Conditions: Heart Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8256
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if treatment with omecamtiv mecarbil when added to standard of care is well tolerated and superior to placebo in reducing the risk of cardiovascular death or heart failure events in adults with chronic heart failure with reduced ejection fraction (HFrEF).

Detailed description:
This study was conducted by Amgen as the IND holder, with Cytokinetics as a collaborator. Due to the termination of the collaboration agreement between Amgen and Cytokinetics in May 2021 and subsequent transfer of the omecamtiv mecarbil IND from Amgen to Cytokinetics, Cytokinetics is now listed as the sponsor.

Arms:
arm 1: Participants received oral omecamtiv mecarbil (OM) twice daily in addition to standard heart failure therapy. The starting dose of OM was 25 mg; At week 4, participants with week 2 OM predose plasma concentrations \< 200 ng/mL had their dose increased to 50 mg BID; participants with week 2 predose plasma concentrations ≥ 200 and \< 300 ng/mL had their dose increased to 37.5 mg BID and participants with week 2 predose plasma concentrations ≥ 300 ng/mL and \< 1000 ng/mL maintained a 25 mg BID dosing regimen. arm 2: Participants received matching placebo tablets twice a day in addition to standard heart failure therapy.

Interventions: intervention 1: Omecamtiv Mecarbil intervention 2: Placebo intervention 3: Standard of Care
Intervention descriptions: intervention 1: Omecamtiv mecarbil tablets for oral administration intervention 2: Matching placebo tablets intervention 3: Participants were required to be optimally managed with standard of care therapies for chronic HF (eg, beta blockers, renin angiotensin aldosterone system inhibitors), consistent with regional clinical practice guidelines, unless contraindicated.

Protocol document:
Prot_000.pdf: 
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 1 of 85 
CONFIDENTIAL 
 
 
Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter Study to 
Assess the Efficacy and Safety of Omecamtiv Mecarbil on Mortality and Morbidity 
in Subjects With Chronic Heart Failure With Reduced Ejection Fraction 
Amgen Protocol Number (Omecamtiv Mecarbil [AMG 423]) 20110203 
EudraCT number 2016-002299-28 
NCT Number NCT02929329 
GALACTIC-HF 
Global Approach to Lowering Adverse Cardiac Outcomes Through Improving 
Contractility in Heart Failure 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone:  1-805-447-1000 
Key Sponsor Contact(s): 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Phone: 
Email: 
Date: 
31 August 2016 
Amendment 1 
07 September 2017 
Amendment 2 
13 November 2018 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1-800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; all other countries call 1-800-772-6436.  Amgen’s general number in 
the US (1-805-447-1000).  
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 2 of 85 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Double-blind, Randomized, 
Placebo-controlled, Multicenter Study to Assess the Efficacy and Safety of Omecamtiv 
Mecarbil on Mortality and Morbidity in Subjects with Chronic Heart Failure with Reduced 
Ejection Fraction, dated 13 November 2018, and agree to abide by all provisions set 
forth therein. 
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 3 of 85 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy 
and Safety of Omecamtiv Mecarbil on Mortality and Morbidity in Subjects with Chronic Heart 
Failure with Reduced Ejection Fraction 
Study Phase:  3 
Indication:  Heart failure (HF) 
Primary Objective:   
 
to evaluate the effect of treatment with omecamtiv mecarbil (OM) compared with placebo on 
the time to cardiovascular (CV) death or first HF event, whichever occurs first, in subjects 
with chronic HF with reduced ejection fraction (HFrEF) receiving standard of care (SoC) 
therapy 
 
An HF event is defined as presentation of the patient for an urgent, unscheduled 
clinic/office/ED visit, or hospital admission, with a primary diagnosis of HF, where the 
patient exhibits new or worsening symptoms of HF on presentation, has objective 
evidence of new or worsening HF, and receives initiation or intensification of treatment 
specifically for HF (Hicks et al, 2015).  Changes to oral diuretic therapy do not qualify as 
initiation or intensification of treatment.   
Secondary Objectives:   
 
to evaluate the effects of OM on time to: 
 
CV death 
 
HF hospitalization 
 
all-cause death 
 
to evaluate the effects of treatment with OM on change in patient-reported outcomes (PROs)  
Safety Objective:   
 
to evaluate the safety of OM as measured by subject incidence of reported adverse events, 
including serious adverse events of ventricular arrhythmias requiring treatment and positively 
adjudicated major cardiac ischemic events (fatal and nonfatal myocardial infarction, unstable 
angina hospitalization, and coronary revascularization) (Hicks et al, 2015) 
Hypotheses:   
The primary hypothesis is that when added to SoC, OM is well tolerated and superior to placebo 
in reducing the risk of CV death or HF events in subjects with chronic HFrEF. 
Secondary hypotheses are that OM reduces the individual risks of: 
 
CV death 
 
HF hospitalization 
 
all-cause death 
and improves symptoms in subjects with chronic HFrEF compared to placebo. 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 4 of 85 
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Primary Endpoint:   
 
composite of time to CV death or first HF event, whichever occurs first 
 
An HF event is defined as the presentation of the subject for an urgent, unscheduled 
clinic/office/ED visit, or hospital admission, with a primary diagnosis of HF, where the 
patient exhibits new or worsening symptoms of HF on presentation, has objective 
evidence of new or worsening HF, and receives initiation or intensification of treatment 
specifically for HF (Hicks et al, 2015).  Changes to oral diuretic therapy do not qualify as 
initiation or intensification of treatment. 
Secondary Endpoints:   
 
time to CV death 
 
change in Kansas City Cardiomyopathy Questionnaire Total Symptoms Score (KCCQ TSS) 
from baseline to Week 24 
 
time to first HF hospitalization 
 
time to all-cause death 
Safety Endpoints:   
 
subject incidence of reported adverse events 
 
subject incidence of reported serious adverse events of ventricular arrhythmias requiring 
treatment 
 
subject incidence of positively adjudicated major cardiac ischemic events  
 
positively adjudicated major cardiac ischemic adverse events are:  myocardial infarction, 
hospitalization for unstable angina, percutaneous coronary intervention/coronary artery 
bypass graft (Hicks et al, 2015) 
Study Design:  This is a randomized, placebo-controlled, double-blind, parallel group, 
multicenter, CV outcomes study in subjects with HFrEF, including subjects with ongoing or history 
of HF hospitalization.  The study is event-driven and will conclude when approximately 1590 CV 
death events have occurred.  Approximately 8000 eligible subjects will be randomized in a 
1:1 ratio to receive either OM or placebo.  Randomization will be stratified by randomization 
setting (currently hospitalized for HF or recently and not currently hospitalized for HF) and region 
(5 strata:  US and Canada; Latin America; Western Europe, South Africa, and Australasia; 
Eastern Europe including Russia; Asia).  At randomization, all subjects should be managed with 
standard of care therapies consistent with regional clinical practice guidelines.  Approximately 
25% or more of the total planned enrollment will include subjects who are hospitalized for HF at 
randomization.  Enrollment of subjects in atrial fibrillation/flutter at screening is limited to 
approximately 25%. 
Sample Size:  Approximately 8000 subjects will be randomized. 
Summary of Subject Eligibility Criteria:  Subjects must be adults with a history of chronic HF, 
defined as receiving treatment for HF for a minimum of 30 days before randomization.  All 
subjects should be managed with standard of care therapies consistent with regional clinical 
practice guidelines according to investigator judgment.  Oral SoC therapies for chronic HF (eg, 
beta blockers, renin-angiotensin-aldosterone system inhibitors) should be present and optimized 
to the maximally tolerated dose, if not contraindicated.  Subjects enrolled during either HF 
hospitalization or early after HF hospitalization discharge can be reinitiating or titrating oral SoC 
chronic HF therapies at the time of randomization, per usual clinical practice.  For a full list of 
eligibility criteria, please refer to Section 4.1.1 through Section 4.1.2.  
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 5 of 85 
CONFIDENTIAL 
 
 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  OM or placebo will be 
administered orally twice a day (BID) in the morning and evening and can be taken under fasted 
or fed conditions.  Subjects randomized to OM will initiate administration at 25 mg BID.  At study 
visit Week 2 (steady-state for initial dose), a blood sample will be collected from all subjects to 
determine pharmacokinetic (PK) predose level.  The results will be blinded to investigators.   
For subjects randomized to OM, the predose plasma concentration at Week 2 will guide the dose 
adjustment at Week 4 as follows: 
 
Subjects with plasma concentration < 200 ng/mL will start administration of 50 mg BID.  
 
Subjects with plasma concentration ≥ 200 and < 300 ng/mL will start administration of 
37.5 mg BID.  
 
Subjects with plasma concentration ≥ 300 and < 1000 ng/mL will maintain the administration 
of 25 mg BID. 
 
Subjects with plasma concentration ≥ 1000 ng/mL will start administration of placebo BID. 
 
At study visit Week 6, a predose plasma concentration will be collected from all subjects to 
confirm plasma concentration achieved while subjects are receiving their targeted dose and 
assess if potential changes to the dose should be made.  The results will be blinded to 
investigators.  For further guidance on procedures regarding PK assessment, please refer to 
Section 6.2. 
 
A new investigational product supply will be provided to all subjects at the Week 4 and 
Week 8 study visits regardless of randomized treatment group and outcome of the PK 
assessment in order to maintain the blind. 
Procedures:  Written informed consent must be obtained from all subjects before any screening 
procedures are performed.  The following procedures will occur per the Schedule of 
Assessments:  medical/surgical history, New York Heart Association (NYHA) class, physical 
examination/height, vital signs, weight, adverse event and concomitant medication assessment, 
electrocardiogram, PRO assessments, pregnancy testing, urinalysis, blood draw for serum 
chemistry, hematology, n-terminal prohormone brain natriuretic peptide, troponin I, creatine 
kinase-MB (CK-MB), biomarkers, and PK samples.  For a full list of study procedures, including 
the timing of each procedure, please refer to Section 7 and the Schedule of Assessments 
(Table 2).   
Statistical Considerations:  The primary analysis will include hypothesis testing for each of the 
primary and secondary endpoints and include analyses of exploratory endpoints.  The primary 
analysis will occur after approximately 1590 CV deaths have occurred.  Unless specified 
otherwise, efficacy analyses will be performed on the full analysis set, which includes all 
randomized subjects, by randomized treatment group.  The safety analyses will be performed on 
the safety analysis set, which includes all randomized and dosed subjects.  Unless otherwise 
specified, all hypothesis tests will be reported as 2-sided, and the full study will have an overall 
type I error rate of 0.05.  To preserve the overall type I error rate at 0.05, a sequentially rejective 
multiple test procedure will be used.  
An interim analysis for superiority is planned when approximately two-thirds of the planned 
1590 CV deaths are observed and will use a 2-sided alpha of 0.001 and the same multiplicity 
adjustments as for the planned primary analysis.  Interim analyses for futility based on the 
primary composite endpoint are planned when approximately one-third and two-thirds of the 
planned 1590 CV deaths are observed.  
The primary analysis of the primary composite endpoint will use a likelihood ratio test from a Cox 
model including baseline estimated glomerular filtration rate (eGFR) and the treatment group and 
stratified by randomization setting and region.  The secondary endpoints of time to CV death, 
time to first heart failure hospitalization, and time to all-cause death will be assessed using the 
same Cox model setup as the primary composite endpoint.  Change in the KCCQ TSS from 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 6 of 85 
CONFIDENTIAL 
 
 
baseline to Week 24 will be assessed using a mixed model fit within each randomization setting 
containing the baseline TSS value, baseline eGFR, region, visit, treatment, and treatment by visit.  
An omnibus F-test with 2 numerator degrees of freedom will be used to test the treatment effect 
of OM versus placebo. 
All deaths, HF events, major cardiac ischemic events (myocardial infarction, unstable angina 
hospitalization, and coronary revascularization), and strokes will be adjudicated by an 
independent external Clinical Events Committee using standardized definitions  
(Hicks et al, 2015).  For a full description of statistical analysis methods, please refer to 
Section 10. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version/Date:  
Version 5, 20 March 2015   
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 7 of 85 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
BID = twice a day; ED = emergency department; EOS = end of study; ER = emergency room; HF = heart failure; HfrEF = heart failure with reduced ejection fraction; 
IP = investigational product; PK = pharmacokinetics; PO = by mouth; Q16W = every 16 weeks; SoC = standard of care 
 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 8 of 85 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ACCF 
American College of Cardiology Foundation 
ACEi 
angiotensin-converting enzyme inhibitor 
ACS 
acute coronary syndrome 
AHA 
American Heart Association 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ARB 
angiotensin receptor blocker 
ARNi 
angiotensin receptor neprilysin inhibitor 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
twice a day 
BiPAP 
bilevel positive airway pressure 
BNP 
B-type natriuretic peptide 
CEC 
Clinical Events Committee 
CK-MB 
creatine kinase-MB 
Cmax 
maximum observed concentration 
CPAP 
continuous positive airway pressure 
CRF 
case report form 
CGR-S 
Clinician Global Rating Severity 
CRT 
cardiac resynchronization therapy  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
DILI 
drug-induced liver injury 
DMC 
Data Monitoring Committee 
DRE 
disease related events 
EC 
executive committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
emergency department 
EDC 
electronic data capture 
EF 
ejection fraction 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EQ-5D 
EuroQOL-5 dimensions questionnaire 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 9 of 85 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
HF 
heart failure 
HFrEF 
heart failure with reduced ejection fraction 
IBG 
Independent Biostatistical Group 
ICD 
implanted cardiac defibrillator 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IR 
immediate release 
IRB 
institutional review board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
KCCQ TSS 
Kansas City Cardiomyopathy Questionnaire Total Symptom Score 
LDH 
lactate dehydrogenase 
LVEF 
left ventricle ejection fraction 
LVSD 
left ventricular systolic dysfunction 
MR 
modified release 
MRA  
mineralocorticoid receptor antagonist 
NT-proBNP 
n-terminal-prohormone brain natriuretic peptide 
NYHA 
New York Heart Association 
OM 
omecamtiv mecarbil 
PK 
Pharmacokinetic 
PGR-S 
Patient Global Rating Severity 
PO 
by mouth 
PRO 
patient-reported outcome 
Q48W 
every 48 weeks 
SAS 
safety analysis set 
SET 
systolic ejection time 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SoC 
standard of care 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 10 of 85 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
TBL 
total bilirubin 
ULN 
upper limit of normal 
US 
United States 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  13 November 2018 
Page 11 of 85 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 7 
Study Glossary .................................................................................................................. 8 
1. 
OBJECTIVES ......................................................................................................... 16 
1.1 
Primary ....................................................................................................... 16 
1.2 
Secondary .................................................................................................. 16 
1.3 
Safety ......................................................................................................... 16 
1.4 
Exploratory ................................................................................................. 16 
2. 
BACKGROUND AND RATIONALE ........................................................................ 17 
2.1 
Disease ....................................................................................................... 17 
2.2 
Amgen Investigational Product Background ............................................... 18 
2.2.1 
Clinical Experience ..................................................................... 19 
2.2.2 
Studies in Healthy Volunteers .................................................... 19 
2.2.3 
Studies in Patients With Heart Failure ........................................ 21 
2.2.4 
Dose Selection for Phase 3 ........................................................ 25 
2.3 
Rationale .................................................................................................... 25 
2.4 
Clinical Hypotheses .................................................................................... 26 
3. 
EXPERIMENTAL PLAN ......................................................................................... 26 
3.1 
Study Design .............................................................................................. 26 
3.2 
Number of Sites .......................................................................................... 26 
3.3 
Number of Subjects .................................................................................... 26 
3.4 
Replacement of Subjects ............................................................................ 27 
3.5 
Estimated Study Duration ........................................................................... 27 
3.5.1 
Study Duration for Subjects ........................................................ 27 
3.5.2 
End of Study ............................................................................... 27 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 28 
4.1 
Inclusion and Exclusion Criteria ................................................................. 28 
4.1.1 
Inclusion Criteria ......................................................................... 28 
4.1.2 
Exclusion Criteria ........................................................................ 29 
5. 
SUBJECT ENROLLMENT ..................................................................................... 31 
5.1 
Randomization/Treatment Assignment ...................................................... 32 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 32 
6. 
TREATMENT PROCEDURES ............................................................................... 33 
6.1 
Classification of Product ............................................................................. 33 
6.2 
Investigational Product ............................................................................... 33 
6.2.1 
Amgen Investigational Product (OM) .......................................... 33 
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Date:  13 November 2018 
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6.2.1.1 
Dosage, Administration, and Schedule .................... 33 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 34 
6.2.1.3 
Other Protocol-required Therapies .......................... 35 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 36 
6.3.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................. 36 
6.3.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................. 37 
6.3.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 38 
6.4 
Concomitant Therapy ................................................................................. 38 
6.5 
Product Complaints .................................................................................... 38 
6.6 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 39 
7. 
STUDY PROCEDURES ......................................................................................... 39 
7.1 
Schedule of Assessments .......................................................................... 39 
7.2 
General Study Procedures ......................................................................... 43 
7.2.1 
Screening Enrollment ................................................................. 43 
7.2.2 
Retesting .................................................................................... 44 
7.2.3 
Rescreening ............................................................................... 44 
7.2.4 
Treatment ................................................................................... 44 
7.2.5 
End of Study Visit ....................................................................... 45 
7.2.6 
Description of Study Procedures ................................................ 46 
7.2.6.1 
Informed Consent .................................................... 46 
7.2.6.2 
Demographic Data ................................................... 46 
7.2.6.3 
Medical History ........................................................ 46 
7.2.6.4 
Vital Signs ................................................................ 46 
7.2.6.5 
Physical Examination ............................................... 47 
7.2.6.6 
Height and Weight ................................................... 47 
7.2.6.7 
Electrocardiogram .................................................... 47 
7.2.6.8 
Concomitant Therapy ............................................... 47 
7.2.6.9 
Patient-reported Outcomes ...................................... 48 
7.2.6.10 
Laboratory Assessments ......................................... 48 
7.2.6.11 
Safety Data Reporting .............................................. 49 
7.3 
Biomarker Development ............................................................................. 49 
7.4 
Pharmacogenetic Studies ........................................................................... 49 
7.5 
Sample Storage and Destruction ................................................................ 49 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 51 
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8.1 
Subjects’ Decision to Withdraw .................................................................. 51 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 52 
8.3 
Reasons for Removal From Treatment or Study ........................................ 52 
8.3.1 
Reasons for Removal From Treatment ...................................... 52 
8.3.2 
Reasons for Removal From Study ............................................. 52 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 53 
9.1 
Definition of Safety Events ......................................................................... 53 
9.1.1 
Disease Related Events ............................................................. 53 
9.1.2 
Adverse Events .......................................................................... 53 
9.1.3 
Serious Adverse Events ............................................................. 54 
9.2 
Safety Event Reporting Procedures ........................................................... 55 
9.2.1 
Reporting Procedures for Disease Related Events .................... 55 
9.2.2 
Adverse Events .......................................................................... 55 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 55 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 56 
9.2.2.3 
Reporting a Safety Endpoint as a Study 
Endpoint ................................................................... 58 
9.3 
Pregnancy and Lactation Reporting ........................................................... 58 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 58 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 58 
10.1.1 
Study Endpoints ......................................................................... 58 
10.1.1.1 
Primary Endpoint ..................................................... 58 
10.1.1.2 
Secondary Endpoints ............................................... 59 
10.1.1.3 
Safety Endpoints ...................................................... 59 
10.1.1.4 
Exploratory Endpoints .............................................. 59 
10.1.2 
Analysis Sets .............................................................................. 59 
10.1.2.1 
Efficacy Analysis Set ................................................ 59 
10.1.2.2 
Safety Analysis Set .................................................. 60 
10.1.3 
Covariates and Subgroups ......................................................... 60 
10.2 
Sample Size Considerations ...................................................................... 61 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 61 
10.4 
Planned Analyses ....................................................................................... 61 
10.4.1 
Interim Analyses ......................................................................... 61 
10.4.2 
Data Monitoring Committee ........................................................ 62 
10.4.3 
Primary Analysis ......................................................................... 62 
10.5 
Planned Methods of Analysis ..................................................................... 62 
10.5.1 
General Considerations .............................................................. 62 
10.5.2 
Multiplicity Adjustments .............................................................. 63 
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10.5.3 
Primary Efficacy Endpoint .......................................................... 64 
10.5.4 
Secondary Efficacy Endpoints .................................................... 64 
10.5.5 
Safety Endpoints ........................................................................ 65 
10.5.5.1 
Adverse Events ........................................................ 65 
10.5.5.2 
Laboratory Parameters ............................................ 65 
10.5.5.3 
Vital Signs ................................................................ 65 
10.5.5.4 
Electrocardiograms .................................................. 66 
11. 
REGULATORY OBLIGATIONS ............................................................................. 66 
11.1 
Informed Consent ....................................................................................... 66 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 67 
11.3 
Subject Confidentiality ................................................................................ 67 
11.4 
Investigator Signatory Obligations .............................................................. 68 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 68 
12.1 
Protocol Amendments and Study Termination ........................................... 68 
12.2 
Study Documentation and Archive ............................................................. 69 
12.3 
Study Monitoring and Data Collection ........................................................ 69 
12.4 
Investigator Responsibilities for Data Collection ........................................ 70 
12.5 
Language.................................................................................................... 71 
12.6 
Publication Policy ....................................................................................... 71 
12.7 
Compensation ............................................................................................ 72 
13. 
REFERENCES ....................................................................................................... 73 
14. 
APPENDICES ........................................................................................................ 75 
List of Tables 
Table 1.  Examples of Potent Inhibitors of CYP3A4 ........................................................ 39 
Table 2.  Schedule of Assessments ................................................................................ 40 
Table 3.  Analyte Listing .................................................................................................. 48 
List of Figures 
Figure 1.  Chemical Structure of Omecamtiv Mecarbil .................................................... 18 
Figure 2.  Multiplicity Testing Propagation Approach ...................................................... 64 
Approved 
 
 


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Date:  13 November 2018 
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List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 76 
Appendix B.  Sample Serious Adverse Event Report Form ............................................ 78 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 81 
Appendix D.  Summary of Dose Adjustment and Action to be Taken 
Regarding IP Concentration Assessment ................................................ 84 
Appendix E.  List of Class I and Class IIa Guideline Recommended Oral 
Drugs Commonly Used for Heart Failure With Reduced 
Ejection Fraction ...................................................................................... 85 
Approved 
 
 


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1. 
OBJECTIVES 
1.1 
Primary 
 
to evaluate the effect of treatment with omecamtiv mecarbil (OM) compared with 
placebo on the time to cardiovascular (CV) death or first heart failure (HF) event, 
whichever occurs first, in subjects with chronic HF with reduced ejection fraction 
(HFrEF) receiving standard of care (SoC) therapy 
 
An HF event is defined as presentation of the patient for urgent, unscheduled 
clinic/office/emergency department (ED) visit, or hospital admission, with a 
primary diagnosis of HF where the patient exhibits new or worsening symptoms 
of HF on presentation, has objective evidence of new or worsening HF, and 
receives initiation or intensification of treatment specifically for HF 
(Hicks et al, 2015).  Changes to oral diuretic therapy do not qualify as initiation or 
intensification of treatment. 
1.2 
Secondary 
 
to evaluate the effects of OM on time to:  
 
CV death 
 
HF hospitalization 
 
all-cause death 
 
to evaluate the effects of treatment with OM on change in patient-reported outcomes 
(PROs)  
1.3 
Safety 
 
to evaluate the safety of OM as measured by subject incidence of reported adverse 
events, including serious adverse events of ventricular arrhythmias requiring 
treatment and adjudicated major cardiac ischemic events (myocardial infarction, 
unstable angina hospitalization, and coronary revascularization) (Hicks et al, 2015) 
1.4 
Exploratory 
 
to evaluate the effect of OM on the risk for HF events and HF hospitalization in 
subjects randomized during hospitalization for HF during the first: 
 
30 days after discharge 
 
60 days after discharge 
 
to evaluate the effect of OM on n-terminal prohormone brain natriuretic peptide 
(NT-proBNP) changes  
 
to evaluate the effect of OM on first and recurrent HF events 
 
to evaluate the effect of OM on recurrent HF hospitalizations 
 
to evaluate the effect of OM on the composite time of CV death or HF hospitalization, 
whichever occurs first 
 
to evaluate the effect of OM on the composite of time to all-cause death or HF 
hospitalization, whichever occurs first 
 
to evaluate the effect of OM on resting heart rate 
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 
to evaluate the effect of OM on Kansas City Cardiomyopathy Questionnaire Total 
Symptoms Score (KCCQ TSS) changes over time 
 
to evaluate the effect of treatment  with OM on the composite of time to CV death, 
HF event, myocardial infarction, Hospitalization for Unstable Angina, Coronary 
Revascularization, and Stroke whichever occurs first 
 
to further characterize the pharmacokinetics (PK) of OM 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
HF is a clinical syndrome marked by impaired cardiac contractility and is a final pathway 
for many diseases that affect the heart (Hilfiker-Kleiner et al, 2006).  HF affects over 
26 million people worldwide, with more than 3.5 million people newly diagnosed every 
year.  The prevalence has been shown to increase with age (López-Sendón, 2011), 
suggesting that as the population ages, the incidence of HF may rise.  In the United 
States (US), more than 5 million people, or almost 2.0% of the population, have HF 
(Go et al, 2013).  In Europe, it has been estimated that at least 15 million people have 
HF (Dickstein et al, 2008).  The annual mortality rate of HFrEF patients in western 
industrialized countries is typically from 10% to 25% per year; however, depending on 
the HF severity, this rate can be as low as 5% per year in stable New York Heart 
Association (NYHA) class I to II HF patients with mild left ventricular systolic dysfunction 
(LVSD) to as high as 75% per year in patients with NYHA class III to IV and marked 
LVSD (Mozaffarian et al, 2007; Bhatia et al, 2006; Levy et al, 2006; 
Solomon et al, 2004).  The burden of HF can also be seen in data from recurrent 
hospital admission.  Medicare data and data on commercially insured patients indicate 
that 12% to 27% of patients hospitalized for HF are readmitted within 30 days after their 
hospitalization, and all-cause mortality reaches 12% in the same period 
(Jencks et al, 2009; McIlvennan et al, 2014). 
HF is most often caused by coronary artery disease; other common causes include 
idiopathic hypertension and valvular heart disease (Ambrosy et al, 2014).  In an attempt 
to preserve cardiac output and organ perfusion, the condition progresses through stages 
with compensatory mechanisms characterized by increased sympathetic tone, 
peripheral vasoconstriction, and activation of various neurohormonal pathways.  These 
adaptive properties provide short-term relief but can be damaging with long-term or 
prolonged activation.  Patients experience dyspnea, fatigue, and fluid retention and 
eventually develop pulmonary congestion and peripheral edema.  Treatment goals are to 
improve symptoms, prolong survival, and reduce hospital readmissions 
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(Yancy et al, 2013; Ponikowski et al, 2016).  While several pharmacological and 
nonpharmacological interventions have been shown to reduce the rate of HF 
hospitalizations and improve mortality, including angiotensin-converting enzyme 
inhibitors (ACEis), beta-blockers, aldosterone antagonists, coronary revascularization, 
and biventricular pacing (Jessup and Brozena, 2003; Krum and Teerlink, 2011), mortality 
and morbidity still remain high as noted above.  In addition, these available treatments, 
acting on the compensatory mechanisms (eg, sodium retention, arterial and venous 
constriction, neuroendocrine activation, and increased heart rate) often fail to control 
symptoms or restore quality of life.   
Reduced left ventricle ejection fraction (LVEF) is a central factor in HF, yet there are no 
safe medical therapies to directly improve cardiac function at the level of the cardiac 
sarcomere in HF patients.  The compensatory mechanisms cited above are deployed in 
attempt to preserve cardiac output and organ perfusion in a scenario of impaired 
myocardial contractility.  Attempts to improve cardiac contractility through chronic 
stimulation of the adrenergic receptor pathway (eg, dobutamine or ibopamine) or 
phosphodiesterase inhibitors (ie, milrinone) in chronic HF patients have not been 
successful (Tacon et al, 2012).  Both agents have significant safety liabilities due to their 
mechanism of action.  The increase of intracellular calcium can improve contractility but 
at the expense of increased tissue oxygen consumption and arrhythmias.  The addition 
of long-term oral milrinone to SoC in severe chronic HFrEF patients has shown 
increased mortality and morbidity (Packer et al, 1991).  Oral ibopamine, a dopaminergic 
receptor agonist (DA-1 and DA-2) also did not demonstrate clinical benefits when added 
to SoC in HFrEF outpatients (Hampton et al, 1997). 
2.2 
Amgen Investigational Product Background 
The molecular formula of OM is C20H24FN5O3·2HCl·H2O and the chemical structure is 
provided in Figure 1.   
Figure 1.  Chemical Structure of Omecamtiv Mecarbil 
 
OM (AMG 423, CK-1827452) is a novel small molecule classified as a cardiac myosin 
activator that increases cardiac contractility by selectively and directly activating the 
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enzymatic domain of the cardiac myosin heavy chain, the force-generating motor protein 
of the cardiac sarcomere, without increasing cardiac myocyte intracellular calcium 
(Teerlink et al, 2011; Malik et al, 2011).  OM increases the left ventricular systolic 
ejection time (SET) without changing the velocity of contraction (dP/dt) or increasing the 
heart rate.  Additionally, left ventricular filling pressures, left atrial pressures, and total 
peripheral vascular resistance decreased, providing evidence that prolongation of SET 
and increased systolic function can favorably impact the hemodynamics that drive HF 
symptoms.  The salutary effects of OM were achieved without noticeable effect upon 
myocardial oxygen uptake, blood pressure, or coronary blood flow (Shen et al, 2010; 
Malik et al, 2011). 
2.2.1 
Clinical Experience 
The clinical development program currently consists of 9 completed phase 1 studies, 
4 completed phase 2a studies in subjects with chronic HF, 1 completed phase 2b study 
in subjects with acute HF, and 1 completed phase 2b study in subjects with chronic HF.  
The M-F1 formulation was used for 3 phase 1 studies and the phase 2b study in 
subjects with chronic HF.  In addition, 2 studies are ongoing/planned in Japanese 
subjects using the M-F1 formulation and PK-based dose adjustment strategy; a 
phase 1b study in healthy subjects (ongoing) and a phase 2b study in subjects with 
chronic HFrEF.   
2.2.2 
Studies in Healthy Volunteers 
CY 1111, a first-in-human clinical study with OM, was a randomized, double-blind, 
placebo-controlled, 4-period crossover, dose escalation study designed to evaluate the 
safety, tolerability, and PK/pharmacodynamic profile of OM administered intravenously 
to healthy male volunteers (Teerlink et al, 2011).  This study included a total of 
33 subjects who received infusions of OM at doses ranging from 0.005 mg/kg/hr to 
1.0 mg/kg/hr for up to 6 hours.  At an infusion rate of 0.5 mg/kg/hr, given for 6 hours, the 
average maximum observed concentration (Cmax) was 905 ng/mL.  Five subjects 
received OM infusion of 0.625 mg/kg/hr for 6 hours (average Cmax = 1203 ng/mL) and 
tolerated this dose level well.  The highest administered dose of 1.0 mg/kg/hr was given 
to 2 subjects.  During the first 3 hours, both subjects tolerated the dosing rate without 
difficulty; however, both subjects terminated the infusion prematurely, in 1 case at 
3 hours and 22 minutes and in the other case, at 4 hours and 12 minutes.  The plasma 
concentrations at 3 hours were 1338 ng/mL and 1333 ng/mL, and estimated plasma 
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concentrations (based on individual PK modeling) at study drug termination in each 
subject were 1320 ng/mL and 1550 ng/mL, respectively. 
The dose-limiting toxicity of OM in both subjects was consistent with myocardial 
ischemia or infarction, which included feeling hot, palpitations, chest or throat tightness, 
dizziness, tachycardia, electrocardiogram (ECG) ST-segment depression, and, in 
1 subject, a troponin I elevation in the absence of an increase in creatine kinase-MB 
(CK-MB) fraction.  These findings appeared consistent with preclinical experience in 
dogs at similar plasma concentrations.  Across the dosing levels evaluated in CY 1111, 
OM infusions demonstrated generally linear PK with dose-proportional increases in Cmax.  
Concentration-dependent pharmacodynamic effects on cardiac function as measured by 
echocardiography were observed.  These pharmacodynamic effects included statistically 
significant placebo corrected increases from baseline in SET, Doppler-derived stroke 
volume, LVEF, and fractional shortening. 
CY 1013 was an open-label, parallel group study in healthy male volunteers designed to 
understand the potential for certain drug-drug interactions.  To define the contribution of 
the cytochrome P450 isozymes 3A4 and 2D6 to the metabolism of oral OM in humans, 
8 subjects who were extensive metabolizers with respect to their CYP2D6 genotype 
received the potent inhibitor of CYP3A4, ketoconazole, and 9 extensive metabolizers 
subjects the moderately potent inhibitor, diltiazem, dosed to steady-state to evaluate the 
PK parameters of a single dose of OM.  In addition, 8 subjects who were poor 
metabolizers with respect to their defined CYP2D6 genotype received oral OM and 
ketoconazole.  In the 24 subjects who completed the study (8 in each group), CYP3A4 
inhibition by ketoconazole resulted in approximately 50% and 30% increases in area 
under the curve (AUC) in extensive metabolizers and poor metabolizer subjects, 
respectively; but had little impact on Cmax.  Diltiazem had no effect on either the C or 
AUC of OM in extensive metabolizers subjects.  OM was well tolerated in the study with 
no serious adverse events.  These data suggest that CYP3A and CYP2D6 may not be 
the major enzymes contributing to the metabolism of OM. 
Studies CY 1011, CY 1015, and CY 1016 were designed to evaluate the PK parameters 
of oral preparations of OM, with immediate release (CY 1011 and CY1015) and modified 
release (CY1016).  The studies enrolled a total of 44 males and 20 females.  Maximal 
duration of exposure was 10 days and maximal dose was 30 mg 3 times a day for 
7 days.  Results from the studies demonstrated very high oral bioavailability for OM 
approaching 100% under all conditions studied; food appeared to reduce the rate but not 
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the extent of absorption.  OM was well tolerated with no treatment-related serious 
adverse events in these trials. 
2.2.3 
Studies in Patients With Heart Failure 
Study CY 1121 was a randomized, double-blind, placebo-controlled, crossover study 
that enrolled 5 sequential cohorts of patients with stable HF (LVEF ≤ 40% 
[LVEF ≤ 30% in cohort 4]).  A total 45 patients (39 males and 6 females) were enrolled 
and treated with IV study drug infusions ranging from 2 to 72 hours (Cleland et al, 2011). 
Three patients experienced serious adverse events (non-ST-elevation myocardial 
infarction which occurred in the setting of an inadvertent drug overdose [this event was 
considered related to study drug and reported as a suspected unexpected serious 
adverse reaction]; septicemia in the setting of a diabetic foot ulcer that was considered 
unrelated to study drug; and pneumonia that was considered unrelated to study drug) in 
the study.  OM produced increases in echocardiographic indices of cardiac systolic 
function. 
Study CY 1221 was a randomized, double-blind, placebo-controlled study that enrolled 
HF patients with ischemic cardiomyopathy and angina with LVEF ≤ 35%.  A total of 
94 subjects were enrolled and treated with 20 hour IV infusions of study drug followed by 
7 days of oral dosing; 29 subjects received placebo, 31 received OM at a lower dose 
regimen, and 34 at a higher dose regimen.  The primary safety endpoint was defined as 
the proportion of subjects stopping an exercise tolerance test during infusion due to 
unacceptable angina at an exercise stage earlier than baseline.  This endpoint was 
observed in 1 subject receiving placebo and did not occur in any subject receiving OM at 
either dose regimen.  In addition, no consistent differences were observed between 
placebo and lower or higher dosing regimens of OM with respect to any of the secondary 
safety endpoints, vital signs, ECGs, or cardiac enzymes. 
CY 1021 was an open-label with the objective to evaluate the PK and tolerability of an 
oral modified release (MR) and an oral immediate release (IR) formulation of OM in 
patients with stable HF.  A total of 35 subjects were enrolled and treated with a dose of 
50 mg MR twice a day (BID), 37.5 mg IR 3 times a day, or 100 mg MR BID under fed 
conditions.  A 
-year-old 
 patient experienced sudden death in this study after 
6 days of dosing with the IR formulation.  The patient’s history was 
 
 
 
  At the time of enrollment into the study, the patient was NYHA 
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Class III and Canadian Cardiovascular Society Angina Class III.  Study site personnel 
last spoke to the patient on day 6 just prior to the last administered dose.  
 had no 
complaints and reported that 
 was taking the study medication as prescribed.  Shortly 
after the last dose on day 6, the patient suddenly lost consciousness and died.  Based 
on day 1 plasma concentrations, the predicted range of day 6 plasma concentrations 
were approximately 120 to 210 ng/mL. 
Of the 122 healthy volunteers and 147 HF subjects who received at least 1 dose of OM 
in all of the studies described above, 3 subjects (CY 1111, Subject 
; CY 1121, 
Subject 
; and CY 1121, Subject 
) experienced a clinical syndrome 
consistent with myocardial ischemia (feeling hot, palpitations, chest or throat tightness, 
dizziness, tachycardia, ECG ST-segment depression, positive cardiac markers) that 
occurred at OM plasma concentrations > 1200 ng/mL, although plasma concentrations 
of OM exceeding 1200 ng/mL have not always been associated with signs of ischemia.  
In each of these cases, symptoms and signs resolved rapidly with discontinuation of 
study drug, no new wall motion abnormalities appeared, and overall left ventricular 
function was unaffected.  An additional 6 HF subjects had troponin I levels > upper 
reference limit at OM plasma concentrations < 1200 ng/mL.  Of these 6 subjects, 
1 subject (CY 1221, Subject 
) developed troponin elevation only after stenting of 
the left anterior descending artery, and another subject (CY 1121, Subject 
) had 
marked hypertension prior to and during drug administration.  Two subjects enrolled in 
an invasive hemodynamic and cardiac function study (CY 1124, Subjects 
 and 
) had troponin I levels > upper reference limit after their procedures in the 
absence of symptoms or ECG changes.  While manipulation of catheters in the right and 
left ventricles has been reported to be associated with increased troponin levels 
(Kannankeril et al, 2002), a drug association of these troponin elevations cannot be ruled 
out.  The clinical significance of elevated troponins just above the URL in the remaining 
2 subjects is unclear. 
The phase 2b Study 20100754 (ATOMIC-AHF) was designed to address key questions 
regarding the relationship between OM plasma concentrations and its safety, tolerability, 
and efficacy in an intensively monitored, acutely decompensated patient population 
hospitalized for acute HF.  Study 20100754 was a double-blind, randomized, 
placebo-controlled study of 3 ascending dose cohorts in which IV OM or matching 
placebo was infused over 48 hours.  In each cohort, OM was administered as a loading 
dose infusion over 4 hours and a maintenance infusion over the remaining 44 hours.  
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The primary objective of the study was to evaluate the effect of 48 hours of treatment 
with intravenous OM compared with placebo on dyspnea in subjects hospitalized for 
acute HF.  Secondary objectives included assessment of the safety and tolerability of 
3 dose levels of intravenous OM, as well as additional dyspnea assessments, patient 
global assessment, changes in levels of NT-proBNP, other short-term clinical outcomes, 
and characterization of the PK of OM and metabolites, including the relationship 
between OM plasma concentrations and echocardiographic parameters 
(PK/pharmacodynamic substudy).   
A total of 606 subjects comprised the full analysis set (OM, n = 303).  In subjects 
hospitalized due to acute decompensated HF (Study 20100754), OM given as a 48 hour 
intravenous infusion did not significantly improve dyspnea symptom response defined as 
minimally, moderately, or markedly better by 7-point Likert scale at 6 hours after 
investigational product (IP) initiation, and moderately or markedly better at 24 and 
48 hours after IP initiation without worsening of HF or death from any cause by 48 hours 
(p = 0.331).  A numeric trend toward a reduction in the incidence of death from any 
cause or worsening of HF or worsening of HF alone within 7 days of IP initiation was 
observed at higher OM doses compared with placebo.  OM did not significantly reduce 
NT-proBNP levels compared with pooled placebo.   
Subject incidence rates for all treatment emergent adverse events were 58% in the 
pooled OM group and 63% in the pooled placebo group.  The most frequently reported 
treatment-emergent adverse events were cardiac failure (16.5% pooled placebo, 
13.5% pooled OM), hypotension (4.6% pooled placebo, 7.9% pooled OM), and 
hypokalemia (5.9% pooled placebo, 6.6% pooled OM).  The incidence of 
treatment-emergent serious adverse events was similar between the pooled OM and 
pooled placebo groups (21.8% and 23.1%, respectively).  Serious treatment-emergent 
adverse event preferred terms (PTs) that were reported in > 1% of subjects in the study 
included cardiac failure (7.4% overall; 6.6%, pooled OM and 8.3%, pooled placebo 
group), cardiac failure congestive (1.7%; 2.0% and 1.3%), renal failure acute (1.7%; 
2.0% and 1.3%), and pneumonia (1.2%; 1.3% and 1.0%).  Twenty subjects (11 placebo, 
9 OM) died in this study.  A modest increase in the upper quartile troponin I change from 
baseline value was observed in OM groups compared with placebo.  No significant 
association was observed between OM Cmax or AUC and maximum troponin change 
from baseline (p = 0.95 and 0.83, respectively). 
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There was a numerical imbalance in adjudicated myocardial infarctions in OM-treated 
subjects compared with placebo-treated subjects.  
Among the 10 total positively-adjudicated, post-randomization myocardial infarctions in 
the study (7 OM-treated subjects, 3 placebo treated subjects), 5 occurred in OM-treated 
subjects in cohort 3.  Of these 5 events in cohort 3, 2 occurred several days (day 12 and 
day 22) after drug had been discontinued (day 2) (half-life of OM is approximately 
20 hours), while another occurred only after percutaneous coronary intervention.  The 
remaining 2 subjects with myocardial infarctions had troponin elevations (peak of 
0.064 and 0.168 ng/mL); the first of these was asymptomatic and the second was 
related to a transient episode of exertional angina, which was relieved by nitroglycerin in 
the setting of a history of chronic exertional angina.  The remaining 
positively-adjudicated, post-randomization myocardial infarctions occurred in 
cohort 1 subjects (3 placebo, 2 OM). 
The phase 2b Study 20110151 (COSMIC–HF) was designed to evaluate an oral MR 
formulation of OM in subjects with chronic HF with reduced ejection fraction.  The study 
consisted of 2 parts, a dose-escalation phase and a larger and longer expansion phase, 
which was the first study to use a PK-based titration scheme to identify the target OM 
dose.  The dose(s), formulation and PK-based dose adjustment scheme for the 
expansion phase were based on results from the dose escalation phase. 
The expansion phase of Study 20110151 was designed to evaluate the PK, PD, safety, 
and tolerability of oral OM in 448 subjects with chronic HF and left ventricular systolic 
dysfunction.  Subjects were randomized 1:1:1 to receive placebo, OM 25 mg BID, or to a 
PK-based dose adjustment group where 25 mg BID starting dose could be increased to 
50 mg BID at Week 8 depending on plasma concentrations of OM after 2 weeks of 
treatment with the 25 mg dose.  Analysis of PK data showed that the PK-based dose 
adjustment reliably controlled subject exposure to OM .  Following 20 weeks of 
treatment, statistically significant improvements were observed in prespecified 
secondary endpoint measures of cardiac function in the dose-titration group compared 
with placebo.  Systolic ejection time increased by 25.0 msec (p<0.001), stroke volume 
increased by 3.63 mL (p=0.022), and heart rate decreased by 2.97 beats per minute 
(p=0.007).  Left ventricular end-systolic and end-diastolic dimensions decreased by 
1.79 mm (p=0.003) and 1.29 mm (p=0.013), respectively, and were associated with 
statistically significant reductions in left ventricular end-systolic and end-diastolic 
volumes.  There was a 970 pg/mL (p=0.007) decrease in NT-proBNP. 
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Adverse events, including serious adverse events, in subjects receiving OM were 
comparable with those receiving placebo.  The incidence of adjudicated deaths (2.7% in 
placebo group, 1.4% in OM group), myocardial infarction (1.34% and 0.34%, 
respectively), and unstable angina (0% and 0.34%, respectively) was similar across 
groups.  Other cardiac adverse events were balanced between placebo and OM groups.  
In the OM groups compared with placebo, cardiac troponin assessed per protocol 
increased by 0.001 ng/mL and 0.006 ng/mL (median change from baseline at Week 20) 
in the 25 mg twice daily group and dose titration group, respectively.  Events of 
increased troponin (n = 278 across all treatment groups) were independently adjudicated 
and none were determined to be myocardial ischemia or infarction.  
2.2.4 
Dose Selection for Phase 3 
The OM dosing regimen selected for this phase 3 study (20110203) is oral 
administration of 25 mg BID at the initiation of treatment.  At study visit Week 2 (PK 
steady-state for initial dose), a predose PK sample will be collected.  At Week 4, 
subjects with Week 2 OM predose plasma concentrations < 200 ng/mL will have their 
dose increased to 50 mg BID; subjects with Week 2 predose plasma concentrations 
≥ 200 and < 300 ng/mL will have their dose increased to 37.5 mg BID, subjects with 
Week 2 predose plasma concentrations ≥ 300 ng/mL and < 1000 ng/mL will maintain a 
25 mg BID dosing regimen, and subjects with plasma concentration ≥ 1000 ng/mL will 
start administration of placebo BID.  Similar to Study 20110151, PK-based dose 
adjustment in this study will be used to attain effective steady state concentrations for 
desired PD effect while maintaining OM plasma concentrations < 1000 ng/mL.  Please 
refer to Appendix D for further information on dose adjustment. 
Refer to the Investigator’s Brochure for additional information related to the physical, 
chemical, and pharmaceutical properties and formulation(s) of OM. 
2.3 
Rationale 
OM is a promising new oral therapeutic agent for HFrEF patients targeting myocardial 
contractility.  Current recommended pharmacological therapies for chronic HF aim at 
blocking/controlling the physiological compensatory mechanism.  Therapeutic options to 
directly improve myocardial contractility for these patients are lacking. 
The early post-discharge period following a HF hospitalization carries particular high risk 
for poor clinical outcomes and is known as the “vulnerable phase” (Greene et al, 2015).  
To help assess effects of OM during this period, the study will enroll some subjects that 
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are in the hospital transitioning from initial treatment to discharge.  The total population 
in this study allows assessment of OM treatment effect and safety in a more 
representative population of chronic HFrEF patients. 
2.4 
Clinical Hypotheses 
The primary hypothesis is that when added to SoC, OM is well tolerated and superior to 
placebo in reducing the risk of CV death or HF events in subjects with chronic HFrEF. 
Secondary hypotheses are that OM reduces the individual risks of: 
 
CV death 
 
HF hospitalization 
 
all-cause death 
and improves symptoms in subjects with chronic HFrEF compared to placebo. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a randomized, placebo-controlled, double-blind, parallel group, multicenter, CV 
outcomes study for oral OM in subjects with HFrEF, including subjects with ongoing or 
history of HF hospitalization.  Approximately 8000 eligible subjects will be randomized in 
a 1:1 ratio to receive either OM or placebo.  Randomization will be stratified by 
randomization setting (currently hospitalized for HF or recently and not currently 
hospitalized for HF) and region (5 strata:  US and Canada; Latin America; Western 
Europe, South Africa, and Australasia; Eastern Europe including Russia; Asia).  
Approximately 25% or more of the total planned enrollment will include subjects who are 
hospitalized at randomization.  Enrollment of subjects in atrial fibrillation/flutter at 
screening is limited to approximately 25%.  
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 1000 sites globally will participate in this study.  Sites that do not enroll 
subjects within 3 months of site initiation may be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.” 
Approximately 8000 subjects will be randomized. 
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3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced.   
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The study is event-driven and will conclude when approximately 1590 CV death events 
have occurred.  Amgen along with the study Executive Committee will estimate the date 
for initiating the end of study procedures based on the anticipated date of occurrence of 
approximately 1590 CV death events. 
Subject accrual is planned for 24 months.  After signing the informed consent, subjects 
should be randomized within 8 weeks.  The expected length of treatment after 
completion of subject accrual and until the number of required CV death events has 
been reached is 24 months.  Therefore, it is anticipated that follow-up for the first 
randomized subjects will reach approximately 48 months (4 years), and for the last 
randomized subjects approximately 24 months (2 years).  The actual duration of study 
for an individual subject may be longer or shorter based upon the amount of time 
required to reach the specified number of events. 
Experiencing a nonfatal primary endpoint does not end study participation for a study 
subject (see criteria for withdrawal in Section 6.2.1.2 and Section 6.3).  Subjects will 
continue treatment and follow-up procedures until the study ends as described above.  
All subjects will be followed from randomization through the date of study termination 
unless the subject has withdrawn consent, irrespective of whether the subject is 
continuing to receive study treatment. 
3.5.2 
End of Study 
Primary Completion:  The primary completion is the date when the last subject is 
assessed or receives an intervention for the collection of the primary endpoint, for the 
purposes of conducting the primary analysis, whether the study concluded according to 
the prespecified protocol or was terminated.  The primary completion is the same as the 
end of study and is the date when the last subject has completed the study.  If the study 
concludes prior to the time point originally planned in the protocol (ie, early termination of 
the study), then the primary completion will be the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last visit) 
End of Study:  The end of study is the same as the primary completion date and is when 
the last subject has completed the end of study assessments. 
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4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
System (IVRS)/Interactive Web Response System (IWRS).  
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion and Exclusion Criteria  
4.1.1 
Inclusion Criteria  
101 
Subject has provided informed consent  
102 
Male or female, ≥ 18 to ≤ 85 years of age at signing of informed consent 
103 
History of chronic HF (defined as requiring treatment for HF for a minimum of 
30 days before randomization) 
104 
LVEF ≤ 35%, per subject’s most recent medical record, within 12 months prior to 
screening.  The most recent qualifying LVEF must be at least 30 days after any 
of the following, if applicable:  1) an event likely to decrease EF (eg, myocardial 
infarction, sepsis); 2) an intervention likely to increase EF (eg, cardiac 
resynchronization therapy, coronary revascularization); or 3) the first ever 
presentation for HF. 
105 
NYHA class II to IV at most recent screening assessment 
106 
Managed with HF SoC therapies consistent with regional clinical practice 
guidelines according to investigator judgment of subject’s clinical status 
Oral SoC therapies for chronic HF (eg, beta blockers, 
renin-angiotensin-aldosterone system inhibitors) should be present, if not 
contraindicated.  Subjects enrolled during either HF hospitalization or early after 
HF hospitalization discharge can be reinitiating or titrating oral SoC chronic HF 
therapies at the same time of randomization with the goal of achieving optimized 
therapy on study. 
107 
Currently hospitalized with primary reason of HF OR one of the following events 
within 1 year to screening:  1) hospitalization with primary reason of HF; 2) urgent 
visit to ED with primary reason of HF 
108 
B-type natriuretic peptide (BNP) level ≥ 125 pg/mL or an NT-proBNP level 
≥ 400 pg/mL at most recent screening assessment (subjects receiving 
angiotensin receptor-neprilysin inhibitor [ARNi] must use NT-proBNP 
assessment; for subjects in atrial fibrillation/flutter at screening, the cut off levels 
are:  BNP ≥ 375 pg/mL or NT-proBNP ≥ 1200 pg/mL) 
Approved 
 
 


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4.1.2 
Exclusion Criteria  
201 
Currently receiving treatment in another investigational device or drug study, or 
< 30 days since ending treatment on another investigational device or drug 
study(ies).  Other investigational procedures while participating in this study are 
excluded. 
202 
Malignancy within 5 years prior to randomization with the following exceptions:  
localized basal or squamous cell carcinoma of the skin, cervical intraepithelial 
neoplasia, stage 1 prostate carcinoma, breast ductal carcinoma in situ. 
203 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
204 
Factors expected to interfere with the subject’s availability or ability to complete 
all protocol-required study visits or procedures, and/or to comply with all required 
study procedures to the best of the subject and investigator’s knowledge 
(including ongoing substance abuse).  
205 
Inability to swallow study medication tablet (eg, swallowing disorders, feeding 
tubes) 
206 
Receiving mechanical hemodynamic support (eg, intra-aortic balloon pump 
counterpulsation), or invasive mechanical ventilation ≤ 7 days prior to 
randomization 
207 
Receiving IV inotropes (eg, dobutamine, milrinone, levosimendan) or 
IV vasopressors (eg, epinephrine, norepinephrine, dopamine, or vasopressin) 
≤ 3 days prior to randomization 
208 
Receiving IV diuretics or IV vasodilators, supplemental oxygen therapy, or 
non-invasive mechanical ventilation (eg, bilevel positive airway pressure [BiPAP] 
or continuous positive airway pressure [CPAP] ≤ 12 hours prior to randomization 
(Note:  the use of non-invasive ventilation for sleep disordered breathing is 
permitted) 
209 
Acute coronary syndrome (ST-elevation myocardial infarction, non-ST-elevation 
myocardial infarction, unstable angina), stroke, or transient ischemic attack, 
major cardiac surgery or cardiac intervention (ie, implantation of cardiac closure 
devices, cardiac resynchronization therapy, or catheter ablation), percutaneous 
coronary intervention, or valvuloplasty/other cardiac valve repair or implantation 
within the 3 months prior to randomization 
210 
Insertion of other cardiac devices (eg, implantable cardioverter defibrillator, 
permanent pacemaker, monitoring devices) within 30 days prior to randomization 
211 
Severe uncorrected valvular heart disease, hypertrophic or infiltrative 
cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically 
significant congenital heart disease 
212 
Untreated severe ventricular arrhythmia (eg, ventricular tachycardia or ventricular 
fibrillation) 
213 
Chronic antiarrhythmic therapy, with the exception of amiodarone.  Note:  for the 
purposes of this exclusion criterion, digoxin, calcium channel blocker, and 
beta-blocker therapy are not considered to be chronic antiarrhythmic therapies 
214 
Symptomatic bradycardia or second or third degree heart block without a 
pacemaker 
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215 
Routinely scheduled outpatient intravenous infusions for HF (eg, inotropes, 
vasodilators [eg, nesiritide], diuretics) or routinely scheduled ultrafiltration 
216 
Systolic blood pressure > 140 mmHg or < 85 mmHg, or diastolic blood pressure 
> 90 mmHg, or heart rate > 110 beats per minute, or < 50 beats per minute at 
screening 
217 
Estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 or receiving 
dialysis at screening 
218 
Hepatic impairment defined by a total bilirubin (TBL) ≥ 2 times the upper limit of 
normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) ≥ 3 times ULN at screening 
219 
Previously received OM 
220 
Severe, concomitant non-CV disease that is expected to reduce life expectancy 
to < 2 years 
221 
Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, 
renal) or anticipated to receive chronic mechanical circulatory support or heart 
transplantation within 12 months from randomization 
222 
Female subject of childbearing potential who is not willing to inform her partner of 
her participation in this clinical study and to use 2 acceptable methods of 
effective birth control or practice true sexual abstinence (the reliability of sexual 
abstinence must be evaluated by the investigator and be the preferred and usual 
lifestyle of the subject) during treatment with IP (OM or placebo) and for an 
additional 5 days after the last dose of IP.  If the female subject or her sole male 
partner has had a surgical contraceptive method (bilateral tubal ligation/occlusion 
or vasectomy with medical assessment of surgical success), additional 
contraceptive methods are not required.  Male subject with a female partner of 
childbearing potential and not willing to inform his partner of his participation in 
this clinical study. 
 
A female is considered of childbearing potential unless she has had a 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy or she is 
postmenopausal.  Menopause is defined as ≥ 12 months of spontaneous and 
continuous amenorrhea in a female ≥ 55 years old; or no spontaneous 
menses for at least 2 years in a female < 55 years old; or age < 55 years and 
spontaneous menses within the past 1 year, but currently amenorrheic (eg, 
spontaneous or secondary to hysterectomy) and with follicle-stimulating 
hormone (FSH) levels > 40 IU/L, or postmenopausal estradiol levels 
(< 5 ng/dL), or according to the definition of “postmenopausal range” for the 
laboratory involved. 
 
Two acceptable methods of effective birth control include the following 
2 options: 
 
use of hormonal and barrier combination birth control methods 
(intrauterine device and barrier method with spermicide, intrauterine device 
and hormonal birth control method, hormonal birth control method and barrier 
method with spermicide),  
 
2 barrier methods (each partner must use 1 barrier method except a 
female condom) with at least 1 of the barrier methods including spermicide (a 
male and female condom may not be used together due to the risk of tearing) 
Approved 
 
 


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 
Hormonal methods of birth control include oral, intravaginal, transdermal, 
injectable, or implantable.  Barrier methods of birth control include diaphragm 
with spermicide, cervical cap with spermicide, male or female condom with 
spermicide, and contraceptive sponge with spermicide.  If spermicide is not 
commercially available in the local country/region a barrier method without 
spermicide is acceptable. 
 
Note:  If additional medications are given during treatment which may 
alter the contraceptive requirements (these additional medications may 
require an increase in the number of contraceptive methods and/or length of 
time that contraception is to be utilized after the last dose of protocol-required 
therapies) the investigator is to discuss these changes with the study subject. 
223 
Female subject is pregnant or breastfeeding or is planning to become pregnant 
or planning to breastfeed during treatment with IP (OM or placebo) or within 
5 days after the end of treatment with IP. 
224 
Planned to be discharged from the hospital to long term care facility (eg, skilled 
nursing facility) or hospice. 
225 
History or evidence of any other clinically significant disorder (including cardiac 
arrhythmia), condition or disease (with the exception of those outlined above) 
that, in the opinion of the investigator or Amgen physician, if consulted, would 
pose a risk to subject safety or interfere with the study evaluation, procedures, or 
completion. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the informed consent form before 
commencement of study-specific activities/procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the informed consent form [ICF]) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned by the IVRS/IWRS.  This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.   
Subjects who do not meet all eligibility criteria on the first screening attempt may be 
rescreened for the study.  For each rescreening, a new ICF must be signed and the 
Approved 
 
 


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Protocol Number:  20110203 
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rescreening must be reregistered in IVRS/IWRS.  Rescreened subjects who are 
reconsented will repeat all screening procedures (see Section 7.2.1). 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
5.1 
Randomization/Treatment Assignment 
Subjects who meet the eligibility requirements will be randomly assigned in a 1:1 ratio to 
1 of 2 treatment groups (OM or placebo) in a double-blind manner.  Randomization will 
be stratified by randomization setting (currently hospitalized for HF or recently and not 
currently hospitalized for HF) and region (5 strata:  US and Canada; Latin America; 
Western Europe, South Africa, and Australasia; Eastern Europe including Russia; Asia).  
Subjects can only be randomized 1 time for this study.   
Subjects in the recently and not currently hospitalized for HF setting who meet all 
eligibility criteria at the end of screening will return to the study site for randomization 
and day 1 procedures.   
Subjects in the currently hospitalized for HF setting who meet all eligibility criteria at the 
end of screening should be randomized prior to discharge with day 1 procedures 
occurring during the hospitalization. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.  Randomization numbers will be provided to the site through an 
IVRS/IWRS. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation. 
The investigator is strongly encouraged to contact the Amgen Clinical Study Manager 
before unblinding any subject’s treatment assignment, but must do so within 
1 working day after the event.   
Refer to the Investigational Product Instruction Manual (IPIM) for a description regarding 
how responsible pharmacists and investigators will access treatment information via the 
IVR/IWR system, in the event that there is a need to break the blind.  
Approved 
 
 


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6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product 
The Amgen IPs used in this study include:  OM and matching placebo.   
The IPIM, a document external to this protocol, contains detailed information regarding 
the storage, preparation, destruction, and administration of OM and placebo.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product (OM) 
OM will be manufactured and packaged by Amgen Inc.  or designee and distributed 
using Amgen clinical study drug distribution procedures.  OM will be presented as 
tablets.  Tablets will be packaged in 14-count blisters.  Further details regarding IP 
storage condition, dispensation, packaging, labeling, and accounting procedures are 
outlined in the IPIM. 
Placebo will be presented in identical containers and stored/packaged the same as OM. 
6.2.1.1 
Dosage, Administration, and Schedule 
IP will be administered orally BID in the morning and evening by the subjects and can be 
taken under fasted or fed conditions.  IP will be swallowed whole (not chewed, crushed, 
or split) and taken with water as instructed in the IPIM.  Each morning and evening 
administration should be taken at approximately the same time of day.  If IP cannot be 
taken or has not been taken within approximately 12 ± 3 hours from the most recent 
previous dose, the dose should be missed and the next dose should be taken at the 
regular time.  
The amount dispensed, amount returned, date dispensed, date returned, and box 
number of Amgen IP are to be recorded on each subject’s CRF. 
Subjects randomized to OM will initiate administration at 25 mg BID.  At study visit 
Week 2, a predose blood sample will be collected for all subjects.  The results will be 
blinded to investigators.  For subjects randomized to OM, predose PK collected at 
Week 2 will guide the dose adjustment.  A new IP supply will be provided to a subject 
when PK is assessed for the purpose of dose adjustment regardless of randomized 
treatment group and outcome of the PK assessment in order to maintain the blind. 
Subjects randomized to placebo will receive placebo throughout the study and will be 
submitted to all protocol procedures in order to maintain the blindness of treatment 
group allocation and IP dose.  Subjects should continue to take IP through the morning 
of the end of study (EOS) Visit.  
Approved 
 
 


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A direct relationship has been observed between the plasma concentrations of OM and 
increases in systolic ejection time, stroke volume, and left ventricular function 
(Cleland et al, 2011; Teerlink et al, 2011).  Excessive exposure to OM may result in 
signs and symptoms of myocardial ischemia or infarction (eg, increases in heart rate, 
dizziness, dyspnea, hypotension, chest discomfort or pain, ST-segment 
depression/elevation on ECG, and/or elevations in troponin I or T).  No antidote to OM 
currently exists.  In the event of an overdose, health care providers should be especially 
vigilant for signs and symptom of myocardial ischemia.  Standard medical therapies 
should be used to treat adverse signs or symptoms that do not promptly resolve with 
discontinuation of the IP. 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
All subjects will have predose PK assessed at Week 2 in order to guide the dose 
adjustment for subjects randomized to OM.  At Week 6, another predose PK will be 
assessed to reflect the PK results of the previous adjustment.  Pharmacokinetics will be 
assessed on Weeks 12 and 48, and then every 48 weeks throughout the study.  See 
Appendix D for a summary of dose adjustment rules. 
A new investigational product supply will be provided to all subjects at the Week 4 and 
Week 8 study visits regardless of randomized treatment group and outcome of the PK 
assessment in order to maintain the blind.  If the Week 2 PK value is not available in 
time for dose adjustment, subjects randomized to OM will continue with the 25 mg BID 
dose assignment pending the Week 6 PK assessment.  If the Week 6 PK value is not 
available in time for the dose adjustment, subjects randomized to OM will be assigned to 
the lower dosage regimen (25 mg BID). 
At Weeks 12, 48, and then every 48 weeks, PK will be assessed and are not part of the 
PK-based dose adjustment approach (Note:  subjects in between visits week 12 and 
week 24 at the time of local approval of this global amendment number 1 should have a 
PK assessment conducted during the week 24 visit).  Subjects with plasma 
concentration ≥ 1000 ng/mL at assessments after the Week 8 visit will be requested to 
stop IP administration, regardless of signs or symptoms.  An extra visit will be scheduled 
and the subject’s treatment assignment will be unblinded. 
Subjects randomized to placebo will receive placebo throughout the study but will 
undergo identical PK and resupply procedures.  
Approved 
 
 


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Date:  13 November 2018 
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If IP cannot be taken or has not been taken within approximately 12 ± 3 hours from the 
most recent previous dose, the dose should be missed and the next dose should be 
taken at the regular time. 
If a subject experiences clinical signs or symptoms consistent with acute myocardial 
ischemia or infarction, the subject should receive immediate medical attention according 
to the institution’s usual SoC, and the IP administration should be withheld.  Serial 
cardiac ischemic markers and ECGs should be analyzed locally.  Results from local 
laboratory assessment of Troponins (I or T), CK-MB, and BNP or NT-proBNP should be 
recorded in the CRF.  A central laboratory PK sample, Troponin I, CK-MB, and 
NT-proBNP should be collected in all subjects experiencing such events as close as 
possible to the event and the time last IP was taken.  The results of the PK assessment, 
when present, will routinely remain blinded to the sponsor and investigators.  The Data 
Monitoring Committee (DMC), however, will receive unblinded PK data.  Amgen should 
be notified of suspected acute myocardial ischemia or infarction within 24 hours of 
knowledge of the event. 
Restarting IP after a cardiac ischemic event may be considered after appropriate 
management of the case, and assessment of the likely cause of the event and the 
potential relatedness of the event to IP.  The decision to reinitiate the subject after a 
cardiac ischemic event should be discussed and agreed upon unanimously by the 
subject, investigator, and Amgen.  Subjects experiencing acute cardiac ischemic events 
suspected to be related to IP should not be rechallenged.  When restarting, subjects 
initiate OM 25 mg BID or placebo BID, according to initial group allocation.  A new 
predose PK assessment will be conducted after 2 weeks from IP reinitiation, and dose 
adjustment will occur at the next IP dispensation visit.  The adjustment follows the same 
procedures as for study visit Week 4, limiting the maximum dose to what was assigned 
before the event. 
Subjects reinitiating IP after withholding for reasons other than cardiac ischemic events 
will restart on the same IP dose as established before the event. 
6.2.1.3 
Other Protocol-required Therapies 
At randomization, recently and not currently hospitalized for HF or currently hospitalized 
for HF subjects should be optimally managed consistent with HF SoC therapies defined 
by regional clinical practice guidelines.  Oral SoC therapies for chronic HF (eg, beta 
blockers, renin-angiotensin-aldosterone system inhibitors) should be present, if not 
contraindicated.  Subjects enrolled during either HF hospitalization or early after HF 
Approved 
 
 


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hospitalization discharge can be reinitiating or titrating oral SoC chronic HF therapies at 
the time of randomization, per usual clinical practice. 
Use of ARNi or any other agent approved for HFrEF during the conduct of the study will 
be considered SoC if consistent with regional guidelines or standard clinical practice. 
Throughout the study, investigators may prescribe or adjust any concomitant 
medications or treatments deemed necessary to provide adequate supportive care, 
paying special attention to inhibitors of CYP3A4 discussed in Section 6.6.   
All other protocol-required therapies that are commercially available are not provided or 
reimbursed by Amgen (except if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these protocol-required therapies.  
Additional details regarding these protocol-required therapies are provided in the IPIM. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, TBL) and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis 
(as described below) may meet the criteria for withholding or permanent discontinuation 
of Amgen IP or other protocol-required therapies as specified in the Guidance for 
Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009. 
6.3.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
OM must be discontinued permanently and the subject should be followed according to 
the recommendations in Appendix A (Additional Safety Assessment Information) for 
possible drug-induced liver injury (DILI), if ALL of the criteria below are met:  
 
TBL > 2 x ULN or INR > 1.5 
 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
 
AND no other cause for the combination of the above laboratory abnormalities is 
apparent; important alternative causes for elevated AST/ALT and/or TBL values 
include, but are not limited to: 
 
hepatobiliary tract disease 
 
viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
Approved 
 
 


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 
right sided HF, hypotension, or any cause of hypoxia to the liver causing 
ischemia   
 
exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms   
 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, 
indinavir, atazanavir) 
 
alpha-one antitrypsin deficiency 
 
alcoholic hepatitis 
 
autoimmune hepatitis  
 
Wilson’s disease and hemochromatosis 
 
nonalcoholic Fatty Liver Disease including Steatohepatitis 
 
nonhepatic causes (eg, rhabdomylosis, hemolysis) 
6.3.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen IP 
outlined above and have no underlying liver disease, the following rules are 
recommended for withholding of Amgen IP and other protocol-required therapies:  
 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
Any 
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice).   
 
OR:  TBL > 3x ULN at any time 
 
OR:  ALP > 8x ULN at any time 
Amgen IP and other protocol-required therapies, as appropriate must be withheld 
pending investigation into alternative causes of DILI.  If IP is withheld, the subject is to 
be followed according to recommendations in Appendix A for possible DILI.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (Section 6.3.3).   
Approved 
 
 


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6.3.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject must be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then OM must be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Section 6.3.1) must never be rechallenged. 
6.4 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care, paying special 
attention to inhibitors of CYP3A4, discussed in Section 6.6. 
Concomitant therapies are to be collected from screening informed consent date through 
the EOS visit.  The groups of concomitant medications to be recorded will include (but 
not be limited to): 
 
Lipid lowering medications 
 
Analgesics/antipyretics 
 
Antibiotics 
 
Antidepressants 
 
Medication for glycemic control 
 
Hormone replacement therapy 
 
Oral corticosteroids 
 
Cardiovascular medication (eg, HF SoC therapies, antihypertensives, 
anticoagulants, antiplatelets, antiarrhythmics) 
The dosage of beta blockers, ACEi/angiotensin receptor blocker (ARB)/ARNi, isosorbide 
dinitrate/hydralazine hydrochloride, diuretics, and mineralocorticoid receptor antagonists 
(MRAs) will be recorded at each study visit.  If a subject is not taking beta blockers, 
ACEi/ARB/ARNi, or MRA, or taking doses below those recommended by local 
guidelines, investigators should record the reason in the electronic case report form 
(eCRF). 
Please refer to Appendix E to see a list of class I and class IIa Guideline Recommended 
Oral Drugs Commonly Used for Heart Failure with Reduced Ejection Fraction. 
6.5 
Product Complaints 
A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
Approved 
 
 


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performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any drug(s) or device(s) provisioned and/or repackaged/modified by 
Amgen.  Drug(s) or device(s) includes OM.   
Any product complaint(s) associated with an IP(s) or non-IP(s) or device(s) supplied by 
Amgen are to be reported according to the instructions provided in the IPIM. 
6.6 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Investigational treatments or procedures other than study-provided IP are prohibited.   
Medications or foods that are known potent inhibitors of CYP3A4 (see examples 
provided in Table 1) should be avoided, unless deemed necessary by the investigator. 
Table 1.  Examples of Potent Inhibitors of CYP3A4 
CYP3A4 Inhibitors 
Amprenavir 
Nelfinavir 
Cyclosporine 
Ritonavir 
Clarithromycin 
Saquinavir 
Delavirdine 
Telithromycin 
Erythromycin 
Verapamil 
Grapefruit juice 
Voriconazole 
Indinavir 
Nefazodone 
Itraconazole 
Ketoconazole 
Throughout the study, investigators may prescribe or adjust any concomitant 
medications or treatments deemed necessary to provide adequate supportive care.  
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
Screening assessments and study procedures are outlined in this section and in Table 2 
(Schedule of Assessments). 
 
Approved 
 
 


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Table 2.  Schedule of Assessments 
Timepoint/Frequency 
Screena 
Rand 
D1 
W2  
±3d 
W4 
±3d 
W6 
±3d 
W8 
±3d 
W12 
±3d 
W24 
±7d 
W36 
±7d 
W48 
±7d 
Q16Wb 
±7d 
Q48W 
±7d 
EOS visitc 
GENERAL PROCEDURES & SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (heart rate, blood pressure) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events/serious adverse 
events/potential 
endpoints/disease-related eventsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Instruction on IP administration 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Placebo run-ino 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of IP adherencen 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination/heightm 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
ECGe 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
LOCAL LABORATORYr 
Chemistryf 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
Screening BNP or NT-proBNPq 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy/FSHg 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
CENTRAL LABORATORY 
Chemistryh 
Xp 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
Hematology 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
Screening BNP or NT-proBNPq 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy/FSHg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Page 1 of 2 
Footnotes defined on the last page of the table 
 
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Table 2.  Schedule of Assessments 
Timepoint/Frequency 
Screena 
Rand 
D1 
W2 
±3d 
W4 
±3d 
W6 
±3d 
W8 
±3d 
W12 
±3d 
W24 
±7d 
W36 
±7d 
W48 
±7d 
Q16Wb 
±7d 
Q48W 
±7d 
EOS visitc 
Abbreviated laboratory paneli 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
NT-proBNP/Troponin I/CK-MBj 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
Biomarkers 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
PK samples 
 
 
Xk 
 
Xk 
 
X 
 
 
X 
 
X 
 
PATIENT-REPORTED OUTCOMES AND TARGET SYMPTOMS ASSESSMENTS 
KCCQ/PGR-S/CGR-S   
 
X 
 
 
 
 
X 
 X 
X 
X 
 
X 
 
EQ-5D 
 
X 
 
 
 
 
X 
X 
X 
X 
 
X 
 
NYHA Class 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACS signs and symptoms 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INVESTIGATIONAL PRODUCT 
IP administration at site 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
IP dispensation 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
IP tablet count 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Page 2 of 2 
ACS = acute coronary syndrome; ALP = alkaline phosphatase; ALT = alanine phosphatase; AST = aspartate aminotransferase; BNP = brain natriuretic peptide; 
CGR-S = Clinician Global Rating Severity; CK-MB = creatine kinase-MB; EOS = end of study; ECG = electrocardiogram; EQ-5D = EuroQOL 5 dimensions 
questionnaire; FSH = follicle-stimulating hormone; ICF = informed consent form; IP = investigational product; KCCQ = Kansas City Cardiomyopathy Questionnaire; 
NT-proBNP = n-terminal prohormone brain natriuretic peptide; NYHA = New York Heart Association; PGR-S = Patient Global Rating Severity; PK = pharmacokinetic; 
Q16W = every 16 weeks; Q48W = every 48 weeks; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase 
a The screening period can last up to 8 weeks after ICF signature. 
b After study visit Week 48 visits will be conducted every 16 weeks. 
c After the decision to end the study has been made, subjects will be scheduled for a final study visit. 
d Only adverse events possibly related to study procedures and serious adverse events are collected during the screening period.   
e Screening ECG to be performed and read locally for all sites.  On study ECG to be performed and read locally, except on sites that have been provided with 
centralized ECG services equipment. 
f  Chemistry panel for screening includes sodium, potassium, urea, creatinine, total bilirubin, direct bilirubin, CK, AST (SGOT), ALT (SGPT) 
g Serum pregnancy in females of childbearing potential; FSH only at screening if needed.  Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and regulations.   
h Chemistry panel includes sodium, potassium, chloride, calcium, magnesium, phosphorus, urea, creatinine, total bilirubin, direct bilirubin, CK, ALP, LDH, AST (SGOT), 
ALT (SGPT), and HbA1c. 
i Abbreviated laboratory panel includes sodium, potassium, urea, creatinine, AST, ALT, total bilirubin, direct bilirubin, and hemoglobin. 
j Central NT-proBNP, Troponin I, and CK-MB assessments after baseline will be blinded to subjects, investigators, and sponsor (Amgen). 
 
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k All subjects.  Blood sample must be collected before the administration of IP. 
l Local laboratory assessment at screening are accepted only for subjects randomized during hospitalization. 
m Height to be measured during screening only. 
n Investigator to discuss with subject IP administration and adherence during the previous 7 days, as per Section 6.2.1.1. 
o To assess subject’s ability to swallow the whole tablet successfully (open label placebo) per instruction (ie, without chewing).   
p Central laboratory assessment at screening applies to all subjects regardless of randomization setting (currently hospitalized for HF and recently and not currently 
hospitalized for HF). 
q Subjects on therapy with sacubitril/valsartan should have NT-proBNP assessed during screening phase. 
r Local laboratory assessments for screening can be used to support eligibility of hospitalized subjects, in order to provide flexibility for randomization before discharge. 
 
 
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Refer to the applicable supplemental laboratory, ECG, and Potential Endpoint manuals 
for detailed collection and handling procedures.   
7.2 
General Study Procedures  
The procedures performed at each study visit are outlined in Table 2.  Details regarding 
each type of procedure are provided in subsequent sub-sections.   
7.2.1 
Screening Enrollment  
For subjects recently and not currently hospitalized for HF, up to 8 weeks is allowed for 
screening before the subject must be randomized or screen failed in order to provide 
flexibility for HF therapy adjustment, visit scheduling, and potential retesting (see 
Section 7.2.2).  
Subjects currently hospitalized for HF are expected to be randomized before discharge.  
Local laboratory assessments from the current hospitalization can be used to support 
the subject’s eligibility and randomization in order to provide flexibility for randomization 
before discharge.  Central laboratory assessments for screening should be collected 
after ICF signature for those subjects.  If the subject is discharged during screening 
period and randomized later, subject will be included in the recently and not currently 
hospitalized for HF randomization setting stratification.   
The placebo run-in procedure assesses the subject’s ability to swallow an open label 
placebo tablet successfully (ie, without chewing).  The following procedures are to be 
completed during the screening period at time points designated in the Schedule of 
Assessments (Table 2): 
 
confirmation that the ICF has been signed  
 
demographic data including sex, age, race, and ethnicity will be collected in order 
to study their possible association with subject safety and treatment 
effectiveness. 
 
physical examination 
 
medical history   
 
height and weight 
 
vital signs (blood pressure, heart rate) 
 
laboratory assessments (chemistry, serum pregnancy [females of childbearing 
potential only], and FSH [if needed]) 
 
Serious Adverse Event reporting, Adverse Event reporting, Potential Endpoint 
reporting, Hospitalizations, Disease-related Event reporting (only adverse events 
possibly related to study procedures and serious adverse events are collected 
during the screening period from signing of ICF) 
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 
documentation of concomitant therapy 
 
placebo run-in 
 
registration in IVRS/IWRS system 
 
ECG (for cardiac rhythm confirmation) 
7.2.2 
Retesting 
If, in the investigator’s judgment, laboratory abnormalities are likely to be transient, blood 
samples can be retested during screening as long as the subject can be evaluated for 
eligibility and randomized within the allowed screening period.   
7.2.3 
Rescreening 
Subjects who do not meet all eligibility criteria on the first screening attempt may be 
rescreened for the study.  Rescreen subjects must first be registered as screen failed in 
IVRS/IWRS and subsequently registered as rescreened.  Subjects will maintain the 
originally assigned subject identification number.  For each rescreening, a new informed 
consent form must be signed.  Rescreened subjects who are reconsented will repeat all 
screening procedures.   
7.2.4 
Treatment  
Subjects in the recently and not currently hospitalized for HF setting who meet all 
eligibility criteria at the end of screening will return to the study site for randomization 
and day 1 procedures.   
Subjects in the currently hospitalized for HF setting who meet all eligibility criteria at the 
end of screening should be randomized prior to discharge with day 1 procedures 
occurring during the hospitalization.  Subjects can only be randomized 1 time for this 
study. 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 2).  IP is to be administered after 
completion of vital signs, ECG, and blood draw procedures during each visit that these 
are required.  PRO assessments should be completed first at each visit, where they are 
required.   
 
randomization in IVRS/IWRS system 
 
central laboratory assessments (PK, chemistry, hematology, abbreviated 
laboratory panel, NT-proBNP, troponin I, biomarkers, and urinalysis)) 
 
vital signs (blood pressure, heart rate) 
 
weight 
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 
review for adverse events/serious adverse events, potential endpoint reporting 
(PEP), disease related events (DRE), and acute coronary syndrome (ACS) signs 
and symptoms 
 
documentation of concomitant therapy 
 
ECG 
 
PROs (should be done before other study procedures) 
 
NYHA Class/Clinician Global Rating Severity (CGR-S) 
 
IP administration at site 
 
IP dispensation 
 
IP tablet count 
If a subject withdraws from the study early, investigators would make every effort to 
complete and report the observations as thoroughly as possible up to the date of 
withdrawal.  If possible, the end of study procedures should be completed at the time of 
withdrawal (see Section 7.2.5). 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
of death should be obtained.  
7.2.5 
End of Study Visit 
The study is event driven and will conclude when approximately 1590 subjects have 
experienced an event of CV death.  Amgen and executive committee (EC) will determine 
the termination period based on the anticipated date of occurrence of 1590 CV death 
events.  Investigators will be notified in advance and should schedule the End of Study 
(EOS) visits for all subjects.  The following procedures will be completed during the EOS 
visit: 
 
vital signs (blood pressure, heart rate) 
 
height and weight 
 
patient reported outcomes (PROs; should be done before other study 
procedures) 
 
review for adverse events/serious adverse events/PEPs/DRE/ACS signs and 
symptoms 
 
physical examination as per SoC 
 
ECG 
 
documentation of concomitant therapy 
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 
central laboratory assessments (chemistry, hematology, urinalysis, NT-proBNP, 
troponin I, biomarkers) 
 
IP tablet count 
7.2.6 
Description of Study Procedures 
7.2.6.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved ICF before any study 
specific procedures are performed. 
7.2.6.2 
Demographic Data 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.   
7.2.6.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started prior to enrollment through the screening visit.  Medical history will include 
information on the subject’s concurrent medical conditions.  Record all findings on the 
medical history CRF. 
7.2.6.4 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure and 
heart rate.  Use of an automated oscillometric device for blood pressure measurement is 
preferred and recommended.  Blood pressure will be recorded in both of the subject’s 
arms unless a concomitant condition favors the use of a particular arm.  The arm with 
the higher systolic reading will be used for eligibility determination.  The appropriate size 
cuff should be used.  The subject’s pulse should be measured for 30 seconds and the 
number multiplied by 2 to obtain heart rate.  Blood pressure measurement can be 
repeated if the previous reading is outside of the eligibility range.  The repeat blood 
pressure measure should be taken at least 2 minutes following the previous measure.  
Subjects must be in supine position in a rested and calm state for at least 5 minutes 
before blood pressure assessments are conducted.  If the subject is unable to be in the 
supine position, the subject should be in the most recumbent position possible.  The 
position selected for a subject should be the same that is used throughout the study and 
documented on the vital sign CRF.   
Record all measurements on the vital signs CRF. 
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7.2.6.5 
Physical Examination 
A physical examination will be conducted as per SoC.  Breast, genital, and rectal 
examinations are not required unless specific evaluation is warranted.  Physical 
examination findings should be recorded on the appropriate CRF (eg, medical history, 
event). 
7.2.6.6 
Height and Weight 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes. 
7.2.6.7 
Electrocardiogram 
Subject must be in a supine position in a rested and calm state for at last 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in the most recumbent position as possible.  The ECG 
must be performed prior to blood draws or other invasive procedure.  Each ECG must 
include the following measurements:  QRS, QT, QTc, RR, and PR intervals, and 
assessment of cardiac rhythm. 
ECGs must be conducted as follows: 
Screening ECG 
 
1 local ECG (all sites) 
On study ECGs (day 1, week 48, every 48 weeks [Q48W]) 
 
Centralized ECG services:  ECG in triplicate run consecutively 
 
No centralized ECG services:  1 local ECG 
The principal investigator or designated site physician will review all ECGs (regardless of 
using a centralized service or not centralized service).  Once signed, the original ECG 
tracing will be retained with the subject’s source documents.  At the request of the 
sponsor, a copy of the original noncentralized ECG will be made available to Amgen.   
Further detail about the equipment provided and its use for this study will be provided in 
an Investigator ECG Manual distributed to the sites before start of enrollment. 
7.2.6.8 
Concomitant Therapy 
For the following concomitant medications categories (see Section 6.4), investigators 
must document whether therapy was being taken at any time point during the study:  
lipid lowering medications, analgesics / antipyretics, antibiotics, antidepressants, 
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hormone replacement therapy, oral corticosteroids, CV medication (eg, HF SoC 
therapies, antihypertensives, anticoagulants, antiplatelets, and antiarrhythmics). 
The dosage of beta blockers, ACEi/ARB/ARNi, diuretics, and MRAs will be recorded.  If 
a subject is not taking beta blockers, ACEi/ARB/ARNi, or MRA, or taking doses below 
those recommended by local guidelines, investigators should record the reason in the 
eCRF. 
Initiation of nonpharmacological treatments for HF (eg, implantable cardioverter 
defibrillator, cardiac resynchronization therapy [CRT]) and coronary revascularization will 
be recorded on the CRF. 
7.2.6.9 
Patient-reported Outcomes 
Subjects will be asked to complete the KCCQ, Patient Global Rating Severity (PGR-S), 
and EQ-5D questionnaires in a quiet place prior to the medical consultation and prior to 
undergoing any tests and procedures to avoid biasing their response to the 
questionnaires.  Site staff will be asked to check the questionnaires for completeness 
before the subject leaves the clinic or hospital.  
7.2.6.10 
Laboratory Assessments 
The schedule of assessments (Table 2) defines the analytes to be collected at each 
study visit.  The date and time of sample collection will be recorded in the source 
documents at the site.  Table 3 below outlines the specific analytes to be tested and 
reported.   
Table 3.  Analyte Listing 
Chemistry 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Creatinine 
Specific 
gravity 
Hemoglobin 
OM plasma 
concentration (PK) 
Potassium 
 
pH 
Hematocrit 
Pregnancy testa 
Chloride 
Total bilirubin 
Blood 
RBC 
FSHa 
Calcium 
Direct 
bilirubin 
Protein 
RDW 
NT-proBNP 
Magnesium 
CK 
Glucose 
MCV 
Troponin I 
Phosphorus 
ALP 
Bilirubin 
MCH 
HbA1c 
 
LDH 
 
MCHC 
CK-MB 
Urea 
AST (SGOT) 
 
WBC 
 
 
ALT (SGPT) 
 
Platelets 
 
OM = omecamtiv mecarbil; PK = pharmacokinetic; RBC = red blood cell; FSH = follicle-stimulating hormone; 
RDW = red cell distributions width; NT-proBNP = N-terminal pro-B-type natriuretic peptide; CK = creatine 
kinase; MCV = mean corpuscular volume; ALP = alkaline phosphatase; MCH = mean corpuscular 
hemoglobin; HbA1c = Glycated hemoglobin; LDH = lactic acid dehydrogenase; MCHC = mean corpuscular 
hemoglobin concentration; CK-MB = creatine kinase-MB;  AST = aspartate aminotransferase; WBC = white 
blood cell; ALT = alanine aminotransferase 
a A pregnancy test is required for females of childbearing potential; FSH only per exclusion. 
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Omecamtiv mecarbil plasma concentrations will be measured using an 
investigational assay.  The investigation assay is identified as QMS Omecamtiv 
Mecarbil Immunoassay which was developed by Thermo Fisher Scientific.  The 
investigational assay will be used in accordance with local regulatory and labeling 
requirements along with the Instructions for Use provided. 
7.2.6.11 
Safety Data Reporting 
Adverse events, serious adverse events, adverse device effects, and disease-related 
events observed by the investigator or reported by the subject will be collected at all 
study visits from the signing of the ICF through the EOS visit or 30 days after the last 
dose of IP, whichever is later (see Section 9 for details). 
7.3 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Biomarker development can be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity.   
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to OM.   
Blood Samples 
Blood samples are to be collected for biomarker development at the following time 
points:  day 1, Week 6, Week 24, and EOS visit. 
7.4 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of OM and/or to identify 
subjects who may have positive or negative response to OM.  No additional samples are 
collected for this part of the study.  For subjects who consent to this/these 
analysis/analyses, DNA may be extracted.  
7.5 
Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments (Table 2) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
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produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand HF, 
the dose response and/or prediction of response to OM, and characterize aspects of the 
molecule (eg, mechanism of action/target, metabolites).  Results from this analysis are 
to be documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
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discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving IP 
and/or other protocol-required therapies or procedures at any time during the study but 
continue participation in the study.  If this occurs, the investigator is to discuss with the 
subject the appropriate processes for discontinuation from IP or other protocol-required 
therapies and must discuss with the subject the options for continuation of the Schedule 
of Assessments (Table 2) including different options of follow-up (eg, in person, by 
phone/mail, through family/friends, in correspondence/communication with other 
treatment physicians, from the review of medical records) and collection of data, 
including endpoints and adverse events.  Subjects who have discontinued 
investigational product and/or protocol required therapies or procedures should not be 
automatically removed from the study.  Whenever safe and feasible it is imperative that 
subjects remain on-study to ensure safety surveillance and/or collection of outcome 
data.  The investigator must document the change to the Schedule of Assessments 
(Table 2) and the level of follow-up that is agreed to by the subject (eg, in person, by 
telephone/mail, through family/friends, in correspondence/communication with other 
physicians, from review of the medical records).   
Withdrawal of consent for follow-up should be accompanied by documentation of the 
reason for withdrawal.  Withdrawal of consent for treatment should be distinguished from 
withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up (eg, medical records checks).  Subjects requesting withdrawal should 
be informed that withdrawal of consent for follow-up will jeopardize the public health 
value of the study. 
Subjects who withdraw should be asked explicitly about the contribution of possible 
adverse events to their decision to withdraw consent, and any adverse event information 
elicited should be documented. 
Preferably the subject should withdraw consent in writing and, if the subject or the 
subject’s representative refuses or is physically unavailable, the site should document 
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and sign the reason for the subject’s failure to withdraw consent in writing.  The informed 
consent for the study should note that although a subject is free to leave the study and 
stop taking study medication, the investigators hope the patient will remain for follow-up 
status evaluations. 
For subjects who have withdrawn consent for further follow-up, investigators will review 
public records as permitted by applicable law to determine vital status of the subject at 
the end of the study or before. 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from IP and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
prior to study completion.    
Subjects may be eligible for continued treatment with Amgen IP and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required IP or procedural assessments include any 
of the following: 
 
subject request   
 
safety concern (eg, due to an adverse event, pregnancy) 
 
death 
 
lost to follow-up 
 
decision by sponsor (other than subject request, safety concern, lost to follow-up)  
 
OM plasma concentration ≥ 1000 ng/mL when assessed after Week 8 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
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9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease Related Events 
Events that are not submitted for adjudication as potential endpoints, but that are 
anticipated to occur in the study population due to the underlying disease, may be 
reported as Disease Related Events.  In this study, subjects will have HFrEF with an 
LVEF of ≤ 35%.  It is expected that the study subjects will experience events related to 
chronic HFrEF.  Examples of events related to HF include: 
 
fluid overload signs and symptoms (eg, edema, pulmonary congestion, dyspnea, 
orthopnea, hepatic congestion) not requiring urgent, unscheduled clinic/office/ED 
visit, or hospital admission 
 
renal function impairment (eg, cardiorenal syndrome, acute renal failure) not 
requiring urgent, unscheduled clinic/office/ED visit, or hospital admission 
If the event is considered worse than that which would normally be expected for the 
subject, or if the investigator believes there is a causal relationship between the IP and 
disease worsening, the event should not be considered a Disease Related Event and 
must be reported as an Adverse Event or Serious Adverse Event. 
If a Disease Related Event is considered as an adverse event and is serious, the event 
should be reported within 24 hours of the acknowledgement of the event. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease (eg, 
diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
Only adverse events considered related to study procedures and serious adverse events 
are reported after signing of the informed consent until randomization. 
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If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Event as 
defined in Section 9.1.1): 
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
A disease related event, as described above, is to be reported as a serious adverse 
event if  
 
the subject’s pre-existing condition becomes worse than what the investigator 
would consider typical for a patient with the same underlying condition, or 
 
if the investigator believes a causal relationship exists between the 
investigational medicinal product(s)/protocol-required therapies and the event,  
 
and the event meets at least 1 of the serious criteria above. 
An adverse event would meet the criterion of “requires hospitalization,” if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event.”  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
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9.2 
Safety Event Reporting Procedures  
9.2.1 
Reporting Procedures for Disease Related Events 
The investigator is responsible for ensuring that all Disease Related Events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
medicinal product(s)/study treatment/protocol-required therapies through the EOS visit, 
or 30 days after the last administration of IP, whichever is later, are reported using the 
Event CRF.   
Events assessed by the investigator to be related to the investigational medicinal 
product(s) or considered worse than that which would normally be expected for the 
subject and determined to be serious, require reporting of the event on the Event CRF 
as a Serious Adverse Event rather than as a Disease Related Event, and within 
24 hours from the acknowledgement of the event.  
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after randomization through end of 
study/safety follow-up visit, or 30 days after the last administration of IP, whichever is 
later, are reported using the Event CRF. 
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms), 
 
Dates of onset and resolution (if resolved), 
 
Severity (and/or toxicity per protocol), 
 
Assessment of relatedness to OM, and 
 
Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  Because the criteria for the CTCAE grading scale differs 
from the regulatory criteria for serious adverse events, if adverse events correspond to 
grade 4 “life-threatening” CTCAE grading scale criteria (eg, laboratory abnormality 
reported as grade 4 without manifestation of life-threatening status), it will be left to the 
investigator’s judgment to also report these abnormalities as serious adverse events.  
For any adverse event that applies to this situation, comprehensive documentation of the 
event’s severity status must be recorded in the subject’s medical record.  The grading 
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scale used in this study is described in Appendix A.  The investigator must assess 
whether the adverse event is possibly related to the OM.  This relationship is indicated 
by a “yes” or “no” response to the question:  Is there a reasonable possibility that the 
event may have been caused by the IP?   
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.   
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after informed consent through end 
of study/safety follow-up visit, or 30 days after the last administration of IP, whichever is 
later, are recorded in the subject’s medical record and are submitted to Amgen.  All 
serious adverse events must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the Event CRF.   
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event.   
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
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Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet /electronic Serious Adverse Event Contingency Report Form.  
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available.   
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice.   
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
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9.2.2.3 
Reporting a Safety Endpoint as a Study Endpoint 
All potential endpoints (death, HF events, major cardiac ischemic event, and stroke) 
must be recorded on the Event CRF within 24 hours of knowledge of the event.  
Information regarding dates of onset and resolution, severity, action taken, investigator 
assessment of relatedness, and assessment of seriousness must be collected.   
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur after the last dose of protocol-required therapies through 
5 days after the end of treatment with IP.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).   
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur after the last dose of protocol-required therapies through 
5 days after the end of treatment with IP. 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C). 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
 
composite of time to CV death or first HF event, whichever occurs first 
 
An HF event is defined as an urgent, unscheduled clinic/office/ED visit, or hospital 
admission, with a primary diagnosis of HF, where the patient exhibits new or 
worsening symptoms of HF on presentation, has objective evidence of new or 
worsening HF, and receives initiation or intensification of treatment specifically for 
HF(Hicks et al, 2015).  Changes to oral diuretic therapy do not qualify as initiation or 
intensification of treatment.   
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10.1.1.2 
Secondary Endpoints 
 
time to CV death 
 
change in Kansas City Cardiomyopathy Questionnaire Total Symptom Score 
(KCCQ TSS) from baseline to Week 24 
 
time to first heart failure hospitalization 
 
time to all-cause death 
10.1.1.3 
Safety Endpoints 
 
subject incidence of reported adverse events 
 
subject incidence of reported serious adverse events of ventricular arrhythmias 
requiring treatment 
 
subject incidence of positively adjudicated major cardiac ischemic events 
 
adjudicated major cardiac ischemic adverse events are:  myocardial infarction, 
hospitalization for unstable angina, percutaneous coronary intervention/coronary 
artery bypass graft (Hicks et al. 2015) 
10.1.1.4 
Exploratory Endpoints 
 
incidence of HF events within the first 30 days and the first 60 days after index 
hospitalization in subjects randomized during HF hospitalization 
 
incidence of HF hospitalizations within the first 30 days and the first 60 days after 
index hospitalization in subjects randomized during HF hospitalization 
 
change in NT-proBNP from baseline to each assessment 
 
change in resting heart rate from baseline to each assessment 
 
time to first HF event 
 
times to recurrent HF events 
 
times to recurrent HF hospitalizations 
 
composite of time to CV death or first HF hospitalization, whichever occurs first 
 
composite of time to all-cause death or first HF hospitalization, whichever occurs first 
 
changes in KCCQ scores from baseline to each assessment 
 
OM concentration at Week 2 and Week 6 
 
composite of time to CV death, HF event, myocardial infarction, hospitalization for 
unstable angina, coronary revascularization, and stroke, whichever occurs first 
10.1.2 
Analysis Sets 
10.1.2.1 
Efficacy Analysis Set 
Efficacy analyses will be performed on the full analysis set (FAS), which includes all 
randomized subjects.  Subjects will be analyzed according to their randomized treatment 
group assignment. 
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10.1.2.2 
Safety Analysis Set 
Safety analyses will be performed on the safety analysis set (SAS), which includes all 
randomized subjects who receive at least 1 dose of IP on study.  Unless otherwise 
specified, for safety analyses, subjects will be grouped according to their randomized 
treatment group assignment with the following exception:  if a subject receives treatment 
throughout the study that is different than the randomized treatment group assignment, 
then the subject will be grouped by the actual treatment group. 
10.1.3 
Covariates and Subgroups 
Baseline covariates include, but are not limited to eGFR and the stratification factor of 
randomization setting and region. 
Prespecified subgroups for the analysis include, but are not limited to: 
 
stratification factor of randomization setting (currently hospitalized for HF or 
recently and not currently hospitalized for HF) 
 
stratification factor of region (5 strata:  US and Canada; Latin America; Western 
Europe, South Africa, and Australasia; Eastern Europe including Russia; Asia) 
 
age (< 65 years, ≥ 65 years) 
 
sex (male, female) 
 
baseline weight (quartiles) 
 
race (black or African American, white, Asian, other) 
 
ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 
baseline NYHA Class (II, III/IV) 
 
diabetes mellitus at baseline (yes, no) 
 
primary cause of HF (ischemic, nonischemic) 
 
medical history of myocardial infarction (yes, no) 
 
presence of atrial fibrillation/flutter at screening (yes, no) 
 
baseline LVEF (≤ median, > median) 
 
baseline NT-proBNP by randomization setting excluding subjects in atrial 
fibrillation/flutter at screening (≤ median and > median) 
 
baseline resting heart rate (≤ median and > median) 
 
baseline systolic blood pressure (≤ median and > median) 
 
baseline eGFR (≤ 60 mL/min/1.73m2, > 60 mL/min/1.73m2) 
 
baseline use of ACEi 
 
baseline use of ARB 
 
baseline use of aldosterone inhibitor 
 
baseline use of ARNi 
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 
baseline presence of CRT 
 
baseline presence of implanted cardiac defibrillator (ICD) 
10.2 
Sample Size Considerations 
The sample size calculation is based on the CV death component of the primary 
composite endpoint.  The control group event rate is assumed to vary by randomization 
setting.  Subjects randomized in a hospital setting are assumed to have greater risk in 
the first year of 19% followed by the constant yearly outpatient setting rate of 7%.  
Assuming 25% of subjects will be randomized in the hospital setting, the CV death rate 
in the first year is expected to be 10% overall subjects and 7% for each year thereafter. 
A 24 month enrollment period is assumed and the total study duration set to 48 months.  
The hazard ratio for CV death alone is assumed to be 0.8 after a 3 month treatment lag 
at the beginning of the trial, where the hazard ratio is assumed to be 1.  Additionally, 
assume 10% of subjects discontinue therapy per year and 10% of subjects over the 
course of the trial will be lost to endpoint determination.  The overall type I error is 
0.05 for 2-sided testing.  After accounting for these factors, a total sample size of 
approximately 8000 subjects with approximately 1590 subjects experiencing CV death 
events is required to ensure a power of 90% for testing superiority for CV death 
(Shih, 1995).  Assuming the rates for experiencing either a HF event or CV death are 
double those for CV death alone and the same other assumptions as for CV death 
alone, the primary composite endpoint is expected to have greater than 99% power 
when the primary analysis is triggered. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded except as specified (eg, Section 5.2 and Section 9.2.2.2).  
10.4 
Planned Analyses 
10.4.1 
Interim Analyses 
Futility for the primary endpoint will be assessed when approximately one-third and 
two-thirds of the overall required CV deaths are observed.  Efficacy will be assessed 
when approximately two-thirds of the overall required CV deaths are observed.  An 
alpha of 0.001 (Haybittle-Peto approach; Haybittle, 1971; Peto et al, 1976) will be used 
for assessing superiority.  The DMC can recommend stopping the trial if the primary 
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composite endpoint and the secondary endpoint time to CV death reach statistical 
significance.  The remainder of the secondary endpoints will be assessed with an overall 
alpha of 0.001 following the testing diagram if the study is stopped early. 
Interim futility and efficacy assessments will be conducted by the Independent 
Biostatistical Group (IBG) and reviewed by the DMC.  
Blinded event rate monitoring during the study will be conducted periodically to assess 
the study planning assumptions versus the trial aggregate data.  This monitoring will be 
conducted by the sponsor’s clinical study team.  Appropriate operational actions may be 
implemented due to results from this monitoring. 
10.4.2 
Data Monitoring Committee  
An external independent DMC will be established to formally review the accumulating 
data from this study to ensure there is no avoidable increased risk for harm to subjects 
and conduct the interim analyses for futility and efficacy.  The independent DMC is 
chaired by an external academic cardiologist who is an expert in HF and clinical trials.  
Analyses for the DMC will be provided by the IBG, which is external to Amgen.  Details 
will be provided in the DMC charter.  The independent DMC members and the IBG will 
have access to treatment assignments and subject level data from the clinical trial 
database. 
10.4.3 
Primary Analysis 
The primary analysis will include hypothesis testing for each of the primary and 
secondary endpoints and include analyses of exploratory endpoints.  The primary 
analysis will occur after the primary completion milestone of observing approximately 
1590 CV deaths is achieved.  At that point, the database will be cleaned, processed and 
a snapshot will be taken.  The study will also be unblinded.  Based on the snapshot, 
unless specified otherwise, efficacy analyses will be performed on the FAS by 
randomized treatment group and safety analyses will be performed on the SAS.   
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Unless otherwise specified, all hypothesis tests will be reported as 2-sided and the full 
study will have an overall type I error rate of 0.05.  Missing data will not be imputed in 
the primary analysis of the primary and secondary endpoints.  
Subject disposition, demographics, baseline characteristics, and exposure to IP will be 
summarized. 
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Continuous variables will be summarized using descriptive statistics, including the 
number of observations (n), mean, standard deviation or standard error, median, the first 
quartile and third quartile, minimum, and maximum.  Categorical variables will be 
summarized using the number and percent of subjects. 
All deaths, HF events, major cardiac ischemic adverse events (myocardial infarction, 
unstable angina hospitalization, and coronary revascularization), and strokes will be 
adjudicated by an independent external CEC, using standardized definitions.  The CEC 
is external to Amgen and primarily comprises both academic clinical physicians (to 
include cardiologists) and medical reviewers trained on the clinical trial protocol, the 
CEC charter, and CEC processes.  The chairman of the CEC is responsible for 
overseeing the operations in conformance with the CEC charter and for supervising the 
flow of data between the sponsor/data management and the CEC.  Committee members 
are qualified in the appropriate subspecialty and free of conflict of interest.  The CEC is 
blinded to treatment allocation and reviews events according to prespecified criteria 
defined in the CEC charter. 
10.5.2 
Multiplicity Adjustments 
In order to preserve an overall type I error rate of 0.05 for the primary and secondary 
endpoints, the following multiplicity adjustment will be performed:  
A total alpha of 0.001 (one-sided 0.0005) will be used for assessing superiority at the 
second interim analysis.  If the study continues, a total alpha of 0.05 will be used for 
testing at the primary analysis triggered based on observing approximately 1590 CV 
deaths.  Within an analysis, the total alpha will apply to all primary and secondary 
endpoint hypothesis tests.  The primary endpoint will be tested first with the total alpha.  
If the primary endpoint reaches statistical significance, a Bonferroni split will be used 
where 0.96α is allocated to testing the time to CV death and 0.04α is allocated to testing 
change baseline in the KCCQ TSS.  Alpha from a statistically significant result for these 
2 endpoints after the split will propagate to the other endpoint (Bretz et al, 2009) with a 
small alpha (0.0001 x fraction of the α used in the statistically significant test) 
propagating to testing time to first heart failure hospitalization.  If statistical significance is 
achieved for both the time to CV death and change from baseline in the KCCQ TSS, 
time to first heart failure hospitalization will be tested at the full alpha.  If time to first 
heart failure hospitalization is statistically significant, time to all-cause death will be 
tested with the same alpha as time to first heart failure hospitalization.  Figure 2 
illustrates the multiplicity testing propagation approach.  Alpha will only propagate if the 
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direction of the statistically significant effect favors omecamtiv mecarbil.  Exploratory 
endpoints will be assessed using a nominal alpha level of 0.05 and not have multiplicity 
adjustments. 
Figure 2.  Multiplicity Testing Propagation Approach 
 
AC DTH = time to all-cause death; CV = cardiovascular death; CV DTH = time to CV death; HFH = time to 
first heart failure hospitalization; KCCQ TSS = Kansas City Cardiomyopathy Questionnaire Total Symptom 
Score; PC = primary composite endpoint 
Each circle represents a hypothesis test.  The values in boxes on the arrows indicate the fraction of 
α propagated in the direction of the arrow to the next hypothesis test(s). ε = 0.0001, a small value to 
complete the graph while prioritizing the CV death and KCCQ TSS endpoints over the time to first heart 
failure hospitalization and all-cause death endpoints.  Dashed arrows used to emphasize this prioritization. 
No multiplicity adjustment will be made for exploratory or sensitivity analyses. 
10.5.3 
Primary Efficacy Endpoint 
The primary endpoint is the composite of time to CV death or first HF event, whichever 
occurs first.  The composite endpoint will be assessed using a Cox model stratified by 
randomization setting and region.  The Cox model will include terms for baseline eGFR 
and the treatment group.  The treatment effect will be tested using a likelihood ratio test 
and 95% confidence intervals for the model parameters will be computed.  
Kaplan-Meier estimates of cumulative incidence of the composite endpoint will be 
computed.   
The Cox model will be fit for subgroups of the stratification factors and the other 
prespecified subgroups. 
10.5.4 
Secondary Efficacy Endpoints 
The secondary endpoints of time to CV death, time to first HF hospitalization, and time to 
all-cause death will be assessed using a Cox model stratified by randomization setting 
and region and include terms for baseline eGFR and treatment. 
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Change in KCCQ TSS from baseline to Week 24 will be assessed using a mixed model 
fit within each randomization setting containing the baseline TSS value, region, baseline 
eGFR, visit, treatment, and treatment by visit.  Only the planned visits at Week 12 and 
Week 24 will be included.  An unstructured covariance matrix will be used within each 
randomization setting.  Treatment group means and differences in means for each visit 
will be estimated marginalizing over the baseline TSS value, baseline eGFR, and region 
using the pooled mean over all subjects in the FAS within each randomization setting.  
Associated 95% confidence intervals for change from baseline will be reported for each 
visit within each randomization setting.  An omnibus F-test with two numerator degrees 
of freedom will be used to test the treatment effect of OM versus placebo.  The test will 
use the marginalized mean differences to placebo within each randomization setting at 
Week 24. 
10.5.5 
Safety Endpoints 
10.5.5.1 
Adverse Events 
The current Medical Dictionary for Regulatory Activities version at the time of the data 
lock will be used to code all adverse events to a system organ class and a preferred 
term. 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from IP, and significant treatment-emergent 
adverse events will also be provided. 
Subject incidence of serious adverse events of ventricular arrhythmias requiring 
treatment and positively adjudicated major cardiac ischemic adverse events will be 
tabulated. 
10.5.5.2 
Laboratory Parameters 
The analyses of safety laboratory endpoints will include summary statistics at each 
scheduled visit by treatment group. 
Shifts in grades or between relevant thresholds of safety laboratory values between 
baseline and the worst on-study value will be tabulated by treatment group. 
10.5.5.3 
Vital Signs 
The analyses of vital signs will include summary statistics at each scheduled visit by 
treatment group. 
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10.5.5.4 
Electrocardiograms 
Selected sites will be provided with centralized ECG services equipment specifically for 
this study.  For these central ECG measurements, summaries over time and/or changes 
from baseline over time will be provided for all ECG parameters.  Subjects’ maximum 
change from baseline in QTcF and QTcB will be categorized and the number and 
percentage of subjects in each group will be summarized.  Subjects’ maximum post 
baseline values will also be categorized and the number and percentage of subjects in 
each group will be summarized. 
The ECG measurements taken at other sites are performed as per SoC for routine 
safety monitoring, rather than for purposes of assessment of potential QTc effect.  Since 
these evaluations may not necessarily be performed under the rigorous conditions 
expected to lead to meaningful evaluation of QTc data; summaries and statistical 
analyses of these ECG measurements are not planned, and these data would not be 
expected to be useful for meta-analysis with data from other trials.  These locally 
collected ECG measurements will not be combined with central ECG measurements. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any IP(s) is/are administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
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The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen IP. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval throughout the 
duration of the study.  Copies of the investigator’s reports and the IRB/IEC continuance 
of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance 
with local laws and regulations.   
 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
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 
For Serious Adverse Events reported to Amgen, subjects are to be identified by 
their unique subject identification number, initials (for faxed reports, in 
accordance with local laws and regulations), and date of birth (in accordance with 
local laws and regulations). 
 
Documents that are not submitted to Amgen (eg, signed informed consent forms) 
are to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit such individuals to have access to his/her 
study-related records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
a recognized expert in the therapeutic area 
 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen IP(s) by an extension 
protocol or as provided for by the local country’s regulatory mechanism.  However, 
Amgen reserves the unilateral right, at its sole discretion, to determine whether to supply 
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Amgen IP(s) and by what mechanism, after termination of the study and before the 
product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the 
IRB/IEC and Amgen 
 
IP-related correspondence including Proof of Receipts, IP Accountability 
Record(s), Return of IP for Destruction Form(s), Final IP Reconciliation 
Statement, as applicable. 
 
Non-IP(s) and or medical device(s) documentation, as applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
Amgen is responsible for verifying the CRFs at regular intervals throughout the study to 
verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
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and adherence to local regulations on the conduct of clinical research.  The Amgen 
representative is to have access to subject medical records and other study-related 
records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the CRFs must be maintained 
and readily available. 
 
Updates to CRFs will be automatically documented through the software’s “audit 
trail.” 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During 
this review, subject data are checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data are reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries are created in the EDC system 
database for site resolution and subsequently closed by the EDC system or by 
an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this electronic 
data capture study or the investigator applies an electronic signature in the EDC 
system if the study is set up to accept an electronic signature.  This signature 
indicates that investigator inspected or reviewed the data on the CRF, the data 
queries, and agrees with the content. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 2), the investigator can search publically available 
records (where permitted) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
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12.5 
Language 
CRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals (International Committee of Medical Journal 
Editors, 2013, updated 2014), which states: 
 
Authorship credit should be based on (1) substantial contributions to conception 
and design, acquisition of data, or analysis and interpretation of data; (2) drafting 
the article or revising it critically for important intellectual content; (3) final 
approval of the version to be published; (4) agreement to be accountable for all 
aspects of the work in ensuring that questions related to the accuracy or integrity 
of any part of the work are appropriately investigated and resolved.  Authors 
should meet conditions 1, 2, 3, and 4. 
 
When a large, multicenter group has conducted the work, the group should 
identify the individuals who accept direct responsibility for the manuscript.  These 
individuals should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those 
who qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
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Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
Ambrosy AP, Fonarow GC, Butler J, et al.  The global health and economic burden of 
hospitalizations for heart failure.  J Am Coll Cardiol.  2014;63(12):1123-1133. 
Bhatia RS, Tu JV, Lee DS, et al.  Outcome of heart failure with preserved ejection 
fraction in a population-based study.  N Engl J Med.  2006;355(3):260-269. 
Bretz F, Maurer W, Brannath W, Posch M.  A graphical approach to sequentially 
rejective multiple test procedures.  Statistics in Medicine.  2009;28:586–604. 
Cleland JG, Teerlink JR, Senior R, et al.  The effects of the cardiac myosin activator, 
omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo 
controlled, crossover, dose-ranging phase 2 trial.  Lancet.  2011;378:676-683. 
Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, 
Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, 
Priori SG, Swedberg K; ESC Committee for Practice Guidelines (CPG) .  ESC 
Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the 
Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of 
the European Society of Cardiology.  Developed in collaboration with the Heart Failure 
Association of the ESC (HFA) and endorsed by the European Society of Intensive Care 
Medicine (ESICM).  Eur Heart J.  2008 Oct;29(19):2388-442. 
Hampton JR, van Veldhuisen DJ, Kleber FX, Cowley AJ, Ardia A, Block P, Cortina A, 
Cserhalmi L, Follath F, Jensen G, Kayanakis J, Lie KI, Mancia G, Skene AM.  
Randomized study of effect of ibopamine on survival in patients with advanced severe 
heart failure.  Second Prospective Randomised Study of Ibopamine on Mortality and 
Efficacy (PRIME II) Investigators.  Lancet. 1997 Apr; 5(349): 971-7. 
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, et al. Heart disease and stroke 
statistics—2013 update: a report from the American Heart Association. Circulation. 
2013;127:e6–e245. 
Greene SJ, Fonarow GC, Vaduganathan M, Khan SS, Butler J, Gheorghiade M.  The 
vulnerable phase after hospitalization for heart failure.  Nat Rev Cardiol.  2015 
Apr;12(4):220-9. 
Haybittle JL.  Repeated assessment of results in clinical trials of cancer treatment.  Br J 
Radiol.  1971;44(526):793-797. 
Hicks KA, et al.  2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular 
Endpoint Events in Clinical Trials:  A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Data Standards.  J Am 
Coll Cardiol.  2015;28;66:403-69. 
Hilfiker-Kleiner D, Landmesser U, Drexler H.   Molecular mechanisms in heart failure.  
Focus on cardiac hypertrophy, inflammation, angiogenesis, and apotosis.  J Am Coll 
Cardiol.  2006;48(9) (Suppl A:A56-66). 
Jencks SF, Williams MV, Coleman EAN.  Rehospitalizations among patients in the 
Medicare fee-for-service program.  Engl J Med.  2009 Apr 2;360(14):1418-28.  
Jessup M, Brozena S.  Heart Failure.  N Engl J Med.  2003;348:2007-18. 
Kannankeril PJ, Pahl E, Wax DF.  Usefulness of troponin I as a marker of myocardial 
injury after pediatric cardiac catheterization.  Am J Cardiol.  
2002 Nov 15;90(10):1128-32. 
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Krum H, Teerlink JR.  Medical therapy for chronic heart failure.  Lancet. 
2011;378(9792):713-21. 
Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, et al.  The Seattle Heart 
Failure Model:  prediction of survival in heart failure.  Circulation.  2006;113(11):1424-33. 
López-Sendón J.  The heart failure epidemic.  Medicographia.  2011;33(4):363-369. 
Malik FI, Hartman JJ, Elias KA, et al.  Cardiac myosin activation: a potential therapeutic 
approach for systolic heart failure.  Science.  2011;331:1439-1443. 
McIlvennan CK, Allen LA.  Outcomes in acute heart failure: 30-day readmission versus 
death.  Curr Heart Fail Rep.  2014 Dec;11(4):445-52. 
Mozaffarian D, Anker S, Anand I, et al.  Prediction of mode of death in heart failure:  the 
Seattle heart failure model.  Circulation.  2007;116:392-398. 
Omecamtiv mecarbil Investigator’s Brochure.  Thousand Oaks, CA.   Amgen Inc. 
Packer M, Carver JR, Rodeheffer RR, et al.  Effect of oral milrinone on mortality in 
severe chronic heart failure.  The PROMISE Study Research Group.  N Engl J Med. 
1991 Nov 21;325 (21): 1468-75. 
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson 
K, Peto J, Smith PG.  Design and analysis of randomized clinical trials requiring 
prolonged observation of each patient. I. Introduction and design.  Br J Cancer.  
1976; 34(6):585-612. 
Ponikowski P, Voors AA, Anker SD, et al.  2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure.   Eur Heart J.  2016 Aug; 18(8):891-975. 
Shen YT, Malik FI, Zhao X, et al.  Improvement of cardiac function by a cardiac Myosin 
activator in conscious dogs with systolic heart failure.  Circ. Heart Fail.  2010;3:522-527. 
Shih JH.  Sample size calculation for complex clinical trials with survival endpoints. 
Control Clin Trials.  1995 Dec;16(6):395-407. 
Solomon SD, Wang D, Finn P, et al.  Effect of candesartan on cause-specific mortality in 
heart failure patients the candesartan in heart failure assessment of reduction in 
mortality and morbidity (CHARM) program.  Circulation.  2004;110:2180-2183. 
Tacon CL, McCaffrey J, Delaney A.  Dobutamine for patients with severe heart failure:  a 
systematic review and meta-analysis of randomised controlled trials.  Intensive Care 
Med.  2012 Mar;38(3):359-67. 
Teerlink JR, Clarke CP, Saikali KG, et al.  Dose-dependent augmentation of cardiac 
systolic function with the selective cardiac myosin activator, omecamtiv mecarbil:  a first 
in-man study.  Lancet.  2011;378:667-675. 
Yancy C, Jessup M, Bozkurt B et al.  2016 ACC/AHA/HFSA Focused Update on New 
Pharmacological Therapy for Heart Failure:  An Update of the 2013 ACCF/AHA 
Guideline for the Management of Heart Failure.  Circulation.  20 May 2016.  Epub ahead 
of print. PMID 27208050. doi:  10.1161/CIR.0000000000000435. 
Yancy C, Jessup M, Bozkurt B, Butler J, Casey D, et al.  2013 ACCF/AHA guideline for 
the management of heart failure:  A report on the American College of Cardiology 
Foundation/ American Heart Association Task Force on practice guidelines.  Circulation. 
2013;128:e240-e327. 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Refer to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0.  When an adverse event (AE) cannot be graded by CTCAE Version 4.0, the 
following severity grade may be used: 
Grade 
Amgen Standard Adverse Event Severity Scoring System 
1 
MILD:  Aware of sign or symptom, but easily tolerated. 
2 
MODERATE:  Discomfort enough to cause interference with usual activity. 
3 
SEVERE:  Incapacitating with inability to work or do usual activity. 
4 
LIFE-THREATENING:  Refers to an event in which the patient was, in the view of 
the investigator, at risk of death at the time of the event (This category is not to 
be used for an event that hypothetically might have caused death if it were more 
severe). 
5 
FATAL 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) and total bilirubin (TBL) 
and/or international normalized ratio (INR) elevation according to the criteria specified in 
Section 6.3 require the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The Event CRF that captures information necessary to facilitate the evaluation of 
treatment-emergent liver abnormalities is to be completed and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
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Additional Clinical Assessments and Observation 
All subjects in whom IP(s) or protocol-required therapies is/are withheld (either 
permanently or conditionally) due to potential DILI as specified in Sections 6.3.1 
and 6.3.2 or who experience AST or ALT elevations > 3 x ULN are to undergo a period 
of “close observation” until abnormalities return to normal or to the subject’s baseline 
levels.  Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
 
Obtain serum acetaminophen (paracetamol) levels 
 
Obtain a more detailed history of: 
Prior and/or concurrent diseases or illness 
Exposure to environmental and/or industrial chemical agents  
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Obtain viral serologies 
 
Obtain creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase 
(LDH), and peripheral blood smear 
 
Perform appropriate liver imaging if clinically indicated 
 
Obtain appropriate blood sampling for PK analysis if this has not already been 
collected  
 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of all IP(s) and 
protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications, and laboratory results must be captured in corresponding CRFs.   
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Appendix B.  Sample Serious Adverse Event Report Form 
  
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Appendix D.  Summary of Dose Adjustment and Action to be Taken Regarding IP 
Concentration Assessment 
Study Visit 
Week 2 Plasma 
Concentration (ng/mL) 
Current Dose BID 
New Dose BID 
Week 4 
< 200  
25 mg  
50 mg  
≥ 200 - < 300  
37.5 mg  
≥ 300 - < 1000  
no change 
≥ 1000  
placebo  
Study Visit 
Week 6 Plasma 
Concentration (ng/mL) 
Current Dose BID 
New Dose BID 
Week 8 
< 750  
Any 
no change 
≥ 750 - < 1000  
25 mg  
no change 
37.5 mg  
25 mg  
50 mg  
37.5 mg  
≥ 1000  
25 mg  
placebo  
37.5 mg  
25 mg  
50 mg  
Study Visit 
Any Plasma 
Concentration (ng/mL) 
Current Dose 
New Dose 
Week 12 
≥ 1000  
Any 
Withdraw IP 
Week 48 
Q 48 weeks 
Unscheduled  
BID = twice a day; IP = investigational product; Q 48 = every 48 
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Appendix E.  List of Class I and Class IIa Guideline Recommended Oral Drugs 
Commonly Used for Heart Failure With Reduced Ejection Fraction 
Adapted from Yancy et al, 2016.  ACC/AHA/HFSA Focused Update on New 
Pharmacological Therapy for Heart Failure and Ponikowski et al, 2016 ESC Guidelines 
for the diagnosis and treatment of acute and chronic heart failure. 
Drug 
AHA/ACCF Recommended 
Maximum Daily Dose(s) 
ESC Recommended 
Target Daily Dose(s) 
ACE inhibitor 
Captopril 
50 mg 3 times 
50 mg 3 times 
Enalapril  
10 to 20 mg twice 
10 to 20 mg twice 
Fosinopril 
40 mg once 
NA 
Lisinopril 
20 to 40 mg once 
20 to 35 mg once 
Perindopril 
8 to 16 mg once 
NA 
Quinapril 
20 mg twice 
NA 
Ramipril 
10 mg once 
5 mg twice 
Trandolapril 
NA 
4 mg once 
ARB 
Candesartan 
32 mg once 
32 mg once 
Losartan 
50 to 150 mg once 
150 mg once 
Valsartan 
160 mg twice 
160 mg twice 
ARNi 
Valsartan/sacubitril 
97/103 mg twice 
97/103 mg twice 
MRA 
Spironolactone 
25 mg once or twice 
25 mg once or twice 
Eplerenone 
50 mg once 
50 mg once 
Beta-blockers 
Bisoprolol 
10 mg once 
10 mg once 
Carvedilol 
50 mg twice 
25 to 50 mg twice 
Carvedilol CR 
80 mg once 
NA 
Metoprolol succinate extended 
release 
200 mg once 
200 mg once 
Nebivolol 
NA 
10 mg once 
Other 
Hydralazine and isosorbide 
dinitrate - Fixed-dose 
combination 
75 mg hydralazine/40 mg 
isosorbide dinitrate 3 times daily 
NA 
Hydralazine and isosorbide 
dinitrate 
Hydralazine:  300 mg daily in 
divided doses and isosorbide 
dinitrate 120 mg daily in divided 
doses 
NA 
Ivabradine 
5 to 7.5 mg twice 
5 to 7.5 mg twice 
ACCF = American College of Cardiology Foundation; ACE = angiotensin-converting enzyme; 
AHA = American Heart Association; ARB = angiotensin receptor blocker; ARNi = angiotensin receptor 
neprilysin inhibitor; CR = controlled release MRA = mineralocorticoid receptor antagonist; NA = not 
applicable 
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Amendment 1 
Protocol Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter 
Study to Assess the Efficacy and Safety of Omecamtiv Mecarbil on Mortality and 
Morbidity in Subjects With Chronic Heart Failure With Reduced Ejection Fraction 
Amgen Protocol Number (AMG 423) 20110203 
EudraCT Number 2016-002299-28 
GALACTIC-HF 
Global Approach to Lowering Adverse Cardiac Outcomes Through Improving 
Contractility in Heart Failure 
Amendment Date: 
7 September 2017 
Rationale: 
This protocol is being amended to: 

Move pharmacokinetic (PK) and associated assessments from week 24 to
week 12

Add electrocardiograms (ECGs) at screening and update guidance language for
ECGs

Clarify that there can be limited enrollment of subjects in atrial flutter at screening

Clarify language around hospitalization in terms of inclusion criteria

Update inclusion criteria #104 to provide guidance for qualifying left ventricle
ejection fraction (LVEF)

Add exception to exclusion criteria #206 to indicate that noninvasive ventilation is
permitted for specific indications

Update exclusion criteria #209 to include cardiac intervention and other cardiac
valve repair

Update exclusion criteria #211 to include infiltrative cardiomyopathy

Update exclusion criteria #221 to indicate that subjects anticipated to receive
cardiac support or heart transplantation are not eligible

Clarifications of windows for randomization, day 1, and IP administration

Administrative and editorial edits, and edits made for clarification of protocol
Approved


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 2 of 20 
CONFIDENTIAL 
 
 
Description of Changes: 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Global 
Replace: 
31 August 2016 
With: 
07 September 2017 
Administrative change. 
Global 
 
Change: 
Editorial changes (including typographical, 
grammatical, and formatting) have been made 
throughout the document. 
Editorial 
Title Page 
 
Add: 
Amendment 1 
07 September 2017 
Administrative change 
Investigator’s Agreement 
Replace: 
31 Aug 2016 
With: 
07 September 2017 
Administrative change 
Study Glossary 
 
Add: 
 
eCRF 
electronic case report form 
EF 
ejection fraction 
Q48W 
every 48 weeks 
Editorial 
Section:  Protocol 
Synopsis, Study Design 
Replace: 
Enrollment of subjects with atrial fibrillation 
will be limited to 20% of each enrollment 
setting. 
With: 
Enrollment of subjects in atrial 
fibrillation/flutter at screening is limited to 
approximately 25%. 
Clarify limited enrollment 
includes subjects in atrial 
flutter 
Page 1 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 3 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  Protocol 
Synopsis, Summary of 
Subject Eligibility Criteria 
Replace: 
For a full list of eligibility criteria, please refer to 
Section 4.1 through Section 4.1.2. 
With: 
For a full list of eligibility criteria, please 
refer to Section 4.1.1 through Section 4.1.2. 
Editorial change to include 
accurate Section numbers 
for eligibility criteria 
Protocol Synopsis:  Study 
Design and Treatment 
Schema 
Replace: 
With: 
 
Updated to reflect PK 
assessment at week 12 
instead of week 24. 
Section:  3.1 Study 
Design, Paragraph 1 
Replace: 
Enrollment of subjects with atrial fibrillation will 
be limited to 20% of each enrollment setting. 
With: 
Enrollment of subjects in atrial 
fibrillation/flutter at screening is limited to 
approximately 25%. 
Clarify limited enrollment 
includes subjects in atrial 
flutter at screening 
Section:  3.2 Number of 
Sites 
Replace: 
Approximately 800 sites globally will participate 
in this study. 
With: 
Approximately 1000 sites globally will 
participate in this study. 
Updated number of sites 
that will participate in this 
study 
Page 2 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 4 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  4.1.1 Inclusion 
Criteria, Criterion 104 
Replace: 
LVEF ≤ 35%, per subject’s most recent 
medical record, not in the setting of acute 
decompensation 
With: 
LVEF ≤ 35%, per subject’s most recent 
medical record, within 12 months prior to 
screening.  The most recent qualifying 
LVEF must be at least 30 days after any 
of the following, if applicable:  1) an 
event likely to decrease EF (eg, 
myocardial infarction, sepsis); 2) an 
intervention likely to increase EF (eg, 
cardiac resynchronization therapy, 
coronary revascularization); or 3) the 
first ever presentation for HF. 
 
Clarify the acceptable date 
of the most recent LVEF 
assessment. 
Clarify the instances which 
the assessment of the LVEF 
are not acceptable for 
eligibility 
Section:  4.1.1 Inclusion 
Criteria, Criterion 107  
Replace: 
Current hospitalization with primary reason of 
HF or prior HF hospitalization, or urgent HF 
admission to emergency department 
(ED)within 1 year prior to screening 
With: 
Currently hospitalized with primary reason 
of HF OR one of the following events 
within 1 year to screening:  
1) hospitalization with primary reason of 
HF; 2) urgent visit to ED with primary 
reason of HF 
Clarification of medical 
history requirements for 
subjects not currently 
hospitalized for HF during 
randomization. 
Page 3 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 5 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  4.1.1 Inclusion 
Criteria, Criterion 108 
Replace: 
B-type natriuretic peptide (BNP) level 
≥ 125 pg/mL or an NT-proBNP level 
≥ 400 pg/mL at most recent screening 
assessment (subjects receiving angiotensin 
receptor-neprilysin inhibitor [ARNi] must use 
NT-proBNP assessment; for subjects with 
atrial fibrillation, the cut off levels are:  
BNP ≥ 375 pg/mL or 
NT-proBNP ≥ 1200 pg/mL) 
 
With: 
B-type natriuretic peptide (BNP) level 
≥ 125 pg/mL or an NT-proBNP level 
≥ 400 pg/mL at most recent screening 
assessment (subjects receiving angiotensin 
receptor-neprilysin inhibitor [ARNi] must use 
NT-proBNP assessment; for subjects in 
atrial fibrillation/flutter at screening, the cut 
off levels are:  BNP ≥ 375 pg/mL or 
NT-proBNP ≥ 1200 pg/mL) 
Clarify limited enrollment 
includes subjects in atrial 
flutter at screening 
Section:  4.1.2 Exclusion 
Criteria, Criterion 204 
Replace: 
Subject not likely to be available to complete 
all protocol-required study visits or 
procedures, and/or to comply with all 
required study procedures to the best of the 
subject and investigator’s knowledge.  
 
With: 
Factors expected to interfere with the 
subject’s availability or ability to complete 
all protocol-required study visits or 
procedures, and/or to comply with all 
required study procedures to the best of the 
subject and investigator’s knowledge 
(including ongoing substance abuse).  
Clarification that substance 
abuse should be 
considered an exclusion 
criterion for eligibility 
Page 4 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 6 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  4.1.2 Exclusion 
Criteria, Criterion 206 
Replace: 
Receiving mechanical hemodynamic support 
(eg, intra-aortic balloon pump 
counterpulsation), or mechanical ventilation 
(including non-invasive mechanical 
ventilation, ie, bilevel positive airway 
pressure [BiPAP] or continuous positive 
airway pressure [CPAP] devices) ≤ 7 days 
prior to randomization 
With: 
Receiving mechanical hemodynamic support 
(eg, intra-aortic balloon pump 
counterpulsation), or invasive mechanical 
ventilation  ≤ 7 days prior to randomization 
 
Moved non-invasive 
ventilation indication to 
criterion 208. 
 
Section:  4.1.2 Exclusion 
Criteria, Criterion 208 
Replace: 
Receiving IV diuretics or IV vasodilators, or 
supplemental oxygen therapy ≤ 12 hours 
prior to randomization 
With: 
Receiving IV diuretics or IV vasodilators, 
supplemental oxygen therapy, or 
non-invasive mechanical ventilation (eg, 
bilevel positive airway pressure [BiPAP] 
or continuous positive airway pressure 
[CPAP] ≤ 12 hours prior to randomization 
(Note:  the use of non-invasive ventilation 
for sleep disordered breathing is 
permitted) 
Clarification about a 
non-invasive ventilation 
indication which is an 
exception to  the exclusion 
criteria 
Page 5 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 7 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  4.1.2 Exclusion 
Criteria, Criterion 209 
 
Add: 
Acute coronary syndrome (ST-elevation 
myocardial infarction, non-ST-elevation 
myocardial infarction, unstable angina), 
stroke, or transient ischemic attack, major 
cardiac surgery or cardiac intervention (ie, 
implantation of cardiac closure devices, 
cardiac resynchronization therapy, or 
catheter ablation), percutaneous coronary 
intervention, or valvuloplasty/other cardiac 
valve repair or implantation within the 
3 months prior to randomization 
Inclusion of the initiation of 
cardiac resynchronization 
therapy to the 3-month 
window from procedure to 
randomization. 
Section:  4.1.2 Exclusion 
Criteria, Criterion 210 
Replace: 
Implantable cardioverter defibrillator or 
initiation of cardiac resynchronization therapy 
(CRT) (with/without implantable cardioverter 
defibrillator) within 30 days prior to 
randomization 
 
With: 
Insertion of other cardiac devices (eg, 
implantable cardioverter defibrillator, 
permanent pacemaker, monitoring 
devices) within 30 days prior to 
randomization 
Clarification of cardiac 
devices referred in this 
criterion.  Deletion of 
“initiation of cardiac 
resynchronization therapy” 
from this criterion. 
Section:  4.1.2, Exclusion 
Criteria, Criterion 211 
Replace: 
Severe uncorrected valvular heart disease, 
or hypertrophic obstructive cardiomyopathy, 
active myocarditis, constrictive pericarditis, or 
clinically significant congenital heart disease 
With: 
Severe uncorrected valvular heart disease, 
hypertrophic or infiltrative cardiomyopathy, 
active myocarditis, constrictive pericarditis, 
or clinically significant congenital heart 
disease 
Addition of infiltrative 
cardiomyopathy as an 
exclusion criteria 
Page 6 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 8 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  4.1.2 Exclusion 
Criteria, Criterion 221 
 
Add: 
Recipient of any major organ transplant (eg, 
lung, liver, heart, bone marrow, renal) or 
anticipated to receive chronic mechanical 
circulatory support or heart 
transplantation within 12 months from 
randomization 
Clarification about eligibility 
of subjects listed for heart 
transplantation or 
mechanical circulatory 
support. 
Section:  5.1 
Randomization/Treatment 
Assignment, 
Paragraphs 2, 3 and 4 
Replace: 
Subjects in the recently and not currently 
hospitalized for HF setting who meet all 
eligibility criteria at the end of screening will 
return to the study site for day 1.  Subjects in 
the currently hospitalized for HF setting who 
meet all eligibility criteria at the end of 
screening will be randomized with day 1 
occurring during the admission. 
With: 
Subjects in the recently and not currently 
hospitalized for HF setting who meet all 
eligibility criteria at the end of screening will 
return to the study site for randomization 
and day 1 procedures.   
Subjects in the currently hospitalized for HF 
setting who meet all eligibility criteria at the 
end of screening should be randomized 
prior to discharge with day 1 procedures 
occurring during the hospitalization. 
Updated to add 
randomization for 
clarification 
Section:  6.2.1.2 Dosage 
Adjustments, Delays, 
Rules for Withholding or 
Restarting, Permanent 
Discontinuation, 
Paragraph 1 
Replace: 
Pharmacokinetics will be assessed on 
Week 24 and Week 48, and every 48 weeks 
throughout the study.  See Appendix D for a 
summary of dose adjustment rules. 
With: 
Pharmacokinetics will be assessed on 
Weeks 12 and 48, and then every 48 weeks 
throughout the study.  See Appendix D for a 
summary of dose adjustment rules. 
Changed PK from week 24 
to week 12. 
Page 7 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 9 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  6.2.1.2 Dosage 
Adjustments, Delays, 
Rules for Withholding or 
Restarting, Permanent 
Discontinuation, 
Paragraph 3 
Replace: 
At Week 24, Week 48, and every 48 weeks, 
PK will be assessed and are not part of the 
PK based dose adjustment approach.   
With: 
At Weeks 12, 48, and then every 48 weeks, 
PK will be assessed and are not part of the 
PK-based dose adjustment approach (Note:  
subjects in between visits week 12 and 
week 24 at the time of local approval of 
this global amendment number 1 should 
have a PK assessment conducted during 
the week 24 visit). 
To provide guidance for PK 
assessment for those 
subjects that are in between 
visits at the time of this 
protocol amendment. 
Section:  6.2.1.2 Dosage 
Adjustments, Delays, 
Rules for Withholding or 
Restarting, Permanent 
Discontinuation, 
Paragraph 6 
Replace: 
A central laboratory PK sample, Troponin I, 
CK-MB, and NT-proBNP should be collected 
in all subjects experiencing such events as 
close as possible to the event, and the last IP 
administration time recorded. 
With: 
A central laboratory PK sample, Troponin I, 
CK-MB, and NT-proBNP should be collected 
in all subjects experiencing such events as 
close as possible to the event and the time 
last IP was taken. 
Clarification of language 
Section:  6.2.1.2 Dosage 
Adjustments, Delays, 
Rules for Withholding or 
Restarting, Permanent 
Discontinuation, 
Paragraph 8 
 
Add: 
Subjects reinitiating IP after withholding 
for reasons other than cardiac ischemic 
events will restart on the same IP dose as 
established before the event. 
To provide guidance for 
subjects who restart IP for 
AEs other than cardiac 
ischemic events. 
Page 8 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 10 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  6.3.1 Criteria for 
Permanent 
Discontinuation of Amgen 
Investigational Product 
and Other 
Protocol-required 
Therapies due to Potential 
Hepatotoxicity, 
Paragraph 1 
Replace: 
OM should be discontinued permanently and 
the subject should be followed according to 
the recommendations in Appendix A 
(Additional Safety Assessment Information) 
for possible drug-induced liver injury (DILI), if 
ALL of the criteria below are met: 
With: 
OM must be discontinued permanently and 
the subject should be followed according to 
the recommendations in Appendix A 
(Additional Safety Assessment Information) 
for possible drug-induced liver injury (DILI), if 
ALL of the criteria below are met: 
Editorial change to clarify IP 
discontinuation. 
Section:  6.3.2 Criteria for 
Conditional Withholding of 
Amgen Investigational 
Product and Other 
Protocol-required 
Therapies due to Potential 
Hepatotoxicity, 
Paragraph 2 
Replace: 
Amgen IP and other protocol-required 
therapies, as appropriate should be withheld 
pending investigation into alternative causes 
of DILI. 
With: 
Amgen IP and other protocol-required 
therapies, as appropriate must be withheld 
pending investigation into alternative causes 
of DILI. 
Editorial change to clarify IP 
discontinuation. 
Section:  6.3.3 Criteria for 
Rechallenge of Amgen 
Investigational Product 
and Other 
Protocol-required 
Therapies After Potential 
Hepatotoxicity 
Replace: 
The decision to rechallenge the subject 
should be discussed and agreed upon 
unanimously by the subject, investigator, and 
Amgen. 
If signs or symptoms recur with rechallenge, 
then OM should be permanently 
discontinued.  Subjects who clearly meet the 
criteria for permanent discontinuation (as 
described in Section 6.3.1) should never be 
rechallenged. 
With: 
The decision to rechallenge the subject 
must be discussed and agreed upon 
unanimously by the subject, investigator, 
and Amgen. 
If signs or symptoms recur with rechallenge, 
then OM must be permanently discontinued.  
Subjects who clearly meet the criteria for 
permanent discontinuation (as described in 
Section 6.3.1) must never be rechallenged. 
Editorial change to clarify 
conditions that must be met 
before rechallenge. 
Page 9 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 11 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  6.4 Concomitant 
Therapy, Paragraph 3 
Replace: 
If a subject is not taking beta blockers, 
ACEi/ARB/ARNi, or MRA, investigators 
should record the reason why any of those 
agents are not prescribed. 
Add: 
If a subject is not taking beta blockers, 
ACEi/ARB/ARNi, or MRA, or taking doses 
below those recommended by local 
guidelines, investigators should record the 
reason in the electronic case report form 
(eCRF). 
Clarification 
Section:  7.1 Schedule of 
Assessments, Table 2, 
Assessment of IP 
Adherence Row 
 
Delete: 
“X”under week 24 
Add: 
“X” under week 12 ± 3d 
Assessments changed from 
week 24 to week 12. 
Section:  7.1 Schedule of 
Assessments, Table 2, 
ECG Row 
 
Add: 
“X” in the column “Screen” 
Add screening ECG 
Section:  7.1 Schedule of 
Assessments, Table 2, 
Serum pregnancy/FSH 
row (footnote) 
 
Delete:  
Xl 
Editorial change, not 
correct footnote 
Section:  7.1 Schedule of 
Assessments, Table 2, 
Abbreviated Laboratory 
Panel Row 
 
Add: 
“X” in the column W12 ± 3d 
“X” in the column W36 ± 7d 
Added assessments for 
abbreviated laboratory 
panel to weeks 12 and 36. 
Section:  7.1 Schedule of 
Assessments, Table 2, PK 
Samples Row 
 
Delete: 
“Xk” in the column W2 ± 3d 
Add: 
“X” in the column W12±3d 
Assessments changed from 
week 24 to week 12. 
Page 10 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 12 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  7.1 Schedule of 
Assessments, Table 2, 
KKCQ/PGR-S/CGR-S and 
EQ-5D Rows 
 
Delete: 
“X” in the column W8 ± 3d 
Add: 
“X” in the column W36 ± 7d 
Assessments changed from 
week 8 to week 36. 
Section:  7.1 Schedule of 
Assessments, Table 2 
footnote e 
Replace: 
ECG to be read locally, except on sites that 
have been provided with centralized ECG 
services equipment. 
With: 
Screening ECG to be performed and read 
locally for all sites.  On study ECG to be 
performed and read locally, except on 
sites that have been provided with 
centralized ECG services equipment. 
Addition of screening ECG 
and clarification of language 
about locally read ECGs. 
Section:  7.1 Schedule of 
Assessments, Table 2 
footnote j 
Replace: 
NT-proBNP, Troponin I, and CK-MB results 
will be blinded to subjects, investigators, and 
sponsor (Amgen). 
With: 
Central NT-proBNP, Troponin I, and CK-MB 
assessments after baseline will be blinded 
to subjects, investigators, and sponsor 
(Amgen). 
Editorial change to clarify 
that central assessments of 
these parameters will be 
done kept blinded to all 
players after day 1.  
Section:  7.1 Schedule of 
Assessments, Table 2 
footnote m 
Replace: 
Height to be measured at study visit D1 only. 
With: 
Height to be measured during screening 
only. 
Updated to indicate that 
height only measured at 
screening, not day 1. 
Section:  7.1 Schedule of 
Assessments, Table 2 
footnote n 
Replace: 
Date and time of IP administration during the 
previous 48 hours. 
With: 
Investigator to discuss with subject IP 
administration and adherence during the 
previous 7 days, as per Section 6.2.1.1. 
Editorial changes for clarity 
and addition of link for 
reference. 
Section:  7.1 Schedule of 
Assessments, Table 2 
footnote o 
Replace: 
(eg, without chewing) 
With: 
(ie, without chewing) 
Editorial change 
Page 11 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 13 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  7.2.1 Screening 
Enrollment, Paragraph 2 
 
Add: 
Subjects currently hospitalized for HF are 
expected to be randomized before 
discharge.  Local laboratory assessments 
from the current hospitalization can be 
used to support the subject’s eligibility and 
randomization in order to provide flexibility 
for randomization before discharge.  Central 
laboratory assessments for screening should 
be collected after ICF signature for those 
subjects.  If the subject is discharged during 
screening period and randomized later, 
subject will be included in the recently and 
not currently hospitalized for HF 
randomization setting stratification.   
The placebo run-in procedure assesses 
the subject’s ability to swallow an open 
label placebo tablet successfully (ie, 
without chewing).   
To clarify language 
regarding laboratory 
assessments/randomization 
window, and to define the 
purpose of the placebo 
run-in. 
Section:  7.2.1 Screening 
Enrollment, Paragraph 2 
Bullet 6 
 
Delete: 
 
vital signs (sitting blood pressure, heart 
rate) 
Editorial change to make 
consistent with the rest of 
the protocol. 
Section:  7.2.1 Screening 
Enrollment, Paragraph 2 
Bullets 10, 11, and 12 
 
Add: 
 
placebo run-in 
 
registration in IVRS/IWRS system 
 
ECG (for cardiac rhythm 
confirmation) 
 
Updated to add ECG at 
screening to align with 
updated Schedule of 
Assessments, and to 
include placebo run-in at 
screening. 
Page 12 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 14 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  7.2.4 Treatment, 
Paragraphs 1 and 2 
Replace: 
Subjects in the recently and not currently 
hospitalized for HF setting who meet all 
eligibility criteria at the end of screening will 
be randomized and will return to the study 
site for day 1.  Subjects in the currently 
hospitalized for HF setting who meet all 
eligibility criteria at the end of screening will 
be randomized with day 1 occurring during 
the ongoing.  Subjects can only be 
randomized 1 time for this study. 
With: 
Subjects in the recently and not currently 
hospitalized for HF setting who meet all 
eligibility criteria at the end of screening will 
return to the study site for randomization 
and day 1 procedures.   
Subjects in the currently hospitalized for HF 
setting who meet all eligibility criteria at the 
end of screening should be randomized 
prior to discharge with day 1 procedures 
occurring during the hospitalization.  
Subjects can only be randomized 1 time for 
this study. 
 
Updated to add 
randomization for 
clarification. 
Page 13 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 15 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  7.2.6.7 
Electrocardiogram, 
Paragraphs 1 and 2 
Replace: 
Subject must be in a supine position in a 
rested and calm state for at last 5 minutes 
before ECG assessment is conducted.  If the 
subject is unable to be in the supine position, 
the subject should be in the most recumbent 
position as possible.   
Sites who have been provided with 
centralized ECG services equipment 
specifically for this study ECGs should be 
performed in a standardized method, 
≥ 3 baseline ECGs collected ≥ 30 minutes 
apart, with each baseline ECG in triplicate 
run consecutively (ie, total ≥ 9 ECGs), and 
run consecutively, prior to blood draws or 
other invasive procedures.  Each ECG must 
include the following measurements:  QRS, 
QT, QTc, RR, and PR intervals.   
With: 
Subject must be in a supine position in a 
rested and calm state for at last 5 minutes 
before ECG assessment is conducted.  If the 
subject is unable to be in the supine 
position, the subject should be in the most 
recumbent position as possible.  The ECG 
must be performed prior to blood draws 
or other invasive procedure.  Each ECG 
must include the following 
measurements:  QRS, QT, QTc, RR, and 
PR intervals, and assessment of cardiac 
rhythm. 
ECGs must be conducted as follows: 
Screening ECG 
 
1 local ECG (all sites) 
On study ECGs (day 1, week 48, every 
48 weeks [Q48W]) 
 
Centralized ECG services:  ECG in 
triplicate run consecutively 
 
No centralized ECG services:  1 local 
ECG 
Updated to add guidance 
for screening ECGs and on 
study ECGs. 
Page 14 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 16 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  7.2.6.8 
Concomitant Therapy, 
Paragraph 2 
Replace: 
The dosage of beta blockers, 
ACEi/ARB/ARNi, diuretics, and MRAs will be 
recorded.  If a subject is not taking beta 
blockers, ACEi/ARB/ARNi, or MRA, 
investigators should record the reason why 
any of those agents are not prescribed. 
With: 
The dosage of beta blockers, 
ACEi/ARB/ARNi, diuretics, and MRAs will be 
recorded.  If a subject is not taking beta 
blockers, ACEi/ARB/ARNi, or MRA, or 
taking doses below those recommended 
by local guidelines, investigators should 
record the reason in the eCRF. 
Clarification 
Section:  8.1 Subject’s 
Decision to Withdraw 
 
Add: 
For subjects who have withdrawn consent 
for further follow-up, investigators will 
review public records as permitted by 
applicable law to determine vital status of 
the subject at the end of the study or 
before. 
Clarification 
Page 15 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 17 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  9.1.1, Disease 
Related Events 
Replace: 
Disease Related Events are events (serious 
or non-serious) anticipated to occur in the 
study population due to the underlying 
disease.  In this study, subjects will have 
HFrEF with an LVEF of ≤ 35%.  It is expected 
that the study subjects will experience events 
related to chronic HFrEF.  Examples of 
events related to HF include: 
 
fluid overload signs and symptoms 
(eg, edema, pulmonary congestion, 
dyspnea, orthopnea, hepatic 
congestion) 
 
renal function impairment (eg, 
cardiorenal syndrome, acute renal 
failure) 
 
Such events do not meet the 
definition of an Adverse Event unless 
assessed to be more severe than 
expected for the subject’s condition.  
 
With: 
Events that are not submitted for 
adjudication as potential endpoints, but 
that are anticipated to occur in the study 
population due to the underlying disease, 
may be reported at Disease Related 
Events.  In this study, subjects will have 
HFrEF with an LVEF of ≤ 35%.  It is 
expected that the study subjects will 
experience events related to chronic HFrEF.  
Examples of events related to HF include: 
 
fluid overload signs and symptoms 
(eg, edema, pulmonary congestion, 
dyspnea, orthopnea, hepatic 
congestion) not requiring urgent, 
unscheduled clinic/office/ED visit, 
or hospital admission 
 
renal function impairment 
(eg, cardiorenal syndrome, acute 
renal failure) not requiring urgent, 
unscheduled clinic/office/ED visit, 
or hospital admission 
Clarification on Disease 
Related Events definition. 
Page 16 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 18 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  9.1.1, Disease 
Related Events 
(Continued) 
Disease Related Events and/or Disease 
Related Outcomes that do not qualify as 
Serious Adverse Events:  
 
An event which is part of the normal 
course of disease under study (eg, 
disease progression in oncology or 
hospitalization due to disease 
progression) is to be reported as a 
Disease Related Event.  
 
Death due to the disease under 
study is to be recorded on the Event 
CRF. 
If the outcome of the underlying disease is 
worse than that which would normally be 
expected for the subject, or if the investigator 
believes there is a causal relationship 
between the IP/study treatment protocol 
required therapies and disease worsening, 
this must be reported as an Adverse Event or 
Serious Adverse Event. 
If the event is considered worse than that 
which would normally be expected for the 
subject, or if the investigator believes there 
is a causal relationship between the IP and 
disease worsening, the event should not 
be considered a Disease Related Event 
and must be reported as an Adverse Event 
or Serious Adverse Event. 
If a Disease Related Event is considered 
serious, the event should be reported 
within 24 hours of the acknowledgement 
of the event. 
 
Section:  9.2.1 Reporting 
Procedures for Disease 
Related Events 
 
Add: 
Events assessed by the investigator to be 
related to the investigational medicinal 
product(s) and determined to be serious, 
require reporting of the event on the Event 
CRF as a Serious Adverse Event rather 
than as a Disease Related Event, and 
within 24 hours from the 
acknowledgement of the event.  
Clarification of serious 
adverse event reporting. 
Page 17 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 19 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  9.2.2.3 Reporting 
a Safety Endpoint as a 
Study Endpoint 
Replace: 
Safety events (eg, mortality and morbidity) 
that are efficacy endpoints (death and HF 
events) are reported on an Event CRF.  
Death and HF events will be recorded in the 
CRF within 24 hours of knowledge of the 
event.  Information regarding dates of onset 
and resolution, severity, action taken, 
investigator assessment of relatedness, and 
assessment of seriousness will be collected.  
The Clinical Events Committee (CEC) will 
adjudicate all events of death, HF, 
myocardial infarction, hospitalization for 
unstable angina, coronary revascularization, 
and stroke events using prespecified criteria 
(Hicks et al. 2015).   
Investigators will be informed if a reported 
potential endpoint is negatively adjudicated 
(does not meet the definitions of an 
endpoint) and may be prompted for 
additional information for adverse event 
reporting.   
A negatively adjudicated safety endpoint will 
be reviewed by Amgen.  Action taken could 
include no action, or reporting on the Event 
CRF as a disease-related event, adverse 
event, or serious adverse event. 
With: 
All potential endpoints (death, HF events, 
major cardiac ischemic event, and 
stroke) must be recorded on the Event 
CRF within 24 hours of knowledge of the 
event.  Information regarding dates of onset 
and resolution, severity, action taken, 
investigator assessment of relatedness, and 
assessment of seriousness must be 
collected.   
Clarification that all serious 
adverse events should be 
reported to Amgen within 
24 hours of 
acknowledgement. 
Page 18 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20110203 
Date:  05 September 2017 
Page 20 of 20 
CONFIDENTIAL 
 
 
Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text 
Rationale for Change 
Section:  9.2.2.3 
Reporting a Safety 
Endpoint as a Study 
Endpoint  
(Continued) 
Death events that are associated with drug 
exposure or toxicity (eg, angioedema, blood 
dyscrasias, rhabdomyolysis, hepatic injury, 
anaphylaxis, and Stevens-Johnson 
Syndrome), and all major cardiac ischemic 
events (safety endpoints) must also be 
communicated to Amgen within 24 hours of 
knowledge of the event for adverse event 
evaluation 
 
 
Section:  10.1.3 
Covariates and 
Subgroups, Paragraph 2, 
Bullet 12 
 
Add: 
 
presence of atrial fibrillation/flutter at 
screening (yes, no) 
Updated this prespecified 
subgroup to clarify that 
atrial fibrillation should be 
present at screening, and 
that this can include atrial 
flutter. 
Section:  10.1.3 
Covariates and 
Subgroups, Paragraph 2, 
Bullet 14 
Replace: 
 
baseline NT-proBNP by randomization 
setting excluding atrial fibrillation/flutter 
subjects (≤ median and > median) 
With: 
 
baseline NT-proBNP by randomization 
setting excluding subjects in atrial 
fibrillation/flutter at screening (≤ median 
and > median) 
Updated this prespecified 
subgroup to clarify that 
baseline NT-proBNP by 
randomization excludes 
subjects in atrial 
fibrillation/flutter at 
screening. 
Section:  Appendix D, 
Study Visit Column 
Replace: 
Week 24 
With: 
Week 12 
Assessments changed from 
week 24 to week 12. 
Page 19 of 19 
 
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423)
Protocol Number:  20110203
Date:  13 November 2018
Page 1 of 4
CONFIDENTIAL
Amendment 2
Protocol Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter 
Study to Assess the Efficacy and Safety of Omecamtiv Mecarbil on Mortality and 
Morbidity in Subjects With Chronic Heart Failure With Reduced Ejection Fraction
Amgen Protocol Number (Omecamtiv Mecarbil [AMG 423]) 20110203
EudraCT number 2016-002299-28
NCT Number NCT02929329
Amendment Date:
13 November 2018
Rationale:
This protocol is being amended to:

Align with the language in the informed consent form, which states omecamtiv 
mecarbil plasma concentrations will be measured using an investigational device

Update language surrounding disease related events (DREs) to align with text in 
other sections of the protocol

Remove self-evident corrections language as Amgen is retiring the use of 
self-evident corrections

Make editorial, typographical, and formatting changes throughout the document
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423)
Protocol Number:  20110203
Date:  13 November 2018
Page 2 of 4
CONFIDENTIAL
Description of Changes
Section:  Global
Change:  Updated version date from 07 September 2017 to 13 November 2018.
Section: Global
Change:  Made editorial (formatting, typographical, and grammatical) corrections 
throughout the protocol.
Section: Title Page
Add:
NCT Number NCT02929329
Section: Title Page
Add:
Date:
31 August 2016
Amendment 1 Date:
07 September 2017
Amendment 2 Date:
13 November 2018
Section: 7.2.6.10 Laboratory Assessments, Paragraph 2
Add:
Omecamtiv mecarbil plasma concentrations will be measured using an 
investigational assay.  The investigation assay is identified as QMS Omecamtiv 
Mecarbil Immunoassay which was developed by Thermo Fisher Scientific.  The 
investigational assay will be used in accordance with local regulatory and labeling 
requirements along with the Instructions for Use provided.
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423)
Protocol Number:  20110203
Date:  13 November 2018
Page 3 of 4
CONFIDENTIAL
Section:  9.1.1 Disease Related Events
Replace:
Events that are not submitted for adjudication as potential endpoints, but that are 
anticipated to occur in the study population due to the underlying disease, may be 
reported at Disease Related Events.  In this study, subjects will have HFrEF with an 
LVEF of ≤35%.  It is expected that the study subjects will experience events related to 
chronic HFrEF.  Examples of events related to HF include:

fluid overload signs and symptoms (eg, edema, pulmonary congestion, dyspnea, 
orthopnea, hepatic congestion) not requiring urgent, unscheduled clinic/office/ED 
visit, or hospital admission

renal function impairment (eg, cardiorenal syndrome, acute renal failure) not 
requiring urgent, unscheduled clinic/office/ED visit, or hospital admission
If the event is considered worse than that which would normally be expected for the 
subject, or if the investigator believes there is a causal relationship between the IP and 
disease worsening, the event should not be considered a Disease Related Event and 
must be reported as an Adverse Event or Serious Adverse Event.
If a Disease Related Event is considered serious, the event should be reported within 
24 hours of the acknowledgement of the event.
With:
Events that are not submitted for adjudication as potential endpoints, but that are 
anticipated to occur in the study population due to the underlying disease, may be 
reported as Disease Related Events.  In this study, subjects will have HFrEF with an 
LVEF of ≤35%.  It is expected that the study subjects will experience events related to 
chronic HFrEF.  Examples of events related to HF include:

fluid overload signs and symptoms (eg, edema, pulmonary congestion, dyspnea, 
orthopnea, hepatic congestion) not requiring urgent, unscheduled clinic/office/ED 
visit, or hospital admission

renal function impairment (eg, cardiorenal syndrome, acute renal failure) not 
requiring urgent, unscheduled clinic/office/ED visit, or hospital admission
If the event is considered worse than that which would normally be expected for the 
subject, or if the investigator believes there is a causal relationship between the IP and 
disease worsening, the event should not be considered a Disease Related Event and 
must be reported as an Adverse Event or Serious Adverse Event.
Approved 
 
 


Product:  Omecamtiv Mecarbil (AMG 423)
Protocol Number:  20110203
Date:  13 November 2018
Page 4 of 4
CONFIDENTIAL
If a Disease Related Event is considered as an adverse event and is serious, the event 
should be reported within 24 hours of the acknowledgement of the event.
Section:  9.2.1 Reporting Procedures for Disease Related Events, Paragrah 2
Add:
Events assessed by the investigator to be related to the investigational medicinal 
product(s) or considered worse than that which would normally be expected for the 
subject and determined to be serious, require reporting of the event on the Event CRF 
as a Serious Adverse Event rather than as a Disease Related Event, and within 
24 hours from the acknowledgement of the event.
Section:  12.3 Study Monitoring and Data Collection, Paragrah 6
Delete:
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-Week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.  
Approved 
 
 

SAP_001.pdf: 
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