Clinical trial NCT02695420
Conditions: Heart Failure With Reduced Ejection Fraction
Keywords: Heart Failure
Sponsor: Cytokinetics
Start date: 2016-04-14; Completion date: 2017-05-08
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
* To evaluate pharmacokinetics (PK) of omecamtiv mecarbil in Japanese subjects with heart failure (HF) with reduced ejection fraction
* To evaluate the safety and tolerability of oral omecamtiv mecarbil

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 will receive placebo BID. arm 2: Participants will receive 25 mg omecamtiv mecarbil BID. arm 3: Participants will receive omecamtiv mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 37.5 mg BID after Week 4 or Week 8, based on Week 2 PK. arm 4: Participants will receive Omecamtiv Mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 50 mg BID after Week 4 or Week 8, based on Week 2 PK.
Interventions: intervention 1: 25 mg Omecamtiv Mecarbil intervention 2: Placebo intervention 3: 37.5 mg Omecamtiv Mecarbil intervention 4: 50 mg Omecamtiv Mecarbil
Intervention descriptions: intervention 1: oral tablet intervention 2: oral tablet intervention 3: oral tablet intervention 4: oral tablet

Protocol documents:
Prot_002.pdf: 
Approved
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 1 of 73 
CONFIDENTIAL 
Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter Study to 
Evaluate the Safety, Pharmacokinetics, and Efficacy of Omecamtiv Mecarbil in 
Japanese Subjects With Heart Failure With Reduced Ejection Fraction 
AMG 423 (Omecamtiv Mecarbil) 
Amgen Protocol Number (AMG 423) 20120227 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: 1-805-447-1000 
Key Sponsor Contact(s): 
AMGEN Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799, USA 
Phone: 
Fax:
Email:
Local Sponsor: 
Amgen Astellas BioPharma K.K. (AABP)  
Sapia Tower, 1-7-12 Marunouchi, Chiyoda-ku, Tokyo 
100-0005, Japan
Phone: 81-3-5293-9900
Fax: 81-3-5293-9897
Date: 
23 October 2015 
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 in the US (1-805-447-1000).  
NCT Number: NCT02695420
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


Approved 
 
 
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 2 of 73 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Double-blind, Randomized, 
Placebo-controlled, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and 
Efficacy of Omecamtiv Mecarbil in Japanese Subjects With Heart Failure With Reduced 
Ejection Fraction, dated 23 October 2015, 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.  The study will be conducted in compliance with the Ministerial 
Ordinance on Good Clinical Practice for Drugs (Ministry of Health and Welfare 
Ordinance No. 28, 27 March 1997).  
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:  20120227 
Date:  23 October 2015 
Page 3 of 73 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate the Safety, 
Pharmacokinetics, and Efficacy of Omecamtiv Mecarbil in Japanese Subjects With Heart Failure 
With Reduced Ejection Fraction 
Study Phase:  2 
Indication:  Heart Failure 
Primary Objectives:   
• 
To evaluate pharmacokinetics (PK) of omecamtiv mecarbil in Japanese subjects with heart 
failure (HF) with reduced ejection fraction 
• 
To evaluate the safety and tolerability of oral omecamtiv mecarbil  
Secondary Objectives:   
• 
To measure changes in systolic ejection time (SET) by echocardiography following 16 weeks 
of treatment 
Hypotheses:  No formal hypothesis testing will be performed.  PK parameters following chronic 
(twice daily [BID] for 16 weeks) dosing will be estimated. 
Primary Endpoints:   
• 
Concentrations prior to administration (Cpredose) of omecamtiv mecarbil at weeks 2, 4, 12, and 
16, and area under the curve (AUC) at week 8 
Secondary Endpoint:   
• 
Changes from baseline in SET by echocardiography at week 16 
Safety Endpoints:   
• 
Subject incidence of adverse events  
• 
Changes from baseline in laboratory values and vital signs 
• 
Changes from baseline in electrocardiogram (ECG) 
Study Design:  This is a double-blind, randomized, placebo-controlled, multicenter, phase 
2 study in Japanese HF subjects to evaluate 16 weeks of administration of oral modified- release 
(MR) omecamtiv mecarbil formulation at 3 dose levels (25 mg BID, 37.5 mg BID, and 50 mg BID), 
compared with placebo.   
Approximately 80 Japanese subjects with chronic stable HF with reduced ejection fraction will be 
randomized in a 1:1:1:1 manner to receive either placebo (n=20) or omecamtiv mecarbil at a 
target dose of either 25 mg BID (n=20), 37.5 mg BID (n=20), or 50 mg BID (n=20) on an 
outpatient basis.  Subjects randomized to the 37.5 mg BID and 50 mg BID treatment arms will 
initiate administration at 25 mg BID and will be up-titrated to 37.5 mg BID or 50 mg BID target 
dose at the week 4 visit based on steady state Cpredose result from week 2.  Subjects who do not 
have a week 2 PK value in time for dose adjustment at the week 4 visit will be up-titrated at 
week 8 based on the steady state Cpredose result from week 2, if available.  Up-titration at week 4 
or week 8 visits will occur only if the week 2 Cpredose is < 200 ng/mL.  Subjects with a week 2 
Cpredose ≥ 200 ng/mL (or not available at week 8) will continue at 25 mg BID for the remainder of 
the study.  Subjects randomized to placebo or to 25 mg BID will receive the assigned 
investigational product (IP) (omecamtiv mecarbil or placebo) throughout the study.  PK analysis 
and dose assignment will be blinded to the study team.  To maintain blinding, all subjects will 
receive new IP supply at week 4 and week 8 visits.  An independent Data Monitoring Committee 
(DMC) will perform a regular formal unblinded review of the accumulating study data.  An 
independent Clinical Events Classification (CEC) Committee will adjudicate deaths, all 


Approved 
 
 
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 4 of 73 
CONFIDENTIAL 
 
 
hospitalizations, and selected nonfatal cardiovascular (CV) events (including possible myocardial 
infarction or ischemia). 
Sample Size:  Approximately 80 Japanese subjects with chronic stable HF 
Summary of Subject Eligibility Criteria:  
Japanese male and female subjects ≥ 20 and ≤ 85 years of age with chronic stable HF with 
reduced ejection fraction; treated with optimal pharmacological therapy, including a beta blocker 
and either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker 
(ARB) that is expected to remain stable over the period of participation in the study, unless not 
tolerated; and left ventricular ejection fraction (LVEF) must be ≤ 40% as determined by central 
reading of the screening echocardiogram.  Enrollment of subjects with atrial fibrillation/flutter is 
limited to up to approximately 20% of planned enrollment in the study.  Randomization will be 
stratified by presence or absence of atrial fibrillation/flutter at the time of screening via interactive 
voice response system/interactive Web response system (IVRS/IWRS). 
The following are the major exclusion criteria:  New York Heart Association (NYHA) class IV; 
implantation of cardiac resynchronization therapy (CRT) or implantable cardioverter defibrillator 
(ICD) within 30 days prior to randomization; likely to receive the following within 3 months after 
randomization, in the investigator’s opinion: revascularization, implantation of ICD or CRT, 
ventricular assist device, continuous or intermittent inotropic therapy, hospice care, or cardiac 
transplant; severe uncorrected valvular heart disease; hypertrophic obstructive cardiomyopathy, 
active myocarditis, or constrictive pericarditis, or clinically significant congenital heart disease; 
major arrhythmia per investigator’s judgment; acute myocardial infarction, unstable angina, or 
persistent angina at rest within 30 days prior to randomization; chronic antiarrhythmic therapy 
(except amiodarone, digoxin, and beta-blocker therapy), or routinely scheduled outpatient 
intravenous infusions for HF (eg, inotropes, vasodilators [eg, carperitide], diuretics) or routinely 
scheduled ultrafiltration; systolic blood pressure (BP) > 160 mm Hg or < 90 mm Hg or diastolic BP 
> 90 mm Hg, or heart rate (HR) > 110 beats per minute (bpm) or HR < 50 bpm at screening; 
estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 at screening; past recipient of 
any major organ transplant or receiving renal replacement therapy by dialysis; total bilirubin (TBL) 
≥ 2 times the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥ 3 times ULN at screening.  Female subjects of childbearing potential 
cannot be pregnant or planning to become pregnant, or breastfeeding, and must be willing to 
practice sexual abstinence, or surgical contraceptive methods or use 2 acceptable method(s) of 
effective birth control during treatment with IP and for an additional 5 days after the end of 
treatment with IP. 
For a full list of eligibility criteria, please refer to Section 4. 
Amgen Investigational Product Dosage and Administration:  Omecamtiv mecarbil Matrix 
F1 tablets will be dosed orally at 25 mg BID, 37.5 mg BID, and 50 mg BID. 
Procedures:   
Subjects are eligible for screening if they have chronic stable HF and reduced ejection fraction.  
Subjects may also be screened in the hospital setting once they have recovered and are 
considered clinically stable by the investigator.  Subjects must be outpatients at the time of 
randomization.  At the week 4 visit (or at week 8 visit if the week 2 Cpredose result is not available), 
subjects randomized to omecamtiv mecarbil 37.5 mg BID or 50 mg BID will be up-titrated if the 
week 2 Cpredose is < 200 ng/mL.  Subjects will be contacted on day 7 and 6 days after the week 4 
and week 8 visits to ensure IP compliance and for safety observation, and will be seen at the 
study site at weeks 2, 4, 8, 12, and 16, and for the end of study (EOS) visit at week 20.  
All visits after Day 1 include a visit window of ± 3 days with the exception of  
week 2 (-3 days), week 4 (+3 days) and the EOS visit at week 20 (+3 days).  
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).   


Approved 
 
 
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 5 of 73 
CONFIDENTIAL 
 
 
Statistical Considerations:   
All non-PK endpoints analyses will be performed on the full analysis set (FAS) which includes all 
randomized subjects who have received at least 1 dose of IP (omecamtiv mecarbil or placebo).  
PK endpoints analyses will be performed in the subset of FAS where subjects have at least one 
evaluable omecamtiv mecarbil PK parameter (Cmax, Cpredose).  Generally, subjects will be grouped 
according to their randomized target dose treatment group assignment.  Safety endpoints will be 
analyzed in the subjects that received at least 1 dose of IP.  The safety endpoint of subject 
incidence of any treatment-emergent adverse event will be summarized descriptively by 
randomized treatment group.  No formal statistical hypothesis will be tested.   
In the analyses of primary endpoints, PK parameters will be calculated using non-compartmental 
methods.  Individual PK parameters of omecamtiv mecarbil collected in the omecamtiv mecarbil 
arm will be summarized with descriptive statistics.   
The echocardiographic secondary endpoint  will be summarized and analyzed by the stratification 
factor of presence or absence of atrial fibrillation/flutter at randomization. 
Secondary, safety, and exploratory endpoints will be summarized descriptively by randomized 
treatment group and the titration status.  The treatment effect on change from baseline in SET will 
be summarized descriptively by randomized treatment group and the difference between each 
omecamtiv mecarbil dose level and placebo will be estimated.  The relationship of treatment 
effect in the SET and its relationship to omecamtiv mecarbil plasma concentrations will be 
evaluated. 
This study will adjudicate deaths, all hospitalizations, and selected nonfatal cardiovascular events 
by an independent Clinical Events Classification (CEC) Committee.  All events occurring after 
subject randomization until completion of the study at week 20 will be adjudicated. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc. and Amgen Astellas BioPharma K.K. (AABP) 
Data Element Standards 
Version(s)/Date(s):  
5: 20 March 2015 


Approved 
 
 
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 6 of 73 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
BL= baseline; PK=pharmacokinetic;BID=twice daily;EOS=end of study;Wk=week 
1Cpredose in the morning, at study site 
2PK samples at predose, at 2 hours ± 30 minutes; 4 hours ± 30 minutes; 6 hours ± 30 minutes; 8 hours 
± 30 minutes after IP administration in the morning (0 hours = start of IP).  Echocardiogram at week 8 should 
be performed as close as possible after the collection of PK sample at 2 hours ± 30 minutes following IP 
administration. 
3PK samples at predose and at 2 hours ± 30 mins following IP administration.  Echocardiogram at week 16 
should be performed as close as possible after the collection of PK sample at 2 hours ± 30 minutes following 
IP administration.  
Randomization will be stratified by presence or absence of atrial fibrillation/flutter via IVRS/IWRS.  
Blinded titration step at week 4 visit in all arms.  Subjects randomized to 37.5 mg BID or 50 mg BID target 
dose will be up-titrated based on steady state Cpredose result from week 2.  Subjects randomized to 25 mg 
BID or placebo will receive the assigned IP throughout the study.  Up-titration at week 4 or week 8 visits will 
occur in subjects only if the week 2 Cpredose is < 200 ng/mL. 


Approved 
 
 
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 7 of 73 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AABP 
Amgen Astellas BioPharma K.K. 
ACE 
AE 
AHF 
angiotensin-converting enzyme 
adverse event 
acute heart failure 
ALP 
alkaline phosphatase 
ALT 
ARB 
alanine aminotransferase 
angiotensin receptor blocker 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
twice daily 
BP 
blood pressure 
Bpm 
beats per minute 
BMI 
body mass index 
BNP 
B-type natriuretic peptide 
CEC 
Clinical Events Classification 
Childbearing potential 
a female is considered of childbearing potential unless permanently 
sterilized (she has had a hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy or she is postmenopausal).  Menopause is 
defined as: age  ≥ 55 years with cessation of menses for 12 or more 
months; age < 55 years but no spontaneous menses for at least 
2 years; age < 55 years and spontaneous menses within the past 
1 year, but currently amenorrheic (spontaneous), AND with 
postmenopausal gonadotropin levels (luteinizing hormone (LH) and 
follicle-stimulating hormone levels (FSH) > 40 IU/L) or 
postmenopausal estradiol levels (< 5 ng/dL) or according to the 
definition of "postmenopausal range" for the laboratory involved 
CI 
confidence interval 
CK-MB 
creatine kinase MB fraction 
Cmax 
maximum observed concentration 
Cpredose 
concentration prior to the investigational product administration 
CRT 
cardiac resynchronization therapy 
CTCAE 
Common Terminology Criteria for Adverse Events 
Day 1 
day investigational product is first administered 
DILI 
drug-induced liver injury 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate; eGFR will be calculated by the 
central laboratory and provided to the investigator. 


Approved 
 
 
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 8 of 73 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
EM 
extensive metabolizers 
End of study 
the end of the study is defined as the last day on which the last 
randomized subject in this study completes the assessments for 
end-of-study visit (week 20) or terminates the study early 
Enrollment 
a study subject is given a randomization number 
EOS 
eSAE Contingency 
Report Form  
end of study 
electronic serious adverse event contingency report form 
(paper-based form)  
FSH 
follicle-stimulating hormone 
HF 
heart failure 
HR 
heart rate; number of cardiac cycles per unit of time 
ICD 
implantable cardioverter defibrillator 
ICH GCP 
International Conference on Harmonisation Good Clinical Practice 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IP 
investigational product (omecamtiv mecarbil or placebo) 
IPIM 
Investigational Product Instruction Manual 
IR 
immediate release 
IV 
Intravenous 
IVRS/IWRS 
 
interactive voice response system/interactive Web response system; 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information 
LH 
LVEDD 
luteinizing hormone   
left ventricular end-diastolic diameter 
LVEF 
left ventricular ejection fraction 
LVESD 
left ventricular end-systolic diameter 
MR 
modified-release 
NT-proBNP 
n-terminal pro B-type natriuretic peptide 
NYHA 
New York Heart Association 
PEP 
potential endpoint 
PK 
pharmacokinetic(s) 
PKAS 
pharmacokinetic analysis set 
PK/PD 
PM 
pharmacokinetic/pharmacodynamic 
poor metabolizers 
PR interval 
 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
PT 
prothrombin time 


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Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 9 of 73 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
QRS complex 
interval between the Q wave and the S wave in the heart's electrical 
cycle as measured by ECG; represents the time it takes for the 
depolarization of the ventricles 
QT interval 
measure of the time between the start of the Q wave and the end of 
the T wave in the heart's electrical cycle as measured by ECG 
QTc interval 
QT interval corrected for heart rate using accepted methodology 
SAE 
serious adverse event 
SD 
standard deviation 
SET 
systolic ejection time 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical 
research.  The information may include, but is not limited to, clinical 
findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents (original records or certified copies).  
(International Conference on Harmonisation Guideline [E6]).  
Examples of source data include subject identification number, 
randomization number, and stratification value. 
TBL 
total bilirubin 
ULN 
upper limit of normal 
URL 
upper reference limit 
 


Approved 
 
 
Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
Page 10 of 73 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 14 
1.1 
Primary ..................................................................................................... 14 
1.2 
Secondary ................................................................................................. 14 
2. 
BACKGROUND AND RATIONALE ...................................................................... 14 
2.1 
Disease ..................................................................................................... 14 
2.2 
Omecamtiv Mecarbil Background .............................................................. 15 
2.2.1 
Preclinical Information ............................................................... 15 
2.2.2 
Clinical Experience .................................................................... 15 
2.2.2.1 
Studies in Healthy Volunteers ................................. 16 
2.2.2.2 
Studies in Subjects With Heart Failure .................... 17 
2.2.2.3 
Study in Japanese Subjects .................................... 20 
2.3 
Rationale ................................................................................................... 20 
2.4 
Clinical Hypotheses ................................................................................... 22 
3. 
EXPERIMENTAL PLAN ........................................................................................ 22 
3.1 
Study Design ............................................................................................. 22 
3.2 
Number of Sites ........................................................................................ 23 
3.3 
Number of Subjects ................................................................................... 23 
3.4 
Replacement of Subjects .......................................................................... 24 
3.5 
Estimated Study Duration .......................................................................... 24 
3.5.1 
Study Duration for Subjects ....................................................... 24 
3.5.2 
End of Study .............................................................................. 24 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 24 
4.1 
Inclusion and Exclusion Criteria ................................................................ 24 
4.1.1 
Inclusion Criteria ........................................................................ 24 
4.1.2 
Exclusion Criteria ...................................................................... 25 
5. 
SUBJECT ENROLLMENT .................................................................................... 27 
5.1 
Randomization/Treatment Assignment ...................................................... 27 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 28 
6. 
TREATMENT PROCEDURES .............................................................................. 28 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 28 
6.2 
Investigational Product .............................................................................. 29 
6.2.1 
Amgen Investigational Product (Omecamtiv Mecarbil) ............... 29 
6.2.1.1 
Dosage, Administration, and Schedule .................... 29 


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Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
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6.2.1.2 
Rules for Withholding Investigational 
Product due to Myocardial Ischemia or 
Infarction, Abnormal Blood Pressure or 
Heart Rate ............................................................... 30 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 31 
6.3.1 
Criteria for Permanent Discontinuation of Omecamtiv 
Mecarbil due to Potential Hepatotoxicity  ................................... 31 
6.3.2 
Criteria for Conditional Withholding of Omecamtiv 
Mecarbil due to Potential Hepatotoxicity .................................... 32 
6.3.3 
Criteria for Rechallenge of Omecamtiv Mecarbil After 
Potential Hepatotoxicity ............................................................. 33 
6.4 
Concomitant Therapy ................................................................................ 33 
6.5 
Product Complaints ................................................................................... 33 
6.6 
Excluded Treatments, Medical Devices and/or Procedures 
During Study Period .................................................................................. 33 
7. 
STUDY PROCEDURES ....................................................................................... 33 
7.1 
Schedule of Assessments ......................................................................... 33 
7.2 
General Study Procedures ........................................................................ 36 
7.2.1 
Informed Consent ...................................................................... 36 
7.2.2 
Medical History .......................................................................... 36 
7.2.3 
Concomitant Therapy ................................................................ 36 
7.2.4 
Vital Signs ................................................................................. 36 
7.2.5 
Investigational Product Administration Diary .............................. 36 
7.2.6 
Adverse Events ......................................................................... 36 
7.2.7 
Potential Endpoints.................................................................... 37 
7.2.8 
Hospitalizations ......................................................................... 37 
7.2.9 
Physical Examination ................................................................ 37 
7.2.10 
Physical Measurements ............................................................ 37 
7.2.11 
Electrocardiogram ..................................................................... 37 
7.2.12 
Laboratory Assessments ........................................................... 38 
7.2.12.1 
Pregnancy Test ....................................................... 39 
7.2.12.2 
Troponin .................................................................. 39 
7.2.12.3 
Pharmacokinetics of Omecamtiv Mecarbil ............... 40 
7.2.12.4 
Digoxin .................................................................... 41 
7.2.12.5 
Omecamtiv Mecarbil Therapeutic 
Monitoring Assay ..................................................... 41 
7.2.12.6 
Pharmacogenomic Studies...................................... 41 
7.2.13 
Echocardiograms ...................................................................... 41 
7.3 
Screening and Enrollment ......................................................................... 42 
7.3.1 
Screening .................................................................................. 42 
7.3.2 
Rescreening .............................................................................. 42 
7.4 
Treatment Period ...................................................................................... 43 
7.4.1 
Telephone Contact Days 7, 34, and 62...................................... 43 


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Product:  Omecamtiv Mecarbil (AMG 423) 
Protocol Number:  20120227 
Date:  23 October 2015 
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7.5 
Safety Follow-up Visit/End of Study Visit ................................................... 43 
7.6 
Sample Storage and Destruction ............................................................... 44 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 45 
8.1 
Subjects’ Decision to Withdraw ................................................................. 45 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 46 
8.3 
Reasons for Removal From Treatment or Study ....................................... 46 
8.3.1 
Reasons for Removal From Treatment ...................................... 46 
8.3.2 
Reasons for Removal From Study ............................................. 46 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 46 
9.1 
Adverse Events ......................................................................................... 46 
9.1.1 
Definition of Adverse Events ...................................................... 46 
9.1.2 
Definition of Serious Adverse Events ......................................... 47 
9.2 
Reporting of Adverse Events ..................................................................... 47 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria ................................................................. 47 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 49 
9.2.2.1 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 49 
9.2.2.2 
Reporting a Safety Endpoint as a Study 
Endpoint .................................................................. 51 
9.3 
Pregnancy and Lactation Reporting .......................................................... 51 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 51 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 51 
10.1.1 
Study Endpoints ........................................................................ 51 
10.1.1.1 
Primary Endpoints ................................................... 51 
10.1.1.2 
Secondary Endpoint ................................................ 51 
10.1.1.3 
Safety Endpoints ..................................................... 52 
10.1.1.4 
Exploratory Endpoints ............................................. 52 
10.1.2 
Analysis Sets ............................................................................. 52 
10.1.3 
Covariates and Subgroups ........................................................ 53 
10.2 
Sample Size Considerations ..................................................................... 53 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 53 
10.4 
Planned Analyses ..................................................................................... 54 
10.4.1 
Data Monitoring Committee (DMC) ............................................ 54 
10.4.2 
Primary Analysis ........................................................................ 54 
10.5 
Planned Methods of Analysis .................................................................... 55 
10.5.1 
General Considerations ............................................................. 55 
10.5.2 
Primary Endpoint ....................................................................... 55 
10.5.3 
Secondary Endpoint .................................................................. 55 
10.5.4 
Safety Endpoints ....................................................................... 56 


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10.5.4.1 
Adverse Events ....................................................... 56 
10.5.4.2 
Safety Laboratory Tests .......................................... 56 
10.5.4.3 
Vital Signs ............................................................... 56 
10.5.4.4 
Electrocardiogram ................................................... 56 
11. 
REGULATORY OBLIGATIONS ............................................................................ 56 
11.1 
Informed Consent ...................................................................................... 56 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 57 
11.3 
Subject Confidentiality ............................................................................... 58 
11.4 
Investigator Signatory Obligations ............................................................. 58 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 59 
12.1 
Protocol Amendments and Study Termination .......................................... 59 
12.2 
Study Documentation and Archive ............................................................ 59 
12.3 
Study Monitoring and Data Collection ....................................................... 60 
12.4 
Investigator Responsibilities for Data Collection ........................................ 61 
12.5 
Language .................................................................................................. 61 
12.6 
Publication Policy ...................................................................................... 61 
12.7 
Compensation ........................................................................................... 62 
13. 
REFERENCES ..................................................................................................... 63 
14. 
APPENDICES ...................................................................................................... 65 
List of Tables 
Table 1.  Comparison of Omecamtiv Mecarbil Steady State Cmax and AUC 
Following BID Dosing of MR-F1 Table
 
ts in Healthy Japanese 
Subjects.................................................................................................. 22
Table
 
 2.  Schedule of Assessments ............................................................................... 34
Table
 
 3.  Analyte Listing ................................................................................................ 39
Table
 
 4.  PK Parameter 95% Confidence Intervals ........................................................ 53
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 66 
Appendix B.  Sample Serious Adverse Event Report Form ........................................... 68 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 71 
Appendix D.  Excluded Medications and Foods ............................................................. 73 


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1. 
OBJECTIVES 
1.1 
Primary 
The primary objectives of this study are to: 
• 
To evaluate the pharmacokinetics (PK) of omecamtiv mecarbil in Japanese subjects 
with heart failure (HF) with reduced ejection fraction 
• 
To evaluate the safety and tolerability of oral omecamtiv mecarbil  
1.2 
Secondary 
The secondary objectives of the study are: 
• 
To measure changes in systolic ejection time (SET) by echocardiography following 
16 weeks of treatment 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Heart failure is a clinical syndrome marked by impaired cardiac contractility and is the 
final pathway for a diversity of diseases that afflict the heart (Hilfiker-Kleiner et al, 2006).  
The rate of cardiovascular mortality or HF hospitalization approaches 25% to 30% at 
6 months in patients hospitalized for HF (Konstam et al, 2007; Gheorghiade et al, 2013).  
In Japan, approximately 1 million people are believed to have HF (Okamoto and 
Kitabatake, 2003, Okura et al, 2008).  Although the prevalence of HF (< 1%) is lower 
than that in Western industrialized countries, it is expected to rise substantially in the 
coming decades, mainly due to Japan’s rapidly aging population (Japanese Statistics 
Bureau, 2005; Okura et al, 2008).  One-year mortality due to HF is from 4.3% to 9% and 
1-year readmissions range from 7.6% to 17.8% (Shiba et al, 2004; Tsutsui et al, 2007; 
Hamaguchi et al, 2009).  While several pharmacological and non-pharmacological 
interventions have been shown to reduce the rate of HF hospitalizations and improve 
mortality, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, 
aldosterone antagonists, coronary revascularization, and biventricular pacing 
(Krum and Teerlink, 2011), mortality and morbidity still remain high as noted above.  In 
addition, these available treatments that are aimed at diverse targets including sodium 
retention, arterial and venous constriction, neuroendocrine activation, increased heart 
rate (HR), cardiac dyssynchrony, and arrhythmias often fail to control symptoms or 
restore quality of life.  Another target for treatment of HF is to improve myocardial 
contractility.  HF is a condition most commonly marked by cardiac systolic dysfunction.  
Over time, in an attempt to preserve cardiac output, a series of compensatory changes 
can occur characterized by increased sympathetic tone and peripheral vasoconstriction, 


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as well as the activation of various neurohormonal pathways.  Attempts to improve 
cardiac contractility using adrenergic receptor agonists (ie, dobutamine) or 
phosphodiesterase inhibitors (ie, milrinone) have met with little success.  However, these 
mechanisms have significant safety liabilities attributable to increased oxygen 
consumption, intracellular calcium, and arrhythmias (Cuffe et al, 2002;  
Felker et al, 2003).  Cardiac myosin activators like omecamtiv mecarbil are a new 
mechanistic class designed specifically to increase myocardial contractility without these 
liabilities. 
2.2 
Omecamtiv Mecarbil Background 
Omecamtiv mecarbil (AMG 423, CK-1827452) is a novel small molecule that increases 
cardiac contractility by selectively and directly activating the enzymatic domain of cardiac 
myosin heavy chain, the force-generating motor protein of the cardiac sarcomere, 
without increasing cardiac myocyte intracellular calcium (Teerlink, 2009;  
Malik et al, 2011). 
2.2.1 
Preclinical Information 
In vitro experiments demonstrated that omecamtiv mecarbil augments contractility 
without changing the intracellular calcium transient in isolated cardiac myocytes.  It does 
not inhibit phosphodiesterase type 3.  In dog models of systolic HF, infusion of 
omecamtiv mecarbil significantly augmented left ventricular systolic function and cardiac 
output by increasing the left ventricular SET without increasing the rate of pressure 
development (dP/dt) or HR.  Additionally, left ventricular filling pressure, left atrial 
pressure, 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 omecamtiv mecarbil 
were achieved without noticeable effect upon myocardial oxygen uptake, blood pressure 
(BP), or coronary blood flow (Shen et al, 2010; Malik et al, 2011). 
2.2.2 
Clinical Experience 
The safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) of oral and 
intravenous (IV) formulations of omecamtiv mecarbil have been evaluated in 
9 completed phase 1 clinical studies in healthy volunteers/end-stage renal disease 
(ESRD) subjects (Studies CY 1111, CY 1011, CY 1013, CY 1015, CY 1016, 
CY 1211 [20120255], 20080676, 20090229, and 20090727); and in 4 completed phase 
2a studies in chronic HF subjects (Studies CY 1021, CY 1121, CY 1124, and CY 1221); 
and 1 completed phase 2b study in acute heart failure (AHF) subjects (Study 20100754).  


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Efficacy was also evaluated in completed Study 20100754.  The studies pertinent to this 
study are summarized below.  Refer to the Investigator’s Brochure for omecamtiv 
mecarbil for additional information. 
2.2.2.1 
Studies in Healthy Volunteers 
CY 1111, a first-in-human clinical study with omecamtiv mecarbil, was a randomized, 
double-blind, placebo-controlled, 4-period crossover, dose escalation study designed to 
evaluate the safety, tolerability, and PK/PD profile of omecamtiv mecarbil administered 
IV to healthy male volunteers (Teerlink et al, 2011).  This study included a total of 
33 subjects who received infusions of omecamtiv mecarbil at doses ranging from 
0.005 mg/kg/hr to 1.0 mg/kg/hr for up to 6 hours.  The exposures of omecamtiv mecarbil, 
as measured by area under the curve (AUC) and maximum observed concentration 
(Cmax), were approximately dose proportional, with an AUC of 159 (57 standard 
deviation) ng•hr/mL for treatment administered at an infusion rate of 0.005 mg/hr/kg and 
30400 ng•hr/mL when administered at a rate of 1 mg/hr/kg; corresponding Cmax values 
for those administration rates were 8.70 (2.20) ng/mL and 1340 ng/mL.  The mean 
clearance  ranged from 125 to 207 mL/hr/kg and the mean half life  ranged from 17.1 to 
23.2 hours and increased slightly with increasing doses.  The mean steady state 
distribution volume was dose independent and ranged from 3.6 to 5.2 L/kg.  At the dose 
of 0.5 mg/kg/hr over 6 hours, the mean (standard deviation [SD]) Cmax was 
905 (183) ng/mL.  Across the dosing levels evaluated in CY 1111, omecamtiv mecarbil 
infusions demonstrated generally linear PK with dose-proportional increases in Cmax.  
Concentration-dependent PD effects on cardiac function as measured by 
echocardiography were observed.  These PD effects included statistically significant 
placebo corrected increases from baseline in SET, Doppler-derived stroke volume, left 
ventricular ejection fraction (LVEF), and fractional shortening.  
CY 1013 was an open-label, parallel group study in healthy male volunteers designed to 
evaluate the contribution of cytochrome P450 enzymes CYP3A4 and CYP2D6 to the 
elimination of omecamtiv mecarbil.  Healthy volunteer subjects who were either 
extensive metabolizers (EMs) or poor metabolizers (PMs) with respect to their defined 
CYP2D6 genotype received oral omecamtiv mecarbil alone and in combination with 
ketoconazole or diltiazem.  Ketoconazole (a potent inhibitor of CYP3A4) caused 
approximately 51% and 31% increases in the mean AUC of omecamtiv mecarbil in EM 
and PM subjects, respectively; 1 PM subject had a decrease in omecamtiv mecarbil 
AUC when given in combination with ketoconazole which contributed to the observed 


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differences between these 2 groups.  In the presence and absence of diltiazem  
(a moderate inhibitor of CYP3A4), the AUC of omecamtiv mecarbil was similar.  
CYP3A4 inhibition had little impact on Cmax and time to Cmax.  When omecamtiv mecarbil 
was administered alone, the mean AUC was approximately 37% higher in PM subjects 
(990 ng•hr/mL, n = 8) than in EM subjects (720 ng•hr/mL, n = 8).  These results indicate 
minor involvement of CYP3A4 and CYP2D6 in the metabolism of omecamtiv mecarbil. 
Studies CY 1011, CY 1015, and CY 1016 were designed to evaluate the PK parameters 
of oral preparations of omecamtiv mecarbil.  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 omecamtiv mecarbil approaching 100% under all conditions studied; 
food appeared to reduce the rate but not the extent of absorption.  Omecamtiv mecarbil 
was well tolerated with no treatment-related serious adverse events in these trials.  
In Study 20090727, which compared five modified-release (MR) formulations to the IR 
formulation, the mean bioavailability of the MR formulations was ~80% with MR-F1, 
MR-F2 and SCT-F2 and Cmax was reduced by ~70%.  Food had a minimal effect on the 
PK of the oral MR and immediate release (IR) formulations but reduced inter-subject 
variability. 
Study 20090229 was an open-label, single dose study that evaluated the absorption, 
metabolism, and excretion of orally- and IV-administered [14C]-omecamtiv mecarbil in 
14 healthy volunteers.  Approximately 85% of the IV and oral doses of [14C]-omecamtiv 
mecarbil were recovered in urine and feces.  Less than 10% of omecamtiv mecarbil 
appeared in urine.  The major clearance pathway (primarily metabolism) was 
decarbamylation of omecamtiv mecarbil to M3 followed by further biotransformation.  In 
plasma, omecamtiv mecarbil was the most abundant component, with M3 and  
M4 (a lactam of M3) the most abundant metabolites at 6.0% and 3.3% of total 
drug-related AUC, respectively.  M3 and M4 were also the major metabolites in urine 
and feces.  Of note, the biological activity of M3 and M4 when assayed against the 
cardiac sarcomere in vitro was > 10-fold less potent than the parent drug. 
2.2.2.2 
Studies in Subjects With Heart Failure 
Study CY 1121 was a randomized, double-blind, placebo-controlled, crossover study 
that enrolled 5 sequential cohorts of subjects with stable HF (LVEF ≤ 40% 
[LVEF ≤ 30% in cohort 4]).  A total 45 subjects (39 males and 6 females) were enrolled 
and treated with study drug infusions ranging from 2 to 72 hours (Cleland et al, 2011).  


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Three subjects 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.  Omecamtiv mecarbil produced increases in echocardiographic indices of 
cardiac systolic function. 
Study CY 1221 was a randomized, double-blind, placebo-controlled study that enrolled 
HF subjects with ischemic cardiomyopathy and angina with LVEF ≤ 35%.  A total of 
94 subjects were enrolled and treated with 20 hour infusions of study drug followed by 
7 days of oral dosing; 29 subjects received placebo, 31 received omecamtiv mecarbil 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 omecamtiv mecarbil at either dose regimen.  In addition, no consistent 
differences were observed between placebo and lower or higher dosing regimens of 
omecamtiv mecarbil with respect to any of the secondary safety endpoints, vital signs, 
electrocardiograms (ECG) or cardiac enzymes. 
CY 1021 was an open-label study with the objective to evaluate the PK and tolerability of 
a MR and an IR oral formulation of omecamtiv mecarbil in subjects with stable HF.  A 
total of 35 subjects were enrolled and treated with a dose of 50 mg MR twice daily (BID), 
37.5 mg IR 3 times a day, or 100 mg MR BID under fed conditions.  A 
-year-old male 
subject experienced sudden death in this study after 6 days of dosing with the IR 
formulation.  The subject’s history was 
 
 
  At the time of 
enrollment into the study, the subject was New York Heart Association (NYHA) Class III 
and Canadian Cardiovascular Society Angina Class III.  Study site personnel last spoke 
to the subject on Day 6 just prior to the last administered dose.  He had no complaints 
and reported that he was taking the study medication as prescribed.  Shortly after the 
last dose on Day 6, the subject 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. 


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Of the 250 healthy volunteers (including 13 ESRD subjects) and the 147 HF subjects in 
phase 2a studies who received at least 1 dose of omecamtiv mecarbil, 6 healthy 
volunteers and 8 HF subjects had troponin I above the upper reference limit (URL).  
There were no subjects with troponin T > URL in the absence of troponin I > URL post 
baseline.  These 14 subjects are included in the Investigator Brochure (Table 6-22 and 
Appendix B).  In 3 of the 14 subjects with troponin I > URL, the troponin I > URL 
occurred at omecamtiv mecarbil Cmax plasma concentrations of 1333 ng/mL, 
1456 ng/mL, and 1345 ng/mL in healthy volunteer Subject 
 (Study CY 1111), HF 
Subject 
 (Study CY 1121), and HF Subject 
 (Study CY 1121), respectively.  
These 3 subjects had similar clinical presentation in terms of their symptoms/signs 
(tachycardia, chest discomfort, and dizziness), ECG changes, and rise and fall of 
troponin I, consistent with myocardial infarction.  Their symptoms resolved with the 
discontinuation of omecamtiv mecarbil.  In at least 6 of the other 11 subjects with 
troponin I > URL, a causal relationship with omecamtiv mecarbil could not be excluded.  
Study 20100754, (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in 
Acute Heart Failure, ATOMIC-AHF) was a phase 2b multicenter, randomized, 
double-blind, placebo-controlled study to evaluate the effect of 48 hours of IV 
omecamtiv mecarbil compared with placebo on dyspnea in subjects with left ventricular 
systolic dysfunction hospitalized for acute HF.  The study enrolled 613 subjects into 
3 dose escalation cohorts with review of data by an independent external Data 
Monitoring Committee (DMC) before proceeding to the next cohort.   
A total of 303 AHF subjects received at least 1 dose of omecamtiv mecarbil and an 
equal number received placebo.  No statistically significant difference was observed in 
dyspnea symptom response (primary efficacy endpoint) between omecamtiv mecarbil 
treatment groups and the pooled placebo group.  
Major cardiovascular events were adjudicated by an independent, academic committee 
in ATOMIC-AHF (Duke Clinical Research Institute Clinical Events Classification (CEC) 
Committee.  Adverse events (58% vs. 63%), serious adverse events (21.8% vs. 23.1%), 
deaths (2.6% vs. 3.3%), and rehospitalization within 30 days (9.6% vs. 12.2%) were 
similar between the pooled omecamtiv mecarbil group and the pooled placebo group, 
respectively.  At the 6 month vital status assessment, 38 (12.5%) subjects in the 
omecamtiv mecarbil groups died compared with 39 (12.9%) subjects in the placebo 
groups.  There were a limited number (10) of positively adjudicated post-randomization 
myocardial infarctions and a small numeric imbalance was noted in the omecamtiv 


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mecarbil treated groups (total of 7) compared with 3 in placebo groups (2.3% vs. 1%, 
respectively).  Five of the adjudicated myocardial infarctions  in omecamtiv 
mecarbil-treated subjects occurred in cohort 3, however, 2 occurred more than 7 days 
after completion of drug infusion and 1 occurred subsequent to a percutaneous coronary 
intervention.  The overall incidence of reported supraventricular tachyarrhythmias 
(standard MedDRA query [SMQ]) was less (3.6% vs. 6.6%) on omecamtiv mecarbil than 
on placebo and, within each cohort, rates were lower in the omecamtiv mecarbil group 
than the placebo group.  The overall incidence of ventricular tachyarrhythmias (SMQ) 
was similar (5.3% omecamtiv mecarbil, 5.9%, placebo).  For further details on the clinical 
experience with omecamtiv mecarbil please consult the Investigator’s Brochure. 
2.2.2.3 
Study in Japanese Subjects 
Study 20120255 (CY 1211) was a phase I single center, placebo-controlled, double-blind 
study comparing the PK of omecamtiv mecarbil between healthy Japanese and 
Caucasian volunteers.  In a 3-period crossover design, 36 subjects (18 Japanese and 
18 Caucasians) received 3 separate treatments with at least a 7-day washout between 
each dosing period.  Volunteers received in succession an IV infusion (4 hour) of 
omecamtiv mecarbil or placebo, multiple 25 mg doses of a MR oral formulation of 
omecamtiv mecarbil or placebo over 7 days, and a single 50 mg dose of a MR oral 
formulation of omecamtiv mecarbil or placebo.  There were no clinically meaningful 
differences observed in the PK of omecamtiv mecarbil between Japanese and 
Caucasian healthy volunteers and all doses of omecamtiv mecarbil in CY 1211 were well 
tolerated. 
2.3 
Rationale 
Omecamtiv mecarbil is being developed as an adjunctive therapy for subjects with HF 
with reduced ejection fraction (≤40%) who are already taking a beta-blocker and an ACE 
inhibitor and/or angiotensin receptor blocker (ARB), unless not tolerated.  Targeting 
myocardial contractility in subjects with systolic dysfunction would appear to be a rational 
therapeutic approach to preserve cardiac output, to attenuate the compensatory 
mechanisms including neurohormonal activation, and to prevent or even reverse 
ventricular remodeling, which ultimately could translate into clinical benefits for HF 
patients (Hasenfuss and Teerlink, 2011). 
Historically, development of heart failure drugs has required careful assessment of the 
balance of benefit:risk in large phase 3 clinical outcomes studies because there is no 
well-established validated surrogate endpoint in HF for clinical outcomes.  Direct 


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increase of cardiac function can positively impact clinical outcomes in patients with left 
ventricular systolic dysfunction as evidenced by the efficacy of cardiac resynchronization 
therapy (CRT) in HF patients with systolic dysfunction (Moss et al, 2009).  Omecamtiv 
mecarbil is a cardiac myosin activator that has dose-dependent and 
concentration-dependent effects on cardiac function at plasma concentrations that 
appear generally well tolerated by subjects with stable chronic systolic HF (Cleland et al, 
2011).  
The ongoing Study 20110151 (COSMIC-HF) is a global phase 2, randomized, 
double-blind, placebo-controlled study in subjects with chronic stable HF and systolic 
dysfunction.  This study was designed to compare 3 oral MR formulations in 2 cohorts 
(escalation phase) of 25 mg BID and 50 mg BID for 7 days to select the most suitable 
formulation for further study in the dose ranging expansion phase (25 mg BID and 50 mg 
BID of a single oral MR formulation compared with placebo over 20 weeks of treatment 
with echocardiographic evaluations).  The escalation phase of the study has completed.  
Following review of PK and safety data from a total of 96 subjects, a single oral MR 
formulation, MR-F1, was selected for use in the COSMIC-HF expansion phase.  
Enrollment is complete and the MR-F1 formulation is currently being evaluated at 2 dose 
levels (25 mg and 50 mg BID) in approximately 450 subjects.   
Prior to initiation of subject enrollment into this study (Study 20120227) results from the 
planned Japanese phase 1 study 20150134, which include PK and safety assessments 
of repeated 25 mg BID, 37.5 mg BID, and 50 mg BID oral dosing, will be reviewed.  It is 
expected that Study 20150134 will confirm the doses selected are appropriate to be 
studied in this phase 2 study (Study 20120227). 
Study 20120227 will enroll approximately 80 subjects and randomize them to doses of 
omecamtiv mecarbil (25 mg, 37.5 mg, or 50 mg BID), or placebo.  Simulated omecamtiv 
mecarbil exposures in subjects with low body weight, defined as less than 58 kg based 
on the median body weight distribution of Japanese subjects with HF, were 
approximately 25% to 35% higher compared with exposures in non-Japanese HF 
subjects with a higher body weight, defined as greater than 82 kg based the median 
body weight of subjects with HF in the ATOMIC-AHF and COSMIC-HF studies (Table 1).   


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Table 1.  Comparison of Omecamtiv Mecarbil Steady State Cmax and AUC 
Following BID Dosing of MR-F1 Tablets in Healthy Japanese Subjects 
BID Dose 
(mg) 
Simulated Japanese 
Simulated Non-Japanese 
Cmax,ss  
(ng/mL) 
AUCss  
(ng*hr/mL) 
Cmax,ss  
(ng/mL) 
AUCss  
(ng*hr/mL) 
25 
277 [252] 
(129) 
2759 [2501] 
(1305) 
211 [193] 
(94) 
2115 [1918] 
(962) 
37.5 
461 [418] 
(214) 
4613 [4171] 
(2185) 
351 [319] 
(155) 
3521 [3201] 
(1585) 
50 
614 [557] 
(286) 
6143 [5539] 
(2929) 
469 [427] 
(209) 
4707 [4265] 
(2130) 
Data presented as mean [median] (standard deviation); AUCss= area under the curve, steady state; 
Cmax =maximum plasma concentration; HF=heart failure; BID =twice daily 
Though the results of the completed phase 1 Study 20120255 showed that systemic 
clearance in Japanese and Caucasian subjects was not statistically significantly 
different, and that the body weight adjusted clearance was essentially identical, this 
study will include an additional tablet strength of 37.5 mg BID to further explore PK and 
PD parameters with chronic repeated oral dosing.  
2.4 
Clinical Hypotheses 
No formal hypothesis testing will be performed.  PK parameters following chronic dosing 
(BID for 16 weeks) will be estimated.   
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a double-blind, randomized, placebo-controlled, multicenter, phase 2 study in 
Japanese HF subjects to evaluate 16 weeks of administration of oral MR omecamtiv 
mecarbil formulation at 3 dose levels (25 mg BID, 37.5 mg BID, and 50 mg BID), 
compared with placebo.  Potential subjects will be screened to assess their eligibility to 
enter the study within 30 days prior to enrollment.  Subjects are eligible for screening if 
they have chronic stable HF and reduced ejection fraction.  Subjects may also be 
screened in the hospital setting once they have recovered and are considered clinically 
stable by the investigator.  Subjects must be outpatients at the time of randomization.   
Approximately 80 Japanese subjects with chronic stable HF with reduced ejection 
fraction will be randomized 1:1:1:1 to receive omecamtiv mecarbil either 25 mg BID dose 
(n=20), 37.5 mg BID dose (n=20), 50 mg BID dose (n=20) or placebo (n=20) on an 
outpatient basis.  Subjects randomized to 37.5 mg BID target dose and 50 mg BID target 
dose will initiate administration at 25 mg BID and will be up-titrated to 37.5 mg BID or 


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50 mg BID at the week 4 visit based on steady state concentration prior to 
investigational product (IP) administration (Cpredose) result from week 2.  Subjects who do 
not have a week 2 PK value in time for dose adjustment at the week 4 visit will be 
up-titrated at week 8 based on the steady state Cpredose result from week 2, if available.  
Subjects will be up-titrated at the week 4 or week 8 visits only if the week 2 Cpredose is 
< 200 ng/mL.  Subjects with a week 2 Cpredose ≥ 200 ng/mL (or not available at week 8) 
will continue at 25 mg BID for the remaining of the study.  Subjects randomized to 
placebo or to 25 mg BID will receive the assigned IP throughout the study.  IP 
compliance will also be monitored.  PK analysis and dose assignment will be blinded to 
the study team.  To maintain blinding, all subjects will receive new IP supply at the week 
4 and week 8 visits.  The study includes transthoracic echocardiographic assessments 
(screening, week 8, and week 16).  Enrollment of subjects with atrial fibrillation/flutter at 
the time of screening will be limited to approximately 20% of planned enrollment.  
Randomization will be stratified by presence or absence of atrial fibrillation/flutter via the 
interactive voice response system/interactive Web response system (IVRS/IWRS).   
An independent DMC will perform regular formal unblinded review of the accumulating 
study data.  An independent CEC will adjudicate deaths, all hospitalizations, and 
selected nonfatal cardiovascular (CV) events (including possible MI or ischemia).  The 
end of study (EOS) visit will be performed 4 weeks after the last dose of IP  
(Week 20 +3 days).  
Vital signs, physical examinations, ECGs, Adverse Event/Serious Adverse Event 
assessments, clinical laboratory evaluations (see Table 3), and collection of concomitant 
medications will be performed at screening and at specified times per the Schedule of 
Assessments (Table 2).  The overall study design is described in 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 50 centers in Japan will participate in the 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 80 Japanese subjects with chronic stable HF with reduced ejection 
fraction will be enrolled. 


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Rationale for the sample size can be found in Section 10.2. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn, removed from treatment or the study, or who voluntarily 
withdraw prematurely from the study will not be replaced.   
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
After signing the informed consent, all eligible subjects should be randomized within 
30 days.  Treatment duration will be for 16 weeks with the EOS visit at week 20 for a 
maximal duration of study participation of approximately 24 weeks or 6 months (includes 
screening, treatment period, and EOS visit). 
3.5.2 
End of Study 
The end of the study is defined as the last day on which the last randomized subject in 
this study completes the assessments for end-of-study visit (week 20) or terminates the 
study early. 
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).   
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 or their legally authorized representative has provided written informed 
consent prior to initiation of any study-specific activities/procedures 
102 
Japanese male or female ≥ 20 years and ≤ 85 years of age at the time of written 
informed consent 
103 
History of chronic stable HF with reduced ejection fraction, defined as requiring 
treatment for HF for a minimum of 4 weeks prior to screening 
104 
Treated for HF with optimal pharmacological therapy.  In general, optimal 
treatment will include a beta-blocker and either an ACE inhibitor or an ARB that 
is expected to remain stable over the period of participation in the study, unless 
not tolerated 
105 
LVEF ≤ 40% by centrally read screening echocardiogram   


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4.1.2 
Exclusion Criteria 
201 
Implantation of CRT or ICD implantation within 30 days prior to randomization 
202 
NYHA class IV  
203 
Likely to receive within 3 months after randomization, in the opinion of the 
investigator, revascularization, implantation of ICD or CRT, ventricular assist 
device, continuous or intermittent inotropic therapy, hospice care, or cardiac 
transplant 
204 
Severe uncorrected valvular heart disease  
205 
Hypertrophic obstructive cardiomyopathy, active myocarditis, or constrictive 
pericarditis, or clinically significant congenital heart disease 
206 
Acute myocardial infarction, unstable angina, or persistent angina at rest within 
30 days prior to randomization 
207 
Chronic antiarrhythmic therapy, with the exception of amiodarone, digoxin and 
beta-blocker therapy 
208 
Routinely scheduled outpatient IV infusions for HF (eg, inotropes, vasodilators 
[eg, carperitide], diuretics) or routinely scheduled ultrafiltration 
209 
Systolic BP > 160 mm Hg or < 90 mm Hg, or diastolic BP > 90 mm Hg, or HR 
> 110 beats per minute (bpm) or HR < 50 bpm at screening  
210 
Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 by central 
laboratory during screening  
211 
Currently taking, or has taken within 14 days prior to randomization, a potent 
CYP3A4 inhibitor (amprenavir, cobicistat, cyclosporine, clarithromycin, 
delaviridine, erythromycin, indinavir, itraconazole, nelfinavir, ritonavir, saquinivir, 
telaprevir, verapamil, voriconazole, grapefruit juice) 
212 
Currently taking, or has taken within 28 days prior to randomization, a potent 
CYP3A4 inducer (eg, carbamazepine, dexamethasone, efavirenz, etravirine, 
nevirapine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John’s wort) 
213 
Severe, concomitant noncardiovascular disease that is expected to reduce life 
expectancy to less than 1 year 
214 
Past recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, 
renal) or receiving renal replacement therapy by dialysis  
215 
Malignancy within 1 year prior to randomization with the following exceptions: 
localized basal or squamous cell carcinoma of the skin or cervical intraepithelial 
neoplasia  
216 
Known untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, active 
vasculitis due to collagen vascular disease  
217 
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 by central laboratory during screening 
218 
Any acute or serious co-morbid condition (eg, major infection or hematologic, 
renal, metabolic, gastrointestinal or endocrine dysfunction, major arrhythmia) 
that, in the judgment of the investigator, could lead to premature termination of 
study participation or interfere with the measurement of, or the interpretation of, 
the efficacy and safety assessments in the study 


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219 
Previously received omecamtiv mecarbil  
220 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(s) 
221 
Recent (within 3 months) history of alcohol or illicit drug abuse based on 
self-report 
222 
Female subject is pregnant or breastfeeding or is planning to become pregnant 
during treatment with IP (omecamtiv mecarbil or placebo) and within 5 days after 
the end of treatment with IP 
223 
Female subject of childbearing potential who is not willing to inform her partner of 
her participation in this clinical study and to use two (2) acceptable methods of 
effective birth control or practice sexual abstinence or surgical contraceptive 
methods (vasectomy [male partner] or bilateral tubal ligation/occlusion) during 
treatment with IP (omecamtiv mecarbil or placebo) and for an additional 5 days 
after the last dose of IP   
• 
A female is considered of childbearing potential unless permanently 
sterilized (she has had a hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy or she is postmenopausal).  Menopause is defined as: age  
≥ 55 years with cessation of menses for 12 or more months; age < 55 years 
but no spontaneous menses for at least 2 years; age < 55 years and 
spontaneous menses within the past 1 year, but currently amenorrheic  
(spontaneous), AND with postmenopausal gonadotropin levels (luteinizing 
hormone (LH) and follicle-stimulating hormone levels (FSH) > 40 IU/L) or 
postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of 
"postmenopausal range" for the laboratory involved. 
• 
acceptable methods of effective birth control include the following 
combinations: 
intrauterine device and hormonal birth control method, or intrauterine device 
and barrier method with spermicide, or intrauterine hormonal-releasing 
system and barrier method with spermicide, or hormonal birth control method 
and barrier method with spermicide, or two  (2) barrier methods (one by each 
partner) with spermicide (the male partner must use a male condom and the 
female must use a diaphragm) 
Note: spermicides and diaphragm are not approved for use in Japan.  If 
additional medications are given during treatment which may alter the 
contraceptive requirements (these additional medications may require a 
change in the type and/or length of time that contraception is to be utilized or 
length of time that breastfeeding is to be avoided) the investigator is to 
discuss these changes with the study subject. 
224 
Known sensitivity to any of the products to be administered during dosing  


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225 
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 
226 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion 
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 (IRB)/Independent Ethics 
Committee (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 or 
their legally authorized representative must personally sign and date the informed 
consent form before commencement of study-specific activities/procedures.   
A subject is considered enrolled upon randomization in IVRS/IWRS.  The investigator is 
to document this decision and date, in the subject’s medical record and in/on the 
enrollment electronic case report form (eCRF).  Randomization will be stratified by 
presence or absence of atrial fibrillation/flutter via IVRS/IWRS. 
All subjects who enter into the screening period for the study (defined as the point at 
which the subject or legal representative signs the informed consent) will receive a 
unique subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned by 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.   
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 will be randomized in a 1:1:1:1 manner to receive either 25 mg BID omecamtiv 
mecarbil dose (n=20), 37.5 mg BID omecamtiv mecarbil dose (n=20), 50 mg BID 
omecamtiv mecarbil dose (n=20) or placebo (n=20) on an outpatient basis.  Subjects 
randomized to 37.5 mg BID target dose and 50 mg BID target dose will initiate 
administration at 25 mg BID and will be up-titrated to the 37.5 mg BID or 50 mg BID 
target dose at the week 4 visit based on steady state Cpredose result from week 2.  


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Subjects who do not have a week 2 PK value in time for dose adjustment at the week 
4 visit will be up-titrated at week 8 based on steady state Cpredose result from week 2, if 
available.  Subjects will be up-titrated at the week 4 or week 8 visit only if the week 2 
Cpredose is < 200 ng/mL.  Subjects with a week 2 Cpredose ≥ 200 ng/mL (or not available at 
week 8) will continue at 25 mg BID for the remainder of the study.  Subjects randomized 
to placebo or to 25 mg BID will receive the assigned IP throughout the study.  To 
maintain blinding, all subjects will receive new IP supply at week 4 and week 8 visits.  
There is no other dose adjustment for individual subjects during the study.  
Assignment to the treatment arms will be based on a computer-generated randomization 
schedule prepared by Amgen before the start of the study.  A subject may only receive 
one randomization number and each randomization number will only be assigned to 
1 subject. 
Once eligibility into the study has been confirmed, a site representative will make the 
randomization call to the IVRS/IWRS to assign a randomization number to the subject.  
The randomization call to the IVRS/IWRS is accomplished by entering the pertinent 
information detailed in the IVRS/IWRS user manual.  A confirmation will be sent to the 
site to verify that the correct information has been entered and to confirm the 
randomization assigned.  A subject will be considered enrolled and randomized into the 
study when a randomization number is assigned. 
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 a 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 appropriate Amgen study contact 
representative before unblinding any subject’s treatment assignment, but must do so 
within 1 working day after the event.   
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product and/or placebo (IP) used in this study includes: 
omecamtiv mecarbil and placebo.  No investigational medical devices are used in this 
study. 


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The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, destruction, and 
administration of omecamtiv mecarbil and placebo.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product (Omecamtiv Mecarbil) 
Omecamtiv mecarbil will be manufactured and packaged by Amgen Inc. and distributed 
using Amgen clinical study drug distribution procedures.  Omecamtiv mecarbil will be 
presented as tablets in individually labeled 35ct bottles.  Each bottle will have an unique 
bottle number. 
Further details regarding IP storage condition, dispensation, packaging, labeling, 
accounting procedures, and destruction are outlined in the IPIM. 
Placebo will be presented in identical containers and stored/packaged the same as 
omecamtiv mecarbil. 
6.2.1.1 
Dosage, Administration, and Schedule 
Eligible outpatient subjects will be randomized and will initiate administration of IP 
(omecamtiv mecarbil or placebo).  Day 1 is defined as the calendar day when treatment 
with IP is initiated.  The first administration of IP should be on the day of randomization 
but not later than 5 calendar days after randomization.  The time when ingestion of the 
first dose of IP is completed is defined as Time = 0 hours.  Baseline procedures must be 
completed before initiation of IP and can be performed on the same day. 
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) and taken 
with water as instructed in the IPIM.  Administration of each morning and evening dose 
is to be taken at approximately the same time of day (12 ± 3 hours from the most recent 
previous dose).  If IP cannot be taken or has not been taken within this window, the dose 
should be recorded as missed and the next dose should be taken at the regular time.  
Administration of IP will start with the morning dose on day 1 and will end with the 
morning dose on the day of the subject’s week 16 visit.  The quantity, date and time, lot 
number, and bottle number of investigational product is to be recorded on each subject’s 
eCRF. 


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6.2.1.2 
Rules for Withholding Investigational Product due to Myocardial 
Ischemia or Infarction, Abnormal Blood Pressure or Heart Rate  
Omecamtiv mecarbil may result in signs and symptoms of myocardial ischemia or 
infarction, as described in Section 7.1 of the Investigator’s Brochure (eg, increases in 
HR, dizziness, dyspnea, hypotension, chest discomfort or pain, ST-segment depression 
on ECG, and/or elevations in troponin I or T).  If a subject reports clinical signs or 
symptoms suggestive of myocardial ischemia or infarction, and/or experiences changes 
in BP or HR, withholding of IP should be considered.  No antidote to omecamtiv mecarbil 
exists.  Standard medical therapies should be used in the presence of signs or 
symptoms of myocardial ischemia.   
The following are mandatory rules for withholding IP:   
• 
The subject experiences clinical signs or symptoms, including ECG changes, 
consistent with myocardial ischemia or infarction as determined by the 
investigator 
• 
The subject experiences a symptomatic decrease in systolic BP on 2 successive 
measurements 
• 
The subject experiences an asymptomatic decrease in systolic BP to < 80 mmHg 
(measured at 3 successive timepoints over approximately 15 minutes) 
• 
The subject experiences symptoms associated with a HR > 120 bpm, systolic BP 
> 170 mm Hg, or diastolic BP > 110 mm Hg that are determined by the 
investigator to warrant termination of the dosing 
• 
The subject experiences sustained systolic BP > 170 mm Hg (measured at 
3 successive timepoints over approximately 15 minutes) 
• 
The subject experiences a sustained diastolic BP > 110 mm Hg (measured at 
3 successive timepoints over approximately 15 minutes)  
• 
The subject experiences a sustained HR > 120 bpm (measured at 3 successive 
timepoints over approximately 15 minutes)  
• 
The subject experiences a sustained (measured at 3 successive timepoints over 
at least 15 minutes) HR increase ≥ 25 bpm from screening or baseline AND 
HR > 100 bpm 
If suspected adverse drug reactions or changes in vital signs, ECGs, or clinical 
laboratory results are observed during the study and, in the opinion of either the 
investigator or the Study Medical Monitor, these changes pose a significant health risk, 
dosing of an individual subject should be stopped and not resumed. 
If administration of IP is stopped (up to 5 days after last IP) for any of the reasons above, 
a blood sample of 5 mL for PK analysis is to be collected as soon as possible  . 
If a subject experiences clinical signs or symptoms consistent with myocardial ischemia 
or infarction, the subject should receive immediate medical attention according to the 


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institution’s usual standard of care.  Serial cardiac troponin samples (troponin I or T) 
should be analyzed at the local laboratory.  In addition, central laboratory analysis of 
serial samples for cardiac troponin I and/or creatine kinase MB fraction (CK-MB) as well 
as serial 12-lead ECGs should be collected.  The investigator must notify Amgen 
immediately of any subject experiencing clinical signs or symptoms of myocardial 
ischemia or infarction. 
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 omecamtiv mecarbil should be permanently discontinued. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules  
Subjects with abnormal hepatic laboratory values during the study (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 investigational product or other protocol-required 
therapies as specified in the Guidance for Industry Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation, U.S. Department of Health and Human 
Services Food and Drug Administration, July 2009. 
6.3.1 
Criteria for Permanent Discontinuation of Omecamtiv Mecarbil due 
to Potential Hepatotoxicity 
Omecamtiv mecarbil 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:  
• 
TBL > 2x 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 
immediately 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) 
− 
Right sided HF, hypotension or any cause of hypoxia to the liver causing 
ischemia.   


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− 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms   
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− 
Alpha-one antitrypsin deficiency 
− 
Alcoholic hepatitis 
− 
Autoimmune hepatitis  
− 
Wilson’s disease and hemochromatosis 
− 
Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH)  
− 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, the investigator should determine (based on 
patient population and/or severity of the hepatotoxicity or event) if Amgen investigational 
product and other protocol-required therapies should be withheld or permanently 
discontinued, as deemed appropriate for the safety of the subject, and Amgen medical 
monitor should be contacted immediately.  
6.3.2 
Criteria for Conditional Withholding of Omecamtiv Mecarbil due to 
Potential Hepatotoxicity 
For subjects who do not meet the criteria for permanent withholding of IP outlined above, 
omecamtiv mecarbil should be withheld if ANY of the following criteria are met, and the 
subject should be evaluated for DILI:  
• 
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 
Omecamtiv mecarbil should be withheld pending investigation into alternative causes of 
DILI.  If investigational product(s) is withheld, the subject is to be followed according to 
recommendations in Appendix A for possible DILI.  Rechallenge may be considered if an 


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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).   
6.3.3 
Criteria for Rechallenge of Omecamtiv Mecarbil After Potential 
Hepatotoxicity 
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 omecamtiv mecarbil should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.3.1) should 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 except for those 
listed in Section 6.6.  All appropriate concomitant medications taken by a subject while 
on study are to be recorded. 
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 
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 investigational product.  Any product 
complaint(s) associated with an investigational product(s) or non-investigational 
product(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  
Other investigational procedures while participating in this study are prohibited.  
Medications or foods that are known potent inducers or inhibitors of CYP3A4 
(see Section 4.1.2 and Appendix D)are prohibited up to the EOS visit, occurring on 
week 20.   
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 


 
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Table 2.  Schedule of Assessments 
Timepoint - Day/Week/Month (window)* 
Screen 
D1 
D7 
W2 
D15 (-3) 
W4 
D28 (+3) 
D34 
(+3) 
W8 
D56 (±3) 
D62 
(+3) 
W12 
D84 (±3) 
W16 
D112 
(±3) 
W20a 
D140(+3) 
EOS 
General Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs (HR, BP) 
X 
Xc 
 
X 
X 
 
Xj 
 
X 
Xk 
X 
AEs/SAEs/PEPsb 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
AEs/SAEs and IP compliance verification by 
phone or other contact 
 
 
X 
 
 
X 
 
X 
 
 
 
Concomitant therapy 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Body height 
 
X 
 
 
 
 
 
 
 
 
 
Body weight 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
ECG 
X 
Xc 
 
X 
X 
 
Xd 
 
X 
Xd 
X 
Echocardiogram 
X 
 
 
 
 
 
Xj 
 
 
Xk 
 
Central Laboratory 
 
 
 
 
 
 
 
 
 
 
 
PK samplese 
 
Xc 
 
Xc 
Xc 
 
Xj 
 
Xc 
Xk 
 
Chemistry (including eGFR at screening) 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Hematology 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Urinalysis 
 
X 
 
 
 
 
X 
 
 
 
X 
Troponin I, CK-MB e 
 
Xc 
 
X 
X 
 
X 
 
X 
X 
X 
NT-proBNP 
 
Xc 
 
 
X 
 
X 
 
 
X 
 
Samples for Development Therapeutic 
Monitoring Assay  
 
 
 
 
X 
 
 
 
X 
 
 
Serum pregnancy, FSH/LH or estradiolf 
X 
 
 
 
 
 
 
 
 
 
X 
Digoxin sample (in subjects receiving 
digoxin) 
 
X 
 
X 
 
 
 
 
 
 
 
Investigational Productg 
 
 
 
 
 
 
 
 
 
 
 
IP dispensation and/or administration at site 
 
X 
 
X 
X 
 
X 
 
X 
Xh 
 
IP diary dispensation or collectioni 
 
X 
 
 
 
 
 
 
 
X 
 
IP reconciliation  (tablet count) 
 
 
 
X 
X 
 
X 
 
X 
X 
 
Footnotes displayed on the next page of the Table 


 
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AE = adverse event; BP = blood pressure; CK-MB = creatine kinase-MB; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; 
HR = heart rate; IP = investigational product; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; PEP = potential endpoint; 
PK = pharmacokinetic; SAE = serious adverse event.   
Please note: vital signs, ECGs, and laboratory samples can be collected at any time during the study visit, unless otherwise specified below. 
Visit Windows: For week 2 visit, the visit date could be 3 days prior to the scheduled date of W2; for week 4 visit, the visit date could be 3 days after the scheduled date 
of W4; for weeks 8, 12, and 16, the visit dates could be 3 days prior to or after the scheduled date of W8, W12, and W16, respectively; for week 20 visit (EOS), the 
visit date could be up to 3 days after the scheduled date of W20.  The Day 34 and 62 telephone calls could be 3 days after the scheduled date of contact. 
a If early discontinuation, week 20 (EOS) assessments should be performed as close as possible to time of discontinuation 
b Serious adverse events are collected from signing the informed consent until 30 days after the last dose of IP or EOS, whichever is later, adverse events and PEPs 
from randomization until EOS, recording of PEPs and hospitalization only during visits to the study site (day 1, weeks 2, 4, 8, 12, 16, 20 [EOS]); if subject is not seen 
at the study site, AEs/SAEs/PEPs can be collected by phone  
c Predose in the morning, at study site 
d Performed as close as possible after the collection of PK sample at 2 hours ± 30 minutes following IP administration.  
e If cardiac troponin is measured locally to evaluate suspected myocardial ischemia or infarction, send samples for troponin I/CK-MB, and PK (up to 5 days after last 
dose of IP) to the central laboratory 
f Serum pregnancy testing in females of childbearing potential, FSH/LH or estradiol at screening only, and only if applicable per exclusion criteria. 
g IP is taken twice daily except on the last day of administration (week 16 visit).  Subjects randomized to 37.5 mg BID target dose and 50 mg BID target dose will 
initiate administration at 25 mg BID.  Subjects will be up-titrated to 37.5 mg BID or 50 mg BID target dose at the week 4 visit based on steady state Cpredose result from 
week 2.  Subjects who do not have a week 2 PK value in time for dose adjustment at the week 4 visit, will be up-titrated at week 8 based on steady state Cpredose 
result from week 2, if available.  Subjects will be up-titrated at the week 4 or week 8 visits only if the week 2 Cpredose is < 200 ng/mL.  Otherwise, they will continue at 
25 mg BID.  
h Details of IP dispensation and reconciliation are described in the IPIM; dispensation and reconciliation timepoints may differ from the timepoints shown above; IP not 
dispensed at week 16 visit.  
i  Paper Diary  will be dispensed  at Day 1 and will be collected at week 16.  Subjects will be instructed to enter each administration of IP from Day 1 to week 16 or early 
termination.  The date and time of administration will be noted. 
j  Vital signs and PK samples at predose, at 2 hours ±30 minutes; 4 hours ±30 minutes; 6 hours ±30 minutes; 8 hours ±30 minutes after IP administration in the morning  
(0 h = start of IP); echocardiogram performed as close as possible after the collection of PK sample at 2 hours ±30 minutes following IP administration. 
k Vital signs and PK samples at predose and at 2 hours ± 30 mins following IP administration.  Echocardiogram should be performed as close as possible after the 
collection of PK sample at 2 hours ± 30 minutes following IP administration.. 
 


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7.2 
General Study Procedures  
7.2.1 
Informed Consent 
All subjects or their legally authorized representative must personally sign and date the 
IRB/IEC approved informed consent before any study specific procedures are 
performed.  See Section 11.1 for further details. 
7.2.2 
Medical History 
The subject’s relevant medical and surgical history will be obtained prior to enrollment 
and recorded in the eCRF.  
7.2.3 
Concomitant Therapy 
Prior therapies that were being taken within 30 days prior to screening through the 
completion of the study should be reported on the eCRF.  The therapy name, indication, 
dose, frequency, route, and start date and stop date should be recorded in the eCRF. 
7.2.4 
Vital Signs 
The following measurements must be performed: systolic/diastolic BP and HR.  Subjects 
should be in a seated or semi-recumbent position for at least 5 minutes before taking 
vital sign measurements.  The position selected for a subject should be the same that is 
used throughout the study and documented on the vital sign eCRF.  Any abnormal 
measurements may be repeated and reported on the eCRF.  All values must be 
verifiable on the source documents. 
7.2.5 
Investigational Product Administration Diary 
Subjects will be supplied with a diary during the Day 1 visit in which to record the date 
and time of each administration of IP taken away from the site.  Study site staff will 
review the diary with the subject at each clinic visit for compliance with IP dosing.  The 
study site staff will make a copy of the diary at each visit and  transcribe the date and 
time of each morning and evening dose of IP taken, as directed by the Electronic Case 
Report Form Completion and Query Resolution Guide.  The diary will be retained at the 
study site as part of the source documentation once the subject has completed his/her 
study participation. 
7.2.6 
Adverse Events 
Refer to Section 9 for information on the definitions and reporting procedures for adverse 
events and serious adverse events. 


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7.2.7 
Potential Endpoints 
Deaths, hospitalizations and selected nonfatal cardiovascular events will be reported on 
an ongoing basis to Amgen or designee, as potential endpoints (PEPs).  An independent 
CEC committee will adjudicate deaths, all hospitalizations, and selected nonfatal CV 
events (including possible MI or ischemia).  The adjudicated events will include, but may 
not be limited to the following: cardiovascular death, HF, acute myocardial infarction, 
myocardial ischemia, unstable angina, and resuscitated sudden death.  Only events 
occurring after subject randomization until completion of the study will be adjudicated.  
7.2.8 
Hospitalizations 
Information about all hospitalizations up to the EOS (week 20) will be collected. 
7.2.9 
Physical Examination 
The screening physical examination will be a complete physical examination including 
height and weight.  Breast, genital, and rectal examinations are not required at any study 
visit unless specific evaluation is warranted in accordance with the standard of care.  
Physical examination findings at screening are to be recorded in the medical and 
surgical eCRF.  The physical examination at the EOS visit at week 20 will consist of an 
examination to monitor for any changes from the screening physical examination.  Any 
clinically significant change from the baseline physical examination, which represents 
deterioration, is to be recorded on the Events eCRF. 
7.2.10 
Physical Measurements 
Height and weight should be measured without shoes at Day 1.  Weight only will be 
measured at weeks 2, 8, 12, 16, and at week 20 (EOS). 
7.2.11 
Electrocardiogram 
At each scheduled visit where ECGs are being obtained, three 12-lead ECGs will be 
collected consecutively approximately 30 seconds to 1 minute apart.  Using equipment 
supplied to each site, all protocol-specified ECGs will be acquired and transmitted to the 
centralized ECG services provider.  The principal investigator or designated physician 
will review acquired ECGs.  One (1) signed, original ECG tracing should be retained with 
the subject’s source documents.  At the request of the sponsor, the original ECG should 
be made available to Amgen.   
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 


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position, the subject should be in most recumbent position as possible.  The ECG must 
include the following measurements: HR, QRS, QT, QTc, and PR intervals. 
The centralized ECG services cardiologists will perform standard interpretations of all 
tracings.  A cardiologist reviewed ECG report will be provided to the study site.  
Investigators must initial and date the ECG reports upon receipt.  If the investigator’s 
interpretation of any protocol-specified or unscheduled ECG differs from that supplied by 
centralized ECG services provider, it is the responsibility of the investigator to make the 
final clinical decisions.  The investigator’s interpretation does not need to be reconciled 
with that supplied by centralized ECG services cardiologists.  Any clinical interventions 
based on these results need to be documented in the appropriate source documents 
and eCRF as applicable.  It is the responsibility of the investigator to obtain additional 
ECGs required for the clinical management of the subject, using centralized ECG 
services equipment or equipment on-site.   
Further details regarding ECG collection requirements for this study will be provided in 
an Investigator ECG Manual distributed to the sites before start of enrollment. 
7.2.12 
Laboratory Assessments 
Central laboratory assessments are to be used to assess subject eligibility (except for 
the pregnancy test, section 7.2.12.1).  All other screening or scheduled study laboratory 
assessments will also be by central laboratory.   
If cardiac biomarkers (troponin I or T) are analyzed locally to evaluate suspected 
myocardial ischemia or infarction,  additional blood samples for troponin I and/or CK-MB 
analysis by the central laboratory must be collected.  The results of the local testing will 
be maintained in the source documents at the site.  Selected local testing results may be 
entered into the eCRF as instructed by Amgen.   
The central laboratory may ship PK samples to Amgen or a specialty laboratory for 
analysis. 
The central laboratory will provide a study manual that outlines handling, labeling, and 
shipping procedures for all blood and urine samples.  The date and time of sample 
collection will be recorded in the source documents at the site. 
Table 3 below outlines the specific analytes for serum chemistry, hematology, urinalysis, 
and other testing to be conducted on blood and urine samples. 


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Table 3.  Analyte Listing 
Chemistry  
Urinalysis 
Hematology 
Other Labs 
Sodium 
Specific gravity 
Hemoglobin 
Pharmacokinetics 
Potassium 
pH 
Hematocrit 
Pregnancy testa 
Chloride 
Blood 
Mean corpuscular 
volume 
FSH/LH or 
estradiola 
Bicarbonate 
Protein 
Platelets 
NT-proBNP 
Total protein 
Glucose 
White blood cells 
Troponin I 
Albumin 
Bilirubin 
Differential 
CK-MB 
Glucose 
 
• 
Total neutrophils 
PT/INRb 
Blood urea nitrogen 
 
• 
Eosinophils 
Digoxinc 
Creatinine 
 
• 
Basophils 
 
Total creatine kinase 
 
• 
Lymphocytes 
 
TBL 
 
• 
Monocytes 
 
Direct bilirubin 
 
 
 
Alkaline phosphatase 
 
 
 
Alanine aminotransferase 
 
 
 
Aspartate aminotransferase  
 
 
Magnesium 
 
 
 
Cholesterol 
 
 
 
High-density lipoprotein 
 
 
 
Low-density lipoprotein 
 
 
 
Triglycerides 
 
 
 
CK-MB = creatine kinase-MB; FSH = follicle-stimulating hormone; LH= luteinizing hormone 
;NT-proBNP = N-terminal pro-B-type natriuretic peptide; PT/INR = prothrombin time/international normalized 
ratio; TBL=total bilirubin.. 
a A pregnancy test is required for females of childbearing potential; FSH/LH or estradiol only per exclusion 
in Section 4.1.2.  
b Performed as given in Appendix A only if DILI follow-up is needed (see Section 6.3.2)  
c Only in subjects receiving digoxin 
7.2.12.1 
Pregnancy Test 
Qualitative or quantitative human chorionic gonadotropin pregnancy testing will be 
performed locally or per central laboratory, depending on investigator preference and to 
facilitate trial operations.  Pregnancy testing is required as per Schedule of Assessments 
(Section 7.1) for all females of childbearing potential as defined in the exclusion criterion 
(Section 4.1.2). 
7.2.12.2 
Troponin 
Troponin I (also referred to as troponin in this protocol) will be measured by central 
laboratory in this study.  The central laboratory troponin samples may be batched for 


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analysis and may be assayed several weeks or months after collection.  Therefore, the 
results of the central laboratory troponin analysis will not be routinely provided to the 
investigator. 
At any time during a subject’s study participation when local troponin I or T are drawn to 
evaluate suspected myocardial ischemia or infarction, additional samples for cardiac 
troponin and/or CK-MB analysis by the central laboratory must be collected.  A sample 
for PK analysis should be collected as well unless it has been more than 5 days since 
the last administration of IP.   
The cardiac troponin assay selected for Study 20120227 is the Siemens ADVIA Centaur 
Ultra Troponin I, an assay designated as “guideline acceptable” per the European 
Society of Cardiology/American College of Cardiology Foundation/American Heart 
Association/World Heart Federation (ESC/ACCF/AHA/WHF) Expert Consensus 
Document on the Universal Definition of Myocardial Infarction (Apple FS, 2009; 
Thygesen et al, 2012). 
7.2.12.3 
Pharmacokinetics of Omecamtiv Mecarbil 
Blood samples for measurement of omecamtiv mecarbil will be drawn before and after 
administration of investigational product at the timepoints shown in the Schedule of 
Assessments (Section 7.1).  Approximately 5 mL of blood will be collected at each time 
point. 
In addition to the PK samples listed in the Schedule of Assessment, Section 7.1, at any 
time during a subject’s study participation when local troponin I or T are drawn to 
evaluate suspected myocardial ischemia or infarction, additional blood samples for 
cardiac troponin I and/or CK-MB analysis by the central laboratory and, if within 5 days 
of the last dose of IP, a sample for PK analysis must be collected. 
Samples will be processed and frozen per the central laboratory manual.  The site will be 
expected to complete a shipping log or requisition that will include subject identification 
information and the time and date of collection for each sample shipped.  Missing 
samples must be clearly documented on the shipping log or requisition.  Please refer to 
the central laboratory manual for instructions on sample collection, processing, and 
shipping of PK samples. 
Omecamtiv mecarbil will not be measured in screening samples and samples from 
subjects not receiving active investigational treatment (omecamtiv mecarbil). 


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7.2.12.4 
Digoxin 
Blood samples for measurement of digoxin levels (only in subjects taking digoxin) will be 
drawn on Day 1 and week 2 visits as shown in the Schedule of Assessments 
(Section 7.1).  Date, time, and dose of digoxin taken within 3 days prior to the blood 
sampling collection and the date and time of blood sampling must be recorded in the 
Laboratory Requisition Form.  Approximately 2.5 mL of blood will be collected at each 
time point. 
7.2.12.5 
Omecamtiv Mecarbil Therapeutic Monitoring Assay 
Blood samples of 5 mL each will be collected from all subjects at the time points outlined 
in Table 2 to validate the omecamtiv mecarbil drug monitoring (TDM) assay.  The 
omecamtiv mecarbil TDM assay is a fast-turn-around assay intended to aid omecamtiv 
mecarbil dose titration in subjects receiving treatment.   
7.2.12.6 
Pharmacogenomic Studies 
If the subject consents to the optional pharmacogenomic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenomic 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 HF and/or to identify 
subjects who may have positive or negative response to omecamtiv mecarbil.  No 
additional samples will be collected for this part of the study.  For subjects who consent 
to these analyses, DNA may be extracted from samples already collected.   
7.2.13 
Echocardiograms 
Assessments for subjects enrolled into the study includes echocardiograms at the 
timepoints detailed in the Schedule of Assessments (Section 7.1).  Where possible, staff 
involved in the treatment and evaluation of the study subject should not view study 
echocardiograms.  Further, the sonographer should abstain from commenting on any 
observations in the echocardiograms that may be potentially unblinding.  The 
echocardiograms will be sent to the central echocardiography laboratory for analysis.  
Please refer to the echocardiography instruction manual for detailed information on 
acquiring, storing, and transmitting the echocardiograms. 


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7.3 
Screening and Enrollment 
7.3.1 
Screening 
The following procedures are to be completed during the screening period as outlined in 
the Schedule of Assessments (Table 2):  
• 
Written Informed Consent (to be completed prior to any screening procedures) 
• 
Demographic data including sex, age at time of enrollment, race, and ethnicity will be 
collected in order to study their possible association with subject safety and 
treatment effectiveness.  Additionally demographic data will be used to study the 
impact of biomarker variability and pharmacokinetics of the protocol-required 
therapies. 
• 
Vital signs (HR, BP) 
• 
Serious adverse event assessment (from signing of informed consent) 
• 
Concomitant therapy 
• 
Physical examination as per standard of care  
• 
Medical/surgical history 
• 
ECG (centrally read) 
• 
Blood samples for chemistry, hematology, and, for women of childbearing potential, 
serum pregnancy testing, and, if necessary to determine childbearing potential, FSH 
and LH, or estradiol by central laboratory (note that eGFR will be calculated by the 
central laboratory and provided to the investigator for eligibility) 
• 
Echocardiogram (centrally read) 
If eligibility is confirmed, subjects should be randomized within 30 days of signing the 
informed consent form.   
7.3.2 
Rescreening 
Subjects who in the opinion of the investigator, require major medication changes 
(eg, uptitration of BP medications, uptitration of diabetes medications) can be put on the 
new medication schedule and rescreened after at least 4 weeks.  Subjects who screen 
fail due to a transient laboratory abnormality can be considered for rescreening at least 
4 weeks after prior screen fail.  Rescreening requires signing of a new informed consent.  
Rescreened subjects who are reconsented will repeat all screening procedures.  
Rescreened subjects will maintain the originally assigned subject identification number.  
Subjects who fail any of the eligibility criteria during screening or rescreening need to be 
recorded as screen failed in IVRS/IWRS before they can be reconsented and 
reregistered in IVRS/IWRS for rescreening.  Please note that the clinical trial agreement 
may limit the number of paid rescreens. 


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7.4 
Treatment Period 
Adverse events, serious adverse events , PEPs, and concomitant medications, will be 
reported until EOS at week 20.  If a subject is not seen at the study site, adverse 
events/serious adverse events/PEPs should be collected by phone.  For details on 
reporting of adverse events and serious adverse events, please refer to Section 9. 
The following procedures will be completed during the study at the times designated in 
the Schedule of Assessments (Table 2). 
• 
Vital signs (HR, BP) 
• 
Adverse events/serious adverse events/PEPs, if applicable 
• 
Concomitant therapy 
• 
Body height, at Day 1 visit only 
• 
Body weight, at Day 1, weeks 2, 8, 12, and 16  
• 
ECG (centrally read), at Day 1, weeks 2, 8, 12, and 16 
• 
Echocardiogram, at weeks 8  and 16 (centrally read) 
• 
Blood samples for chemistry and hematology, at weeks 2, 8,12, and 16 
• 
Blood samples for digoxin levels (only in subjects taking digoxin), at Day 1 and 
week 2 
• 
PK sample collection, at Day 1, weeks 2, 4, 8, 12, and 16  
• 
Urine sample for urinalysis, at Day 1 and week 8 
• 
Blood samples for troponin I, CK-MB, at Day 1 and weeks 2, 8, 12, and 16 
• 
NT-proBNP, at Day 1, and weeks 4, 8, and 16 
• 
Therapeutic Monitoring Assay sample collection at weeks 4 and 12 
• 
IP dosing on site, at Day 1, weeks 2, 4, 8, 12, and 16 
• 
IP dispensation, at Day 1, week 4 and week 8 
• 
IP reconciliation (tablet count) at weeks 2, 4, 8, 12, and 16 
• 
Diary dispensation, Day 1 
• 
Return diary, week 16 
7.4.1 
Telephone Contact Days 7, 34, and 62 
• 
AEs/SAEs and IP compliance will be verified by phone or other contact 
7.5 
Safety Follow-up Visit/End of Study Visit 
The following procedures will be completed at the week 20 EOS visit as designated in 
the Schedule of Assessments (Table 2).   
• 
Vital signs 
• 
Adverse events/serious adverse events/PEPs, if applicable 


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• 
Concomitant therapy 
• 
Physical examination 
• 
Body weight 
• 
ECG (centrally read) 
• 
Blood samples for chemistry and hematology 
• 
Blood samples for cardiac troponin I, CK-MB 
• 
Urine sample for urinalysis  
• 
Serum pregnancy 
7.6 
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 
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 or 
other cardiovascular conditions, the dose response and/or prediction of response to 
omecamtiv mecarbil, and characterize aspects of the molecule (eg, mechanism of 
action/target).  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, in accordance with applicable law and subject informed consent.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results 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 
samples and any other components from the cells can be located and destroyed.  


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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, 
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) and collection of data, including endpoints and adverse 
events.  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 a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  At a minimum, if possible, 
the procedures listed under the final study visit should be performed.  


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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(s) and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with 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, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, protocol-specified 
criteria [see TREATMENT PROCEDURES], pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
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 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of 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 


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(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.   
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.   
9.1.2 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
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 
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 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.2 
Reporting of Adverse Events 
9.2.1 
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 the Safety 


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Follow-up Visit/End of Study (EOS) are reported using the applicable case report form 
(eg, Event eCRF), including events that are reported to the CEC for adjudication. 
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 investigational product 
• 
Action taken 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) grading scale.  The grading scale used in this study is 
described in Appendix A.  If the severity of an adverse event changes from the date of 
onset to the date of resolution, record a single event for each level of severity on the 
Event eCRF. 
The investigator must assess whether the adverse event is possibly related to IP 
(omecamtiv mecarbil or placebo).  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 IP (omecamtiv mecarbil or placebo)”?   
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, and/or procedure (including an screening procedure(s)).  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 (eg. administration of 
investigational product, protocol-required therapies, and/or procedure?)”  
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.  


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9.2.2 
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 signing of the informed 
consent until 30 days after the last dose of IP or Safety Follow-up Visit/End of Study, 
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 applicable eCRF.   
9.2.2.1 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period defined above or after the end of the study.  
However, these serious adverse events can be reported to Amgen.  In some countries 
(eg, European Union 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 
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.  
If the first notification of a serious adverse event is reported to Amgen via the electronic 
Serious 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 IP 
(omecamtiv mecarbil or placebo).  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 IP (omecamtiv mecarbil or placebo)?” 
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 


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“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 applicable eCRF (eg, Event 
eCRF). 
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. 
In addition, the occurrence of deaths and cardiovascular events will be recorded on 
specific worksheets by the investigative study center.  Source documentation supporting 
each cardiovascular event will be provided to Amgen or designee by the investigative 
study center when the event is reported.  Each package (worksheet and supporting 
documentation) will be provided to a CEC for review and adjudication according to the 
CEC manual.  The CEC committee will provide the results of the adjudication to Amgen 
or designee. 


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9.2.2.2 
Reporting a Safety Endpoint as a Study Endpoint 
The investigator is responsible for ensuring that all serious adverse events/adverse 
events observed by the investigator or reported by the subject that occur after signing of 
the informed consent or randomization, respectively, through the Safety Follow-up 
Visit/EOS are reported using the applicable eCRF (eg, Event eCRF), including events 
that are reported to the CEC committee for adjudication. 
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 following the last dose of 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 following the last dose of 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 Endpoints 
• 
Concentrations prior to administration (Cpredose) of omecamtiv mecarbil at weeks 2, 
4, 12, and 16, and area under the curve (AUC) at week 8  
10.1.1.2 
Secondary Endpoint 
• 
Changes from baseline in SET by echocardiography at week 16  


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10.1.1.3 
Safety Endpoints 
• 
Subject incidence of adverse events  
• 
Changes from baseline in laboratory values and vital signs 
• 
Changes from baseline in ECG 
10.1.1.4 
Exploratory Endpoints 
Exploratory endpoints are as follows: 
• 
observed values and change from baseline to assessed timepoints of stroke volume, 
left ventricular end-systolic diameter (LVESD) and left ventricular end-dyastolic 
diameter (LVEDD). 
• 
observed values and change from baseline to assessed timepoints of HR 
• 
observed values and change from baseline to assessed timepoints of NT-proBNP 
• 
subject incidence of supraventricular tachycardia and ventricular tachycardia 
arrhythmias requiring treatment from initiation of IP to EOS 
• 
subject incidence of  the following clinical outcome endpoints: 
• 
cardiovascular death or HF hospitalization until EOS 
• 
all-cause death or HF hospitalization until EOS 
• 
all adjudicated events until EOS; events include, but may not be limited to: 
cardiovascular death, HF, acute myocardial infarction, myocardial ischemia, 
unstable angina, and resuscitated sudden death 
• 
new onset atrial fibrillation/flutter 
• 
all-cause death 
10.1.2 
Analysis Sets 
The PK analysis set (PKAS) includes all randomized subjects who have received at least 
one dose of omecamtiv mecarbil and have at least one evaluable omecamtiv mecarbil 
PK parameter (Cmax, Cpredose).  This analysis set will be used for analyses of all the PK 
endpoints, unless significant protocol deviations have affected the data or if key dosing 
or sampling information are missing, in which case a modified PKAS will be used. 
The full analysis set (FAS) includes all randomized subjects who have received at least 
one dose of IP (omecamtiv mecarbil or placebo).  This set will be used for all analyses of 
non-PK endpoints. 
The completers analysis set is a subset of the FAS and includes subjects who have 
completed IP administration.  The completers analysis set will be used for sensitivity 
analyses. 


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10.1.3 
Covariates and Subgroups 
The stratification factor is  presence or absence of atrial fibrillation/flutter.  Other baseline 
covariates include the following: 
• 
age (< 65, ≥ 65) 
• 
sex 
• 
LVEF 
• 
Body mass Index (BMI) 
• 
NT-proBNP 
• 
presence of coronary artery disease 
• 
HF treatment at baseline 
10.2 
Sample Size Considerations 
The primary endpoints of this study are the omecamtiv mecarbil PK parameters.  PK 
parameter’s mean will be estimated.  Assuming the SDs for Cmax and AUC are in the 
range of 40 to 90, a sample size of n= 20 subjects in each treatment group, 19 subjects 
(assuming 5% subjects out of a total n = 20 subjects per treatment arm are excluded 
from PKAS) will provide a 2-sided 95% confidence interval (CI) with half width of 18 to 
41.  The SD estimates are from the predicted steady state PK for 25 mg and 50 mg BID 
doses for Matrix F1 formulation based on simulations performed using PK data following 
single dose from study 20090727.  Table 4 below presents CI half widths given particular 
SDs in this range for 19 subjects per treatment group. 
Table 4.  PK Parameter 95% Confidence Intervals 
 
Confidence Interval Half Width 
Standard Deviation 
 
 
N=19 
40 
 
 
18.0 
50 
 
 
22.5 
60 
 
 
27.0 
70 
 
 
31.5 
80 
 
 
36.0 
90 
 
 
40.5 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Unless otherwise specified in this section, subjects, site personnel, or Amgen staff and 
their designees will not have access to unblinding information until the study is formally 


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unblinded.  Unblinded individuals, as designated in this section, are to ensure unblinding 
information and potentially unblinding data are not distributed to blinded individuals until 
the study is formally unblinded. 
Staff involved in randomized treatment assignment, IP packaging and labeling, biological 
sample management, and assaying PK samples are unblinded to the treatment 
assignments in this study, but will not have access to subject-level safety or efficacy 
data.  Staff in Amgen’s Clinical Pharmacology Modeling & Simulation who are 
responsible for PK data analysis and interpretation during the conduct of this study will 
not have knowledge of subject IDs; samples are labeled by an alias before analysis.  
The external independent biostatistics group will have access to treatment assignments 
and will provide unblinded results, including aggregate and subject-level data, to the 
DMC for data reviews. 
10.4 
Planned Analyses 
10.4.1 
Data Monitoring Committee (DMC) 
An external independent DMC will formally review the accumulating data from Amgen’s 
ongoing omecamtiv mecarbil studies to facilitate detection of any increased risk for harm 
to subjects (eg, unexpected PK concentration due to PK variability).  The DMC will 
review unblinded data approximately every month while subjects are receiving IP.  
Based on the totality of evidence, the DMC will make an overall recommendation to the 
sponsor whether to continue the study according to the protocol or whether to make any 
changes (eg, including, but not limited to, dose change or stopping enrollment).  To 
protect the status of the blind and to minimize potential operational bias, analyses for the 
DMC will be provided by the independent biostatistics group which is external to Amgen 
and supported by designated Amgen staff (eg, Clinical Pharmacology Lead in 
Section 10.3), if needed.  Details will be provided in the DMC charter. 
10.4.2 
Primary Analysis 
To evaluate the PK, PD, safety, tolerability of omecamtiv mecarbil in Japanese subjects 
with HF with reduced ejection fraction, the primary analysis will be conducted when all 
the enrolled subjects in the study either complete the EOS visit (week 20) or terminate 
the study early.  At that time, the database will be cleaned, processed and a snapshot 
will be taken.  At this stage, the study will be unblinded to conduct the primary analysis.  
The primary analysis will include estimation for all endpoints.  No formal hypotheses will 
be tested in this study and all statistical approaches are hypothesis-generating.   


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10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Statistical analyses in this study are descriptive in nature. 
Subject disposition, demographics and baseline characteristics will be summarized.   
Summary statistics for continuous variables will include number of subjects, mean, 
median, SD, or standard error, minimum, and maximum.  For PK parameters, coefficient 
of variation will also be included.  For categorical variables, frequency and percentage 
will be presented.  Subjects will be analyzed based on their randomized treatment group 
assignment.   
10.5.2 
Primary Endpoint 
The primary endpoints are the omecamtiv mecarbil PK parameters Cpredose and AUC, 
collected in the study (Section 10.1.1.1). 
In the PK analysis, all plasma concentrations below the quantifiable limits will be 
assigned the value of zero.  For any data excluded from the analyses, specific reasons 
will be provided. 
Individual omecamtiv mecarbil concentration-time data and summary statistics will be 
tabulated for omecamtiv mecarbil.  Individual, mean, and SD concentration-time data 
may be plotted.  The PKAS will contain all subjects for whom at least one PK parameter 
(Cmax, Cpredose) can be adequately estimated.  PK parameters will be calculated using 
non--compartmental methods.  Actual dosing and sampling times will be used for 
calculation of PK parameters.  Descriptive statistics will be generated for each PK 
parameter for each treatment.   
Individual PK parameters will be summarized descriptively at each scheduled 
assessment, in the primary analysis set of PKAS.   
10.5.3 
Secondary Endpoint 
Echocardiographic parameter SET and its change from baseline at week 16 will be 
summarized by treatment group and scheduled assessment.   
In addition, analysis will be performed to explore the potential relationship between 
omecamtiv mecarbil exposure and changes from baseline in SET.  Differences between 
treatment groups in SET will be estimated via repeated-measures model, with difference 
estimates and their 95% CIs presented.  The model will include the stratification factor, 


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treatment group, visit and the interaction of treatment group and visit.  Subgroup 
analyses by baseline covariates in Section 10.1.3 will be provided. 
10.5.4 
Safety Endpoints 
10.5.4.1 
Adverse Events 
The current Medical Dictionary for Regulatory Activities (MedDRA) version at the time of 
the data lock will be used to code all adverse events (AE) 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.   
10.5.4.2 
Safety Laboratory Tests 
The analyses of safety laboratory endpoints will include summary statistics at each 
scheduled assessment by cohort and treatment group.  Shifts in grades of safety 
laboratory values between baseline and the most extreme post-baseline values will be 
tabulated by cohort and treatment group. 
10.5.4.3 
Vital Signs 
The analyses of vital signs will include summary statistics at each scheduled 
assessment by cohort and treatment group. 
10.5.4.4 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.   
Subjects’ maximum change from baseline in QT Fridericia corrected 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. 
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 appropriate Amgen representative to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential subject population. 


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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 IPs 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 or 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.   
The acquisition of informed consent and the subject’s agreement or refusal of his or 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. 


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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 eCRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
• 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and 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 or 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 


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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 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 Amgen 
IP and by what mechanism, after termination of the study and before the product is 
available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he or she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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. 
eCRF entries may be considered source data if the eCRF is the site of the original 
recording (ie, there is no other written or electronic record of data).   
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 should include the following: 
• 
subject files containing completed eCRFs, informed consent forms, and subject 
identification list 
• 
study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation, and all correspondence to and from the IRB/IEC 
and Amgen 


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• 
IP-related correspondence including Proof of Receipts, Investigational Product 
Accountability Records, Return of Investigational Product for Destruction Forms, 
Final Investigational Product Reconciliation Statement, 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, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen Clinical Monitor and/or appropriate Amgen representative 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; and adherence to local 
regulations on the conduct of clinical research.  The Amgen Clinical Monitor and/or 
appropriate Amgen representative is to have access to subject medical records and 
other study-related records needed to verify the entries in the eCRFs. 
The investigator agrees to cooperate with the Amgen Clinical Monitor and/or appropriate 
Amgen representative to ensure that any problems detected in the course of these 
monitoring visits, including delays in completing eCRFs, 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 eCRFs must be maintained and 
readily available. 
• 
Updates to eCRFs 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 


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GCP.  To resolve any questions arising from the clinical data management review 
process, data queries and/or site notifications are created in the EDC system 
database for site resolution and subsequently closed by the EDC system or by an 
Amgen reviewer.  Additional queries may be sent out by the CEC and, upon 
resolution, will be closed by the CEC. 
• 
The investigator signs only the Investigator Verification Form for this EDC study.  
This signature indicates that investigator inspected or reviewed the data on the 
eCRF, the data queries, and the site notifications, and agrees with the content. 
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.   
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.   
12.5 
Language 
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, the investigator will solicit input and 
assistance from Amgen staff as appropriate. 
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 


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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, 
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; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors 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 
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.  If permitted under applicable regional laws and 
regulatory guidelines, subjects may be compensated for other inconveniences not 
associated with study-related injuries (eg, travel costs). 


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13. 
REFERENCES 
Amgen.  Omecamtiv Mecarbil Investigator's Brochure (always refer to the most current 
edition). 
Apple FS. A New Season for Cardiac Troponin Assays: It’s Time to Keep a Scorecard. 
Clin Chem. 2009;55(7):1303-1306. 
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. 
Cuffe MS, Califf MR, Adams KF, Benza R, Bourge R, et al. Short-term intravenous 
milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. 
JAMA. 2002;287(12):1541-7. 
Felker GM, Benza RL, Chandler AB, Leimberger JD, Cuffe MS, et al. Heart failure 
etiology and response to milrinone in decompensated heart failure: results from the 
OPTIME-CHF study. J Am Coll Cardiol. 2003;41(6):997-1003. 
Gheorghiade M, Böhm M, Greene S, Fonarow G, Lewis E, et al. Effect of aliskiren on 
postdischarge mortality and heart failure readmissions among patients hospitalized for 
heart failure: the ASTRONAUT randomized trial. JAMA. 2013;309(11):1125-35. Erratum 
in: JAMA. 2013;309(14)1461. 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009.  http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 
Hamaguchi S, Yokoshiki H, Kinugawa S, et al. Effects of atrial fibrillation on long-term 
outcomes in patients hospitalized for heart failure in Japan: a report from the Japanese 
Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J. 
2009:73(11):2084-2090. 
Hasenfuss G, Teerlink JR. Cardiac inotropes: current agents and future directions. Eur 
Heart J. 2011;32:1838-1845. 
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. 
International Committee of Medical Journal Editors, Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals.  2014. 
http://www.icmje.org/ 
Japan Statistics Bureau Ministry of Internal Affairs. Population Census. 2005. Available 
at:shttp://www.stat.go.jp/english/data/kokusei/2005/poj/mokuji.htm. Accessed August 14, 
2014. 
Konstam M, Gheorghiade M, Burnett J, Grinfeld L, Maggioni A, Swedberg K, et al. 
Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the 
EVEREST Outcome Trial. JAMA. 2007;297(12):1319-31. 
Krum H and Teerlink JR. Medical therapy for chronic heart failure. Lancet. 
2011;378(9792):713-21. 
Malik FI, Hartman JJ, Elias KA, et al.  Cardiac myosin activation: a potential therapeutic 
approach for systolic heart failure.  Science.  2011;331:1439-1443. 
Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the 
prevention of heart-failure events. NEJM. 2009;361:1329-1338. 


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Protocol Number:  20120227 
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Okamoto H, Kitabatake A. The epidemiology of heart failure in Japan. Nippon Rinsho. 
2003;61: 709-714. 
Okura Y, Ramadan M, Ohno Y, Mitsuma W, Tanaka K, Ito M, et al. Impending epidemic: 
future projection of heart failure in Japan to the year 2055. Circ J. 2008;72:489–491. 
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. 
Shiba N, Watanabe J, Shinozaki T, et al. Analysis of chronic heart failure registry in the 
Tohoku District – third year follow-up. Circ J. 2004;68:427-434. 
Teerlink JR.  A novel approach to improve cardiac performance: cardiac myosin 
activators.  Heart Fail Rev.  2009;14:289-298. 
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. 
Thygesen K, Alpert JS, Jaffe AS, et al.  Expert Consensus Document on the Universal 
Definition of Myocardial Infarction. Circulation 2012; 126:00-00. 
Tsutsui H, Tsuchihashi-Makaya M, Kinugawa S, et al. for the JCARE-GENERAL 
Investigators. Characteristics and outcomes of patients with heart failure in general 
practices and hospitals: Japanese Cardiac Registry of Heart Failure in General Practice 
(JCARE-GENERAL). Circ J. 2007;71:449-454. 


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.  As of the protocol date, the CTCAE is available 
at the following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Potential Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in 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 appropriate eCRF (eg, Event eCRF) 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. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
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 investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 


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• 
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:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Obtain viral serologies 
− 
Obtain creatine phosphokinase, haptoglobin lactate dehydrogenase, and 
peripheral blood smear 
− 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic 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 investigational 
product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding eCRFs. 


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Appendix B.  Sample Serious Adverse Event Report Form 
Sample eSAE Contingency Report Form 
 


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Protocol Number:  20120227 
Date:  23 October 2015 
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Date:  23 October 2015 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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Date:  23 October 2015 
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Appendix D.  Excluded Medications and Foods 
CYP3A4 Inducers 
CYP3A4 Inhibitors 
Carbamazipine 
Amprenavir 
Dexamethasone 
Cobicistat 
Efavirenz 
Cyclosporine 
Etravirine 
Clarithromycin 
Nevirapine 
Delaviridine 
Phenobarbital 
Erythromycin 
Phenytoin 
Grapefruit juice 
Rifabutin 
Indinavir 
Rifampicin 
Itraconazole 
St. John’s wort 
Nelfinavir 
 
Ritonavir 
 
Saquinivir 
 
Telaprevir 
 
Verapamil 
 
Voriconazole 
 

SAP_001.pdf: 
Product:  Omecamtiv Mecarbil (AMG 423) 
Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
Page 1 
STATISTICAL ANALYSIS PLAN 
A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate 
the Safety, Pharmacokinetics, and Efficacy of Omecamtiv Mecarbil in Japanese 
Subjects With Heart Failure With Reduced Ejection Fraction 
Protocol Number: 
20120227 
Version: 
1.0 
Date: 
29 February 2016 
Authors: 
PPD
NCT Number: 02695420
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov


Product:  Omecamtiv Mecarbil (AMG 423) 
Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
Page 2 
 
Table of Contents 
Table of Abbreviations ...................................................................................................... 4 
1. 
Introduction .............................................................................................................. 7 
2. 
Objectives ................................................................................................................ 7 
2.1 
Primary ......................................................................................................... 7 
2.2 
Secondary .................................................................................................... 7 
3. 
Study Overview ........................................................................................................ 7 
3.1 
Study Design ................................................................................................ 7 
3.2 
Sample Size ................................................................................................. 8 
4. 
Study Endpoints and Covariates .............................................................................. 9 
4.1 
Study Endpoints ........................................................................................... 9 
4.1.1 
Primary Endpoints ........................................................................ 9 
4.1.2 
Secondary Endpoint ..................................................................... 9 
4.1.3 
Safety Endpoints .......................................................................... 9 
4.1.4 
Exploratory Endpoints .................................................................. 9 
4.2 
Planned Covariates .................................................................................... 10 
5. 
Hypotheses and/or Estimations .............................................................................. 10 
6. 
Definitions .............................................................................................................. 10 
6.1 
Study Time Points ...................................................................................... 10 
6.2 
Demographics and Baseline Related Definitions ....................................... 11 
6.3 
PK Related Definitions ................................................................................ 12 
6.4 
Other Study Related Definitions ................................................................. 12 
7. 
Analysis Subsets .................................................................................................... 14 
7.1 
Pharmacokinetic Analysis Set .................................................................... 14 
7.2 
Full Analysis Set ......................................................................................... 14 
7.3 
Safety Analysis Set ..................................................................................... 14 
7.4 
Completer Analysis Set .............................................................................. 14 
7.5 
Subgroup Analyses .................................................................................... 15 
8. 
Interim Analysis and Early Stopping Guidelines ..................................................... 15 
9. 
Data Screening and Acceptance ............................................................................ 15 
9.1 
General Principles ...................................................................................... 15 
9.2 
Data Handling and Electronic Transfer of Data .......................................... 16 
9.3 
Handling of Missing and Incomplete Data .................................................. 16 
9.3.1 
Patterns of Missing Data ............................................................ 16 
9.3.2 
Handling of Incomplete Dates .................................................... 16 
9.4 
Detection of Bias ........................................................................................ 17 
9.5 
Outliers ....................................................................................................... 17 


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Date:  29 February 2016 
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9.6 
Distributional Characteristics ...................................................................... 17 
9.7 
Validation of Statistical Analyses ................................................................ 17 
10. 
Statistical Methods of Analysis ............................................................................... 18 
10.1 
General Principles ...................................................................................... 18 
10.2 
Subject Accountability ................................................................................ 18 
10.3 
Important Protocol Deviations .................................................................... 19 
10.4 
Demographic and Baseline Characteristics ................................................ 19 
10.5 
Analyses of Primary Endpoints ................................................................... 19 
10.6 
Analyses of Secondary Endpoint ................................................................ 20 
10.7 
Analyses of Exploratory Endpoints ............................................................. 20 
10.8 
Safety Analyses .......................................................................................... 21 
10.8.1 
Adverse Events .......................................................................... 21 
10.8.2 
Laboratory Test Results ............................................................. 22 
10.8.3 
Vital Signs ................................................................................... 23 
10.8.4 
Electrocardiogram (ECG) ........................................................... 23 
10.8.5 
Exposure to Investigational Product ........................................... 23 
10.8.6 
Exposure to Concomitant Medication ......................................... 24 
11. 
Changes From Protocol-specified Analyses .......................................................... 24 
12. 
Literature Citations / References ............................................................................ 25 
13. 
Data Not Covered by This Plan .............................................................................. 26 
14. 
Appendices ............................................................................................................ 27 
List of Appendices 
Appendix A.  Analytical Study Week Assignments ......................................................... 28 
Appendix B.  Treatment Emergent Adverse Event Algorithm ......................................... 29 
 


Product:  Omecamtiv Mecarbil (AMG 423) 
Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
Page 4 
 
Table of Abbreviations  
Abbreviation or Term 
Definition/Explanation 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ARB 
angiotensin receptor blocker 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC12 
area under the concentration-time curve for a 12 hour-dosing interval 
AUCt 
area under the concentration-time curve calculated by linear 
trapezoidal method 
ANCOVA 
analysis of covariance 
BID 
twice daily 
BMI 
body mass index 
BNP 
brain-type natriuretic peptide 
Bpm 
beats per minute 
C2h 
observed plasma concentration 2 hours after morning investigation 
product administration 
CAS 
completer analysis set 
CDM 
clinical data management 
CEC 
clinical events committee 
CHF 
chronic heart failure 
CI 
confidence interval 
CK-MB 
creatine kinase MB fraction 
Cmax 
maximum observed plasma concentration  
CPMS 
Clinical Pharmacology, Modeling and Simulation  
Cpredose 
plasma concentration prior to the investigational product 
administration 
CSR 
clinical study report 
CTCAE 
common terminology criteria for adverse events; common toxicity 
criteria for adverse events 
DLRM 
dose level review meeting 
DMC 
data monitoring committee 
DQR 
data quality review 
ECG 
electrocardiogram 
eCRF 
electronic case report form 


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Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
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Abbreviation or Term 
Definition/Explanation 
eGFR 
estimated glomerular filtration rate; eGFR will be calculated by the 
central laboratory and provided to the investigator 
EOI 
events of interest 
EOS  
end of study (for individual subject) 
E-R 
exposure-response 
FAS 
full analysis set 
HF 
heart failure 
HR 
heart rate 
IBG 
independent biostatistical group 
IP 
investigational product  
IPD 
important protocol deviation 
IVRS 
interactive voice response system 
LLOQ 
lower limit of quatification 
LVEDD 
left ventricular end-diastolic diameter 
LVEDV 
left ventricular end-diastolic volume 
LVEF 
left ventricular ejection fraction 
LVESD 
left ventricular end-systolic diameter 
LVESV 
left ventricular end-systolic volume 
LVFS 
left ventricular fractional shortening 
MedDRA 
medical dictionary for regulatory activities 
MI 
myocardial infarction 
MR 
modified-release 
NYHA  
New York heart association 
NT-proBNP 
n-terminal proBNP (brain natriuretic peptide) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PKAS 
pharmacokinetic analysis set 
PKS 
Pharsight Knowledgebase Server 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart’s electrical cycle as 
measured by ECG 
PT 
prothrombin time 
QRS complex 
interval between the Q wave and the S wave in the heart's electrical 
cycle as measured by ECG; represents the time it takes for the 
depolarization of the ventricles 
QT interval 
measure of the time between the start of the Q wave and the end of 
the T wave in the heart's electrical cycle as measured by ECG 
QTcB interval 
QT interval corrected for heart rate using Bazett’s formula 


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Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
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Abbreviation or Term 
Definition/Explanation 
QTcF interval 
QT interval corrected for heart rate using Fridericia's formula 
RR interval 
interval between successive Rs where R is a point corresponding to 
the peak of the QRS complex as measured by ECG 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SET 
systolic ejection time 
SV 
stroke volume 
t1/2 
terminal half-life 
tmax 
time to Cmax 
ULN 
upper limit of normal 
URL 
upper reference limit 
Also refer to the protocol for more abbreviations on clinical terms. 


Product:  Omecamtiv Mecarbil (AMG 423) 
Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
Page 7 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for AMG 423 (Omecamtiv Mecarbil) 
Study 20120227, dated 23 October 2015.  The scope of this plan includes the final 
analyses that are planned and will be executed by the Biostatistics department.  The 
pharmacokinetics (PK) analysis will be performed by Department of Clinical 
Pharmacology, Modeling and Simulation (CPMS).   
2. 
Objectives 
2.1 
Primary 
The primary objectives of this study are (i) to evaluate the pharmacokinetics (PK) of 
omecamtiv mecarbil in Japanese subjects with heart failure (HF) with reduced ejection 
fraction and (ii) to evaluate the safety and tolerability of oral omecamtiv mecarbil. 
2.2 
Secondary 
Secondary objective is: 
• 
To measure changes in systolic ejection time (SET) by echocardiography following 
16 weeks of treatment. 
3. 
Study Overview 
3.1 
Study Design 
This is a double-blind, randomized, placebo-controlled, multicenter, phase 2 study in 
Japanese HF subjects to evaluate 16 weeks of administration of oral MR omecamtiv 
mecarbil formulation at 3 dose levels (25 mg BID, 37.5 mg BID, and 50 mg BID), 
compared with placebo. Potential subjects will be screened to assess their eligibility to 
enter the study within 30 days prior to enrollment. Subjects are eligible for screening if 
they have chronic stable HF and reduced ejection fraction. Subjects may also be 
screened in the hospital setting once they have recovered and are considered clinically 
stable by the investigator. Subjects must be outpatients at the time of randomization. 
Approximately 80 Japanese subjects with chronic stable HF with reduced ejection 
fraction will be randomized 1:1:1:1 to receive omecamtiv mecarbil either 25 mg BID dose 
(n=20), 37.5 mg BID dose (n=20), 50 mg BID dose (n=20) or placebo (n=20) on an 
outpatient basis. Subjects randomized to 37.5 mg BID target dose and 50 mg BID target 
dose will initiate administration at 25 mg BID and will be up-titrated to 37.5 mg BID or 
50 mg BID respectively at the week 4 visit based on steady state concentration prior to 
investigational product (IP) administration (Cpredose) result from week 2. Subjects who do 
not have a week 2 PK value in time for dose adjustment at the week 4 visit will be 


Product:  Omecamtiv Mecarbil (AMG 423) 
Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
Page 8 
 
up-titrated at week 8 based on the steady state Cpredose result from week 2, if available.  
Subjects will be up-titrated to 37.5 mg BID or 50 mg BID at the week 4 or week 8 visits in 
the titration groups only if the week 2 Cpredose is < 200 ng/mL. Subjects with a week 2 
Cpredose ≥ 200 ng/mL (or not available at week 8) will continue at 25 mg BID for the 
remainder of the study. Subjects randomized to placebo or to 25 mg BID will receive the 
assigned IP throughout the study. IP compliance will also be monitored. PK analysis and 
dose assignment will be blinded to the study team. To maintain blinding, all subjects will 
receive new IP supply at the week 4 and week 8 visits. The study includes transthoracic 
echocardiographic assessments (screening, week 8, and week 16). Enrollment of 
subjects with atrial fibrillation/flutter at the time of screening will be limited to 
approximately 20% of planned enrollment. Randomization will be stratified by presence 
or absence of atrial fibrillation/flutter via the interactive voice response system/interactive 
Web response system (IVRS/IWRS). 
An independent DMC will perform regular formal unblinded review of the accumulating 
study data. An independent CEC will adjudicate deaths, all hospitalizations, and selected 
nonfatal cardiovascular (CV) events (including possible MI or ischemia). The end of 
study (EOS) visit will be performed 4 weeks after the last dose of IP (Week 20 +3 days). 
Vital signs, physical examinations, ECGs, Adverse Event/Serious Adverse Event 
assessments, clinical laboratory evaluations (see Table 3 in protocol), and collection of 
concomitant medications will be performed at screening and at specified times per the 
Schedule of Assessments (see Table 2 in protocol). The overall study design is 
described by a study schema at the end of the protocol synopsis section. Detailed study 
procedures are provided in Protocol Section 7. The study endpoints are defined in 
Section 4.1.  
3.2 
Sample Size 
The primary endpoints of this study are the omecamtiv mecarbil PK parameters. PK 
parameter’s mean will be estimated. Assuming the SDs for Cmax and AUC are in the 
range of 40 to 90, a sample size of n= 20 subjects in each treatment group, 19 subjects 
(assuming 5% subjects out of a total n = 20 subjects per treatment arm are excluded 
from PKAS) will provide a 2-sided 95% confidence interval (CI) with half width of 18 to 
41. The SD estimates are from the predicted steady state PK for 25 mg and 50 mg BID 
doses for Matrix F1 formulation based on simulations performed using PK data following 
single dose from study 20090727. The table below presents CI half widths given 
particular SDs in this range for 19 subjects per treatment group.  


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Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
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PK Parameter 95% Confidence Intervals 
 
Confidence Interval Half Width 
Standard Deviation 
N = 19 
40 
18.0 
50 
22.5 
60 
27.0 
70 
31.5 
80 
36.0 
90 
40.5 
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints  
4.1.1 
Primary Endpoints 
• 
Concentrations prior to administration (Cpredose) of omecamtiv mecarbil at weeks 2, 4, 
12, and 16, and area under the curve (AUC) at week 8  
4.1.2 
Secondary Endpoint  
• 
Changes from baseline in SET by echocardiography at week 16  
4.1.3 
Safety Endpoints  
Safety endpoints are as follows: 
• 
Subject incidence of adverse events (AEs) 
• 
Changes from baseline in laboratory values and vital signs 
• 
Changes from baseline in ECG  
4.1.4 
Exploratory Endpoints 
Exploratory endpoints are as follows: 
• 
observed values and change from baseline to assessed timepoints of stroke volume, 
left ventricular end-systolic diameter (LVESD) and left ventricular end-dyastolic 
diameter (LVEDD) 
• 
observed values and change from baseline to assessed timepoints of HR 
• 
observed values and change from baseline to assessed timepoints of NT-proBNP 
• 
subject incidence of supraventricular tachycardia and ventricular tachycardia 
arrhythmias requiring treatment from initiation of IP to EOS 
• 
subject incidence of the following clinical outcome endpoints: 
• 
cardiovascular death or HF hospitalization until EOS 
• 
all-cause death or HF hospitalization until EOS 


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Date:  29 February 2016 
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• 
all adjudicated events until EOS; events include, but may not be limited to:  
cardiovascular death, HF, acute myocardial infarction, myocardial ischemia, 
unstable angina, and resuscitated sudden death 
• 
new onset atrial fibrillation/flutter 
• 
all-cause death 
4.2 
Planned Covariates 
Covariates include, but are not limited to the following:  
Stratification Factor  
• 
atrial fibrillation/flutter per the interactive voice response system (IVRS stratification 
factor) (presence vs. absence) 
Baseline Covariates  
• 
age at study enrollment (< 65 vs. ≥ 65 years) 
• 
sex (male vs. female) 
• 
LVEF (< median vs. ≥ median) 
• 
body mass index (BMI) (< median vs. ≥ median) 
• 
NT-proBNP (< median vs. ≥ median) 
• 
coronary artery disease (CAD) (presence vs. absence) 
5. 
Hypotheses and/or Estimations 
No formal hypothesis testing will be performed and all statistical approaches are 
hypothesis-generating.  PK parameters following chronic dosing (BID for 16 weeks) will 
be estimated and presented along with confidence interval limits. 
6. 
Definitions 
6.1 
Study Time Points 
Randomization Date 
The randomization date for each subject is the date the investigator (or designee) 
confirms in the IVRS that the subject has met all eligibility criteria and is randomized.  
Enrollment Date 
The enrollment date is the same as the randomization date.  The enrollment date is a 
derived field on the electronic case report form (eCRF) page.  
First Dose Date of Investigational Product (IP) 
For each subject, the First Dose Date of Investigational Product is defined as the date of 
the first administration of IP as recorded on the IP administration eCRF page.  


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Statistical Analysis Plan:  20120227 
Date:  29 February 2016 
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Study Day 1 
The date of the first investigational product (IP) administration or the date of enrollment 
for subjects who were not administrated any dose of IP.  
Study Day 
For each subject and a given date of interest, study day is defined as the number of 
days since study day 1: 
Study day = (date of interest – study day 1 date) + 1. 
If the date of interest is prior to the study day 1: 
Study day = (date of interest – study day 1 date). 
Last Dose Date of Investigational Product 
For each subject, the Last Dose Date of Investigational Product is defined as the date of 
the last administration of investigational product.  
End of Study (EOS) Date 
For each subject, the end of study date is the date recorded on the End of Study eCRF. 
Study End Date 
The study end date is the last end of study date of all randomized subjects. 
6.2 
Demographics and Baseline Related Definitions 
Age 
Age will be calculated as the subject’s age in years at enrollment as recorded on the 
eCRF. 
Baseline ECG 
For ECG, the baseline value is defined as the mean over all non-missing triplicate 
averages of 3 (or all available) readings from each set of triplicate taken prior to or on 
Study Day 1.   
Other Baseline Values  
For all other variables, the baseline value is defined as the last non-missing value 
collected prior to or on Study Day 1.  


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The arithmetic difference between a post-baseline value and baseline for a given time 
point: 
Change from Baseline 
Change from baseline = (post-baseline value – baseline value).  
6.3 
PK Related Definitions  
Cmax  
Observed maximum concentration in Week 8.  
C2h  
Observed concentration at 2 hours after morning IP administration in Week 16.  
tmax  
Observed time to achieve Cmax.  
Cpredose  
Observed concentration at the end of 12-hour treatment interval.  
AUC8h  
Area under the plasma concentration-time curve estimated for 8 hours in week 8.  
Cmax/Cpredose ratio  
6.4 
Other Study Related Definitions  
Estimated with Cmax and Cpredose observed in week 8. 
Analytical windows will be used to assign parameters to study days/weeks.  The 
algorithm is provided in 
Analytical Study Week Assignments 
Appendix A.  
Actual Treatment Group 
A subject’s actual treatment group is the randomized treatment group, unless the subject 
receives the same treatment throughout the study that is different to the randomized 
treatment group assignment, in which case the actual treatment group is the treatment 
received. For subjects randomized to omecamtiv mecarbil 37.5 mg BID and 50 mg BID, 
the actual treatment groups: 25 mg (Not up-titrated to 37.5 mg), 25 mg (Up-titrated to 
37.5 mg) and 25 mg (Not up-titrated to 50 mg), 25 mg (Up-titrated to 50 mg) 
respectively, includes only those subjects who have a minimum IP exposure period of 
25 days. Titration status groups may be used in select outputs and these four actual 
treatment groups should only be compared to each other. The omecamtiv mecarbil 


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Overall 37.5 mg BID, and Overall 50 mg BID actual treatment groups include all the 
subjects included in the omecamtiv mecarbil 37.5 mg BID, and 50 mg BID randomized 
treatment groups respectively. 
Investigational Product (IP) 
IP includes Omecamtiv Mecarbil 25 mg BID, 37.5 mg BID, and 50 mg BID and Placebo 
BID.  
IP Dose Administered (mg) 
From IP administration eCRF, number of tablets administered from each box is # 
dispensed - # lost or missing - # returned.  If any of these numbers is missing, the sum 
of tablets reported on the IP administration eCRF for the same box will be used.  IP dose 
administered is the sum of all the tablets’ dose from all boxes dispensed.  
IP Compliance (%) 
Total IP dose administered divided by the total planned dose (223 tablets), multiplied by 
100.  
IP Exposure Period in Days 
(Last IP administration date in the IP administration form – date of Study Day 1) + 1. 
IP Exposure Period in Weeks 
((Last IP administration date in the IP administration form – date of Study Day 1) + 1) / 7. 
Study Exposure Period in Days 
For each randomized subject, Study Exposure Period = (EOS Date – Randomization 
Date) + 1. 
Study Exposure Period in Weeks 
For each randomized subject, Study Exposure Period = ((EOS Date – Randomization 
Date) + 1) / 7. 
Treatment-Emergent Adverse Event (TEAE) 
Treatment Emergent adverse events are adverse events occurring between the first 
dose of IP and EOS.  If an AE has an onset date after the date of first dose of IP, or the 
answer to the eCRF question “Did event start before first dose of investigational 
product?” is answered “no” then an event will be considered treatment emergent. The 
algorithm is provided in Appendix B. 


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7. 
Analysis Subsets 
7.1 
Pharmacokinetic Analysis Set 
The PK analysis set (PKAS) includes all randomized subjects who have received at least 
one dose of omecamtiv mecarbil and have at least one evaluable omecamtiv mecarbil 
PK concentration.  This analysis set will be used in analyses of all the PK endpoints. 
7.2 
Full Analysis Set 
The full analysis set (FAS) includes all randomized subjects who have received at least 
one dose of IP (omecamtiv mecarbil or placebo).  Efficacy analyses of the secondary 
and exploratory endpoints will be performed on FAS.  All subjects will be analyzed 
according to their randomized treatment assignment. 
7.3 
Safety Analysis Set 
Safety analyses will be performed on Safety Analysis Set which is defined as the same 
as the full analysis set.  For safety analyses, subjects will in general be analyzed 
according to their randomized treatment group assignment.  If a subject receives the 
same treatment throughout the study that is different from their randomized treatment 
group, then the subject will be analyzed by the actual treatment group/schema (note: 
randomized to 25 mg BID, randomized to 37.5 mg BID but received 25 mg BID, and 
randomized to 50 mg BID but received 25 mg BID will all be treated as different 
schemas due to PK levels). 
7.4 
Completer Analysis Set 
The completer analysis set (CAS) includes all subjects in FAS who complete IP 
administration.  This analysis set will be used in sensitivity analysis of the secondary 
endpoint. 


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7.5 
Subgroup Analyses 
The echocardiographic secondary endpoint will be summarized and analyzed by the 
following subgroups: 
IVRS stratification factor 
• 
presence or absence of atrial fibrillation/flutter at randomization. 
Baseline Covariates  
• 
age at study enrollment (< 65 vs. ≥ 65 years) 
• 
sex (male vs. female) 
• 
LVEF (< median vs. ≥ median) 
• 
body mass index (BMI) (< median vs. ≥ median) 
• 
NT-proBNP (< median vs. ≥ median)  
• 
Coronary artery disease (CAD) (presence vs. absence) 
8. 
Interim Analysis and Early Stopping Guidelines 
No interim analyses are planned for this study. 
An external independent DMC will formally review the accumulating data from Amgen’s 
ongoing omecamtiv mecarbil studies to facilitate detection of any increased risk for harm 
to subjects (eg, unexpected PK concentration due to PK variability). The DMC will review 
unblinded data approximately every month while subjects are receiving IP.   
Based on the totality of evidence, the DMC will make an overall recommendation to the 
sponsor whether to continue the study according to the protocol or whether to make any 
changes (eg, including, but not limited to, dose change or stopping enrollment). To 
protect the status of the blind and to minimize potential operational bias, analyses for the 
DMC will be provided by the independent biostatistics group which is external to Amgen 
and supported by designated Amgen staff (eg, Clinical Pharmacology Lead in Protocol 
Section 10.3), if needed. Details will be provided in the DMC charter.   
9. 
Data Screening and Acceptance 
9.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 


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9.2 
Data Handling and Electronic Transfer of Data  
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
An Analysis Dataset for PK Concentrations (ADPC) will be provided to the appropriate 
CPMS representative from Global Biostatistical Sciences.    
9.3 
Handling of Missing and Incomplete Data 
9.3.1 
Patterns of Missing Data 
Subjects may be missing specific data points for various reasons.  In general, data may 
be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a data point or an endpoint at a particular point in time.  All attempts 
will be made to capture missing or partial data for this trial prior to the database lock.   
The frequency and pattern of missing data for efficacy endpoints will be assessed 
through descriptive summaries of the measurements over time.   
For all time-to-event endpoints, there will be no imputation of the data, except for 
incomplete dates of the events. For all other endpoints, unless specified otherwise, 
missing data will not be imputed.   
9.3.2 
Handling of Incomplete Dates  
Adverse event and concomitant medication (collected start date data) with completely or 
partially missing start dates will be queried. After the issue is queried, if the date is still 
incomplete with year only or year and month only, the start date will be imputed as 
described in the table below. 
Imputation Rules for Incomplete Dates 
 
Missing 
Imputation 
Exception 
Start date (AE and 
concomitant edication) 
Day 
1 
Default to Study Day 1 if an event 
starts the same year and month as 
Study Day 1 
Day/Month 
1-Jan 
Default to Study Day 1 if an event 
started the same year as Day 1 


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9.4 
Detection of Bias 
This study has been designed to minimize potential bias by the use of stratified 
randomization of subjects into treatment groups and the use of blinding.  Other factors 
that may bias the results of the study include:  
• 
major protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints  
• 
subject level unblinding before final database lock and formal unblinding 
• 
DMC related analyses  
Important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints will be tabulated in the Clinical Study Report (CSR).   
Any unblinding of individual subjects prior to formal unblinding of the study will be 
documented.  The impact of such unblinding on the results observed will be assessed.    
For DMC related analyses, details of access to subject level treatment assignments are 
provided in the protocol, Section 10.3.  
Additional sensitivity analyses may be included to assess the impact of potential biases 
on the primary and secondary endpoints.  If any sensitivity analyses are required to 
evaluate potential biases in the study’s conclusions, then the sources of the potential 
biases and results of the sensitivity analyses will be documented in the CSR. 
9.5 
Outliers 
Various methods, including univariate summaries, histograms, scatter plots, box plots, 
and line graphs, may be used to identify outliers in key safety and efficacy variables. 
Extreme data points will be identified during the blinded review of the data prior to 
database lock.  Such data points will be reviewed with clinical data management to 
ensure accuracy. The primary analyses will include outliers in the data. Sensitivity 
analyses may be undertaken if extreme outliers for a variable are observed. 
9.6 
Distributional Characteristics 
Distributional assumptions for the primary and secondary endpoints will be assessed.  
Generally, no other transformations will be applied besides those specified in Section 10.  
The use of alternative methods will be fully justified in the CSR. 
9.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   


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Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.3 or 
later. 
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
The final analysis will be conducted when all subjects have either completed all the 
scheduled study visits or have early terminated from the study.  At that time, the 
database will be cleaned, processed and a snapshot will be taken; the study will also be 
unblinded.  All endpoints will be analyzed based on this snapshot. 
No formal hypothesis will be tested, and all statistical approaches are 
hypothesis-generating.  Descriptive statistics will be presented for all endpoints. 
Subject disposition, demographics, baseline characteristics and exposure to IP will be 
summarized. 
Summary statistics for continuous variables will include number of subjects, mean, 
median, SD, or standard error, lower and upper quartiles, minimum, and maximum.  For 
PK parameters, coefficient of variation (CV) will also be included.  For categorical 
variables, frequency and percentage will be presented.  Unless specified otherwise, all 
confidence intervals for estimates will be 2-sided with a significance level of 0.05. 
Subjects will be analyzed based on their randomized or received treatment group 
assignment as described in Section 7. 
Missing data handling is specified in Section 9.3. 
For the secondary endpoint SET, sensitivity analyses using the CAS will be conducted to 
explore the robustness of selected results. 
10.2 
Subject Accountability 
The number and percent of subjects who were randomized, received investigational 
product, completed investigational product, discontinued investigational product and 
reasons for discontinuing, completed study, and discontinued study and reasons for 
discontinuing will be summarized by treatment group.   
Key study dates for the first subject enrolled, last subject enrolled, last subject end of 
study, and last subject end of investigational product will be presented. 


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The number of subjects included in and excluded from each analysis set will be 
summarized.  
10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, sub-category codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 
10.4 
Demographic and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized by randomized 
treatment group and overall for all randomized subjects using descriptive statistics.  If 
multiple races have been reported for a subject, the subject will be categorized as 
multiple race.   
Demographics include: age, sex, race and region.  
Baseline disease characteristics include: 
• 
Physical measurements (height, weight, BMI) and vital signs 
• 
Medical history (HF specific and non-specific, including presence of CAD, HF 
etiology and LVEF) 
• 
HF related medication history including HF treatment at baseline 
• 
Baseline ECG HR and select electrocardiographic parameters, including SET, SV, 
LVESD and LVEDD  
• 
Baseline laboratory measurements (HF specific and non-specific, including 
NT-proBNP and troponin) 
• 
The IVRS stratification factor (presence or absence of atrial fibrillation/flutter). 
10.5 
Analyses of Primary Endpoints 
The primary endpoints are omecamtiv mecarbil PK parameters Cpredose and AUC, 
collected in the study (Section 4.1.1). 
All data for PK analyses will be extracted from a secure folder and mapped via a clinical 
connector into the Pharsight Knowledgebase Server (PKS) system (Pharsight 
Corporation, St. Louis, MO).   
Omecamtiv mecarbil plasma concentration-time data will be analyzed by 
noncompartmental methods using Phoenix WinNonlin (Pharsight Corporation, St. Louis, 
MO) and will be stored in the validated PKS system. Concentration values less than or 


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equal to the lower limit of quantification (LLOQ, 1 ng/mL) will be set to zero in the 
analysis dataset. In the PK data analysis, LLOQ value (zero) will be excluded. 
Actual doses administered and actual or nominal sampling times post drug 
administration will be used in the noncompartmental analysis. Nominal times will be 
used for presenting data in graphs and tables.  All pharmacokinetic parameters and 
summary statistics will be presented to 3 significant digits.   
Summary statistics of PK parameters will include mean, standard deviation and CV%; 
median and range; geometric mean and CV% of geometric mean. Each pharmacokinetic 
parameter will be summarized by dose level and sampling time.    
In the pharmacokinetic analysis, the following parameters will be estimated: 
• 
Observed maximum concentration (Cmax)  
• 
Observed time to achieve Cmax (tmax)  
• 
Observed concentration prior to next dose (Cpredose) 
• 
Area under the plasma concentration-time curve (AUCt) calculated by linear 
trapezoidal method 
• 
Ratio of Cmax /Cpredose  
Individual concentration-time data will be tabulated and presented graphically.  Mean 
concentration-time profiles for each dose will be provided.   
10.6 
Analyses of Secondary Endpoint   
Echocardiographic parameters and their change from baseline will be summarized by 
randomized treatment group and scheduled assessment.   
Mean differences between treatment groups in SET change from baseline at week 16 
will be estimated via repeated-measures model including all observed values, with 
difference estimates and their 95% confidence intervals presented. The model will 
include IVRS stratification factor, baseline, treatment group, visit and the interaction of 
treatment group and visit.  Individual subgroup analyses by the IVRS stratification factor 
and selected baseline covariates as listed in Section 4.2 will be provided.  Baseline 
covariates may also be included in the model one at a time in their original form.  
10.7 
Analyses of Exploratory Endpoints   
Both continuous and categorical exploratory endpoints will be summarized descriptively 
by cohort, treatment group, and scheduled assessment.   
Mean differences between treatment groups in SV, LVESD, LVEDD, and HR change 
from baseline at scheduled assessments will be estimated via repeated-measures model 


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including all observed values, with difference estimates and their 95% confidence 
intervals presented. The model will include IVRS stratification factor, baseline value, 
treatment group, visit and the interaction of treatment group and visit.   
NT-proBNP will be summarized descriptively and analyzed in the same principle as 
echocardiographic parameters.  
For clinical outcome endpoints specified in Section 4.1.4, subject incidence rates for 
each treatment group will be provided.  
For each subject, the first dose date of IP will be used as the starting point for all 
time-to-event calculation. For each qualifying event, the onset date adjudicated by CEC 
will be used as event onset date for time-to-event calculation. If not otherwise specified, 
the adjudicated events that occurred between the first dose date of IP and the end of 
study date will be included in the analyses of the time-to-event clinical outcome 
endpoints. Subjects who did not experience a qualifying event will be right censored at 
the end of study.   
Supraventricular tachycardia and ventricular tachycardia arrhythmias will be identified 
from the corresponding eCRF forms.  Subject incidence of supraventricular tachycardia 
and ventricular tachycardia arrhythmias requiring treatment from initiation of IP to end of 
study will be summarized for each treatment group.   
10.8 
Safety Analyses  
Adverse events that occur after a subjects’s EOS date will be excluded.  
10.8.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA), using the current version at 
the time of final database lock, will be used to code all adverse events (AEs) to a system 
organ class and a preferred term.  All adverse event tables will be summarized by actual 
treatment group.  Treatment-emergent adverse events are events with an onset after the 
administration of the first dose of investigational product through the end of study as 
defined in Section 6.3. 
The subject incidence of AEs will be summarized for all treatment-emergent AEs 
(TEAEs), serious AEs, AEs leading to withdrawal of investigational product, fatal AEs, 
and AEs of interest (EOI).   


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Subject incidence of all treatment-emergent AEs, serious AEs, AEs leading to 
withdrawal of investigational product, and fatal AEs will be tabulated by system organ 
class and preferred term in descending order of frequency.   
Summaries of treatment-emergent and serious AEs by preferred term in any treatment 
arm will be provided in descending order of frequency.   
Subject incidence of EOIs (structured MedDRA queries and/or customized queries) will 
be summarized according to the EOI search strategy categories.  
10.8.2 
Laboratory Test Results 
Laboratory results and their change from baseline will be summarized by actual 
treatment group and scheduled assessment for a subset of laboratory analytes provided 
in the protocol, Table 3. These include creatinine, creatine kinase, total bilirubin, direct 
bilirubin, alkaline phosphatase, alanine aminotransferase, aspartase aminotransferase, 
NT-proBNP, troponin, CK-MB and digoxin. 
Shift tables will be provided by treatment group, which will be based on modified CTCAE 
grades and will compare baseline laboratory values with the most extreme post-baseline 
values.  Summaries of subjects with post-baseline laboratory values with a CTCAE 
grade ≥ 3, if available, will be provided.  The following shift tables will be generated: 
• 
Total bilirubin (blood bilirubin increased) 
• 
ALP (alkaline phosphatase increased) 
• 
AST (SGOT) (aspartate aminotransferase increased) 
• 
ALT (SGPT) (alanine aminotransferase increased) 
Number and percentage of subjects of each troponin status “undetected” 
(< 0.016 ng/mL), “detected” (0.016 – 0.04 ng/mL), and “elevated” (> 0.04 ng/mL) at each 
scheduled assessment will be summarized overall and by baseline status.  Change of 
troponin status from baseline to the worst post-baseline will be tabulated.  These 
summaries will be repeated by using different thresholds of upper reference limit (URL) 
in defining status: URL, 2xURL, 3xURL, 4xURL, 5xURL, 10xURL.  
Summaries will also be presented by treating troponin as continuous variable. Troponin 
values below or above the quantifiable limits will be treated as equal to the limits. 
CK-MB using different thresholds of URL, will be summarized and presented in the 
similar way as for troponin. 


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10.8.3 
Vital Signs 
Vital signs, including HR (based on measurement of pulse), and their change from 
baseline will be summarized by actual treatment group and scheduled assessment. 
10.8.4 
Electrocardiogram (ECG) 
For post-baseline assessments where ECG is performed in triplicate, the average of the 
3 (or all available) readings will be used for analysis.  Observations with the following 
diagnosis or findings will be excluded from analysis: artificial pacemaker, atrial 
fibrillation, atrial flutter, left bundle branch block, and right bundle branch block.  
PR, RR, QRS, QT, QTcB and QTcF intervals and their change from baseline will be 
summarized by actual treatment group and scheduled assessment.   
Subjects will be categorized into the following groups per their maximum change from 
baseline in QTcB and QTcF.  Unscheduled assessments will be included in the 
determination of the maximum change.  The number and percentage of subjects in each 
group will be summarized. 
• 
≤ 30 msec 
• 
> 30 – 60 msec 
• 
> 60 msec 
Subjects will also be categorized into the following groups per their maximum 
post-baseline QTcB and QTcF.  Unscheduled assessments will be included in the 
determination of the maximum post baseline value.  The number and percentage of 
subjects in each group will be summarized. 
• 
≤ 450 msec 
• 
> 450 – 480 msec 
• 
> 480 – 500 msec 
• 
> 500 msec 
10.8.5 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. Indicators of extent of IP exposure include total IP administration 
duration and dosing compliance. 
Exposure definitions are provided in Section 6.4. 


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10.8.6 
Exposure to Concomitant Medication 
Concomitant medications will be coded by the World Health Organization Drug 
(WHO DRUG) dictionary. The number and proportion of subjects receiving oral 
medications of interest will be summarized by medication category, preferred term and 
regimen dose, unit and frequency at baseline and EOS for each treatment group.  
11. 
Changes From Protocol-specified Analyses 
During the initial development of this document, it was realized that there are 
protocol-specified analyses that cannot be implemented/performed and the protocol is 
not required to be amended. HF treatment at baseline will not be included as a baseline 
covariate. HF treatment, including BB, ACEi or ARB, is one of the expansion phase 
inclusion criteria and therefore the study is not expected to support subgroup analysis of 
no HF treatment at baseline. These changes will also be documented in the Clinical 
Study Report. 
The definition of the PKAS was clarified to require one evaluable PK concentration 
rather than PK parameter as stated in the protocol. 


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12. 
Literature Citations / References 


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13. 
Data Not Covered by This Plan 
This SAP does not address the analysis for the secondary objective 
• 
to explore the potential relationship between omecamtiv mecarbil exposure and 
changes from baseline in SET 


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14. 
Appendices 


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Appendix A.  Analytical Study Week Assignments 
Selected endpoints will be summarized by scheduled study visits in descriptive analyses.  
Since the actual visits may not exactly coincide with their scheduled visit day, the actual 
visit day is mapped to the study visit by non-overlapping consecutive intervals covering 
the entire time continuum.  The mapping intervals for all distinct schedules are 
summarized in the following table, for non-PK endpoints: 
 
Actual Visit Day (Study Day) 
Scheduled 
visit 
VS*, CC, 
ECG 
WT, CH, 
HE 
PE 
NT 
ECHO 
UR 
DG 
NYHA 
BL/Day 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Day 15 
(Week 2) 
> 1 – 
≤ 21 
> 1 – 
≤ 35 
 
 
 
 
> 1 
 
Day 28 
(Week 4) 
> 21 – 
≤ 42 
 
 
> 1 – 
≤ 42 
 
 
 
 
Day 56 
(Week 8) 
> 42 – 
≤ 70 
> 35 – 
≤ 70 
 
> 42 – 
≤ 84 
> 1 – 
≤ 84 
> 1 – 
≤ 98 
 
 
Day 84 
(Week 12) 
> 70 – 
≤ 98 
> 70 – 
≤ 98 
 
 
 
 
 
 
Day 112 
(Week 16) 
> 98 – 
≤ 126 
> 98 – 
≤ 126 
 
> 84 
> 84 
 
 
 
Day 140 
(Week 20) 
> 126 
> 126 
> 1 
 
 
> 98 
 
 
VS: vital signs; WT: body weight; CC: cardiac troponin and CK-MB; PE: physical examination; NT: 
NT-proBNP; ECHO: electrocardiography; CH: chemistry; HE: hematology; UR: urinalysis; DG: Digoxin. 
*Vital signs on week 8 and 16 are to be measured multiple times for E-R analysis purpose, and the value 
before morning dose will be used for non-PKPD analysis. 
Handling multiple records assigned to an analytical study day/week: 
If there is more than one record in a study week interval, the analytical record for that 
specific study week will be defined as the record closest to the scheduled study day of 
that specific study week (7 × study week + 1).  If two records are equidistant from the 
scheduled day, then the earlier record will be chosen.  If there are multiple records on 
the same day, the last record will be used. 
Exceptions to these rules are:  
• 
vital signs, the latest one prior to first IP administration on that day will be used in 
the non-PKPD analysis; 
• 
cardiac troponin, CK-MB, and creatine kinase, where the worst non-missing 
value within the interval will be used in the analysis. 


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Appendix B.  Treatment Emergent Adverse Event Algorithm 
 Dates 
eCRF Flag of “Did event 
start before first dose of 
investigational product?” 
Treatment 
Emergent? 
AE onset date > 1st IP date 
No 
Yes 
AE onset date < 1st IP date 
Yes 
No 
AE onset date > 1st IP date 
Yes 
Yes 
AE onset date < 1st IP date 
No 
Yes 
AE onset date = 1st IP date 
No 
Yes 
AE onset date = 1st IP date 
Yes 
No 
Cannot determine even after  date 
imputation specified in section 9.3.2 
Yes 
No 
Cannot determine even after  date 
imputation specified in section 9.3.2 
No 
Yes