified as the primary or the secondary or tertiary endpoints are to be 
considered exploratory. All exploratory analyses are considered descriptive and are used as 
further hypothesis generating endeavors and no p-values will be calculated.    
 Multiple Comparisons  
No multiple comparison adjustment will be used implemented in this study. 
  
14  REFERENCES 
Gray, R. (1988), “A Class of K-Sample Tests for Comparing the Cumulative Incidence of a Competing 
Risk,” The Annals of Statistics, 16, 1141–1154. 


Kang, H. (2013, May). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668100/ 
PRIME-HF. (July 19, 2017). PredischaRge Initiation of Ivabradine in the Management of Heart  
 
Failure (PRIME-HF), Protocol Version 3. 
 
 


 
 
 
 
 
15 APPENDICES 
 


Appendix 1 
 
Data Sources for Endpoints 
1.  Ivabradine use 
 
a)  Ivabradine use (1/0) at 180 days comes from either the current medications data (CM) 
or the ivabradine usage data (DRG). 
If CM.CMIVA=1 and VISITID=50 or DRG.DRIVA=1 and VISITID=50. If missing then 
it is imputed to 0. (Note: analysis will also be done without imputation). 
b) Ivabradine dose change from  baseline to 180 days  
Ivabradine use and dose at baseline comes from the ivabradine initiation in hospital 
(EXH) data EXH.EXRECH (use)   and EXH.EXLDH (dose) EXH.EXRECH (use)   
and EXH.EXLDH (dose) (VISITID=10) and ivabradine obtaining the first time 
(outpatient) (EX) EX.EXREC and EX.EXPDOS (VISITID=60 study wide to be 
merged in) 
 
For other time points use the ivabradine usage data DRG.DRIVA (use) DRG.DRDSG 
(dose). Missing doses will be imputed to 0. (Note: analysis will also be done without 
imputation). 
 
Dose change from baseline to 180 days = EXH.EXLDH, EX.EXDOS (VISITID=10)- 
DRG.DRDSG (where VISITID=50) 
 
c) Proportion with any initiation  
If participant received ivabradine at any time during the visits  
If EXH.EXRECH=1 or EX.EXREC=1 or CM.CMIVA=1 or DRG.DRIVA=1 at any 
visit then ANYIVA=1 else ANYIVA=0; (Note: No imputation of missing ivabradine 
use occurs for this derivation) 
 
d) Proportion on maximum dose at 180 days 
Use ivabradine usage data 
If DRG.DRSG =15 (mg) and VISITID=50 then on ivabradine maximum dose=1; else 
if DRG.DRSG not missing on ivabradine maximum dose=0. 
  
  
2. Heart rate (HR) 
 
Heart rate is obtained from the ECG (EG) data where available. If 180 day ECG data is not 
available, heart rate from the vitals data for the visit or from the medical record close to the visit 
is used. For participants who have two baseline ECG measurements average is taken prior to 
calculating change from baseline. 
 
a) HR change from baseline to 180 days = EG.ECGHR (where VCISITID=10) – 
EG.EGHR (where VISITID=50) if 180 day ECG is not missing. 
or 


                  = EG.ECGHR (where VISITID=10)-VS.PULSE (where VISITID=50) if 180 day 
ECG is missing. 
 
b) HR at 180 days= EG.ECGHR  (where VISITID=50) if 180 day ECG is not missing 
 or 
  =VS.PULSE (where=VISITID=50) if 180 day ECG is missing 
Note: missing HR at 180 days will be imputed using MI technique per (Section 12.5) 
 
c) Proportion of participants with heart rate < 70 bpm at 180 days 
If HR at 180 days (see b) above) is < 70bpm (but not missing) then   HR less than 70 
bpm=1; else HR less than 70 bpm=0. 
 
3. Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
KCCQ change from baseline to 180 days is obtained from the KCCQ analysis (KCCQD) 
data created from the KCCQ survey using the KCCQ scoring algorithm. 
KCCQ change= KCCQD.KCQOSBL –KCCQD.KCCQOSS (where VISITN=50) 
 
 Note: missing KCCQ values at 180 days will be imputed using MI technique per (Section 
12.5) 
 
4. Patient Global Assessment  (PGA) 
 
PGA change from baseline to 180 days is obtained from the PGA (PGA) data. 
PGA change from baseline to 180 days= PGA. PGAMM (where VISITID=10) – PGA.PGAMM  
 
(Where VISITID=50) 
 
Note: missing PGA values at 180 days will be imputed using MI technique per (Section 12.5) 
 
5.  Beta-blocker (BB) use 
 
Beta-blocker use measures were obtained from the current medication (CM) data 
Baseline BB use at baseline = CM.CMBB =1 where VISITID=10). 
 
a) BB use at 180 days = CM.CMBB=1 (where VISITID=50) 
b) Proportion on target dose at 180 days (doses were calculated based on Carvedilol 
equivalent basis). 
If VISITN =50 and Carvedilol equivalent dose = 50 mg then on target dose=1 (yes); else 
if Carvedilol equivalent dose is not missing on target dose=0(no). 
c) Proportion on 50 % of target dose (Carvedilol equivalent) at 180 days. 
If Carvedilol equivalent dose is at least 25 mg then on 50% target dose=1; else if 
Carvedilol equivalent dose is not missing on 50% target dose =0. 
d) Proportion of participants discontinuing (No beta-blocker use at 180 days in those 
who used it during an early visit) 
e) Mean change in dose (Carvedilol equivalent) 
Change in dose from baseline to 180 days (converted to Carvedilol equivalent dose) = 
CM.CMBBDS   (where VISITID=10) – CM. CMBBDS (where VISITID=50) 


 
6. Tolerability of ivabradine and events of interest 
 
a) Symptomatic bradycardia 
 
Use the EVENT data to get unique participant level status. 
If EVENT.EVBRDC=1 and (non-missing EVENT.EVDT-PATIENT.DISDT <=194) 
then symptomatic bradycardia=1; else if participant is assessed at any time point, 
symptomatic bradycardia=0. 
 
b) Symptomatic hypotension 
 
Use the EVENT data to get unique participant level status. 
If EVENT.EVHYPO=1 and (non-missing EVENT.EVDT-PATIENT.DISDT<=194) then 
symptomatic hypotension=1; else if participant is assessed at any time point, 
symptomatic hypotension=0. 
c) Other symptoms leading to ivabradine discontinuation unique participant level status 
Other symptoms leading to ivabradine discontinuation is obtained from the AE data. 
If AE.AETYP=3and (non-missing AE.AESTDT-PATIENT.DISDT <=194) then other 
symptoms leading to ivabradine discontinuation=1; 
Else if participant is assessed at any time point, other symptoms leading to ivabradine 
discontinuation=0;  
 
7. Summary of clinical events 
 
a) All-cause mortality   
Death is obtained from the DEATH data  
If DEATH.DTHDT is not missing then DEATH=1; else if participant is assessed at any 
time point, DEATH=0. 
 
Restrict deaths to within 194 days of discharge. (non-missing DEATH.DTHDT – 
PATIENT.DISDT  <= 194). 
 
b) Worsening heart failure  unique per participant 
Worsening heart failure is defined as hospital admission for worsening signs and/or 
symptoms of HF or receiving unplanned intravenous (IV) diuretics for HF as an 
outpatient is obtained from hospitalization data (REHOSP) and ER/Clinic Visits 
(ERCLIN) data sets. 
If REHOSP.RELHF=1 or ERCLIN.ERIVTMT=1 then Worsening heart failure =1; 
else if participant is assessed at any time point, worsening heart failure =0. 
Restrict HF hospitalizations or ER visits for unplanned IV diuretics to within 194 
days of discharge. (non-missing REHOSP.HOSPDT – PATIENT.DISDT   <= 194) 
and (ERCLIN.ERVISDT- PATIENT.DISDT   <=194). 
 
c) HF hospitalization unique per participant 
 


HF hospitalization is obtained from the hospitalization data (REHOSP), 
If REHOSP.RELHF=1 then heart failure hospitalization=1; else if participant is assessed 
at any time point, heart failure hospitalization=0. 
Restrict HF hospitalizations to within 194 days of discharge 
(non-missing REHOSP.HOSPDT – PATIENT.DISDT   <= 194). 
 
d) All-cause hospitalization unique per participant 
All-cause hospitalization is obtained from the hospitalization data (REHOSP). 
If REHOSP. HOSPDT is not missing then all-cause hospitalization =1; else if participant 
is assessed at any time point, all-cause hospitalization=0. 
 Restrict all-cause hospitalizations to within 194 days of discharge 
(non-missing REHOSP.HOSPDT – PATIENT.DISDT   <= 194). 
e) Composite endpoint of mortality or HF hospitalization 
If DEATH (see  ( a) above) =1 or  HF hospitalization (see (c) above )=1 then 
Composite endpoint =1; 
Else if both are =0 then Composite endpoint=0. 
Event is restricted to within 194 days of discharge per component parts. 
 
8) Barriers to acquisition of ivabradine 
 
Barriers to the acquisition of ivabradine comes from two sources. Barriers to the first 
time acquisition of ivabradine comes from the ivabradine obtaining first time data (EX).   
Get variables EX.EXPRC, EX.EXPHRM, EX.EXAE, EX.EXLBL, EX.EXPDC, 
EX.EXDDC, EX.EXPAN, EX.EXPAS, EX.EXINS, EX.EXAPN, EX.EXAPA, 
EX.EXAPD, and EX.EXOTH (Note: VISITID=60) 
 
For subsequent visits, the data sources is the ivabradine usage (DRG) data (Note: 
VISITID=20, 30, 40, 50).  Get variables  
DRG.DRPRC, DRG.DRPHRM, DRG.DRAE, DRG.DRLBL, DRG.DRPDC, 
DRG.DRDDC, DRG.DRPAN, DRG.DRPAS, DRG.DRINS, DRG.DRAPN, 
DRG.DRAPA, DRG.DRAPD, and DR.DROTH 
 
Note: Since all reasons that apply are checked in both data sets, create separate (1/0) 
variables for each of them. 
 
Summarize reasons from the (1/0) variables. 
 
9) Treatment   
 
Treatment data come from the EDC system in the DAT_RAND data.  The data shows  
both the treatment codes and their descriptions. 
 
 
 


Appendix 2 
Mixed effects model analysis of repeated measures 
Data were collected over time on continuous variables such as vital signs, labs and medication doses. 
Since within participant observations are likely to be correlated, using an analytic method that accounts 
for the correlation is appropriate. The mixed effects modeling approach provides a mechanism for 
accounting such correlations.  Further, the procedure can include data from participants with partially 
complete data, and unequally spaced measurements which are evident in the data collected.  Thus, for 
measurements that are collected over more than two time points, the mixed effects modeling approach is 
used.   The model chosen includes treatment, time, and time by treatment interactions.  Time will be 
modeled as a continuous variable which is the time to actual measurement expressed as days from 
randomization (DAYS).  The model will assume a linear relationship between response measure and time, 
and allow for the intercept and slope of the linear model to differ by treatment group  
The model posited is: 
Response (MEASURE) = intercept + Treatment (TRT) + Time (DAYS) + Treatment (TRT)*Time 
(DAYS) 
 However, the test for treatment effect in the above model tests effects at baseline which is of little value. 
It is more valuable to test treatment effects after the intervention had time to affect outcomes.  
Accordingly, the 180 day time point is recoded to time zero as follows. 
RDAYS=DAYS-180 
And fit the model: 
Response (MEASURE) = intercept + Treatment (TRT) + Time (RDAYS) + Treatment (TRT)*Time 
(RDAYS) 
The within-patient residual covariance matrix will be modeled using a compound symmetry structure, 
which assumes equal correlation between measurement times within a patient. The residual covariance 
matrix will be assumed to be the same in the two treatment groups. 
Tests of fixed effects in the model will be calculated using the Kenward-Roger method for estimating 
denominator degrees of freedom. 
 
To fit the model the mixed effects model below is used; 
proc mixed data=data; 
Class TRT SUBNUM RDAYSC;  *RDAYSC is defined to be equal to RDAYS; 
Model MEASURE= TRT RDAYS TRT*RDAYS / ddfm=KR; 
Repeated RDAYSC /sub=SUBNUM TYPE=CS; /Compound symmetry covariance structure/ 
Run; 
The test for treatment effect (TRT) in this model evaluates treatment effects at 180 days while the 
interaction term (TRT*RDAYS) tests whether treatment effects differ over time, i.e., whether the slope 
(average change in measure per unit time) differs by treatment. The p-values for the treatment effect and 
treatment * time interaction (when appropriate) will be reported. 


If the equality of variance assumption does not hold (the variance differs a lot over time or across groups), 
the following code will be used. The model allows for unstructured covariance matrix. 
proc mixed data=data method=reml; 
   class TRT VISIT SUBNUM; 
   Model Measure = TRT RDAYS TRT*RDAYS/ solution ddfm=KR; 
   Repeated VISIT / subject=SUBNUM type=UN group=TRT; 
   run; 
 


Addendum to SAP version 2.0 (Dated 11January 2019) 
Participant 107-002 was on Ivabradine until the day before (15 August 2018) the date of 180 day visit (16 
August 2018).  
On the 180 day visit: 
To the question “Is subject currently taking Ivabradine” the site answered “No” due to “Physician 
decision”. 
So according to the CRF data, the participant was coded as “Ivabradine at 180 days=No” 
However, the participant was on Ivabradine for a total of 210 days only missing a dose for one day. 
According to the study PI, coding Ivabradine status of this participant as “Yes Ivabradine at 180 
days=Yes” is most appropriate. 
Consequently, coding of Ivabradine status at 180 days has been modified to “Ivabradine at day 180 = 
Yes” if a participant had last dose of Ivabradine administered on day 166 (180 + 14 days) or later. 
This action was take prior to unblinding treatment to avoid bias. 
  
 
 


Addendum 2 to SAP version 2.0 (Dated 11 January 2019) 
Modification to change calculation 
 
The PRIME-HF protocol (Version 3, Dated July 19, 2017 section 10.4 on page 60), specifies that change 
in heart rate (HR) from baseline to 180 days be calculated as (baseline heart rate – 180-day heart rate). 
Accordingly, the statistical analysis plan (SAP) version 2.0 specified that changes (for HR and all other 
measures) to be calculated as baseline line- 180 days results for all change calculations.  Post database 
lock and treatment unblinding, a decision was made to calculate change as 180 day – baseline results so 
that change signs align with the direction of change (increase or decrease