Conditions: QT Intervals Changes QTc Intervals Changes
Keywords: Thorough QT QTc study
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 70
Healthy volunteers: yes

Brief summary:
The primary objective of this study is to assess the effect of a single therapeutic (50 mg) oral dose of omecamtiv mecarbil (OM) on the QT interval / QT interval corrected for heart rate (QTc), relative to placebo, in healthy adults.

The QT interval is the section on an electrocardiogram (ECG) that represents the time it takes for the electrical system to fire an impulse through the ventricles and then recharge, or the time it takes for the heart muscle to contract and then recover.

Detailed description:
The study consists of 2 parts: Part A and Part B. Participants are enrolled in Part A to determine eligibility for Part B.

In Part A participants receive a single oral dose of 25 mg omecamtiv mecarbil; participants with a resulting maximum observed OM plasma concentration (Cmax) ≤ 350 ng/mL are eligible to enter Part B.

Part B is a 3-period cross-over study in which participants are randomized to receive 3 treatments in 1 of 6 sequences, each separated by a washout of at least 7 days.

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: After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1. arm 2: Participants with a maximum observed plasma OM concentration ≤ 350 ng/mL in Part A were randomly assigned to receive a single dose of each the following 3 treatments in one of six treatment sequences:

* Placebo
* 50 mg omecamtiv mecarbil
* 400 mg moxifloxacin Each treatment was separated by a washout of at least 7 days.

Interventions: intervention 1: Omecamtiv Mecarbil (OM) intervention 2: Placebo intervention 3: Moxifloxacin
Intervention descriptions: intervention 1: Oral solution intervention 2: Placebo oral solution intervention 3: 400 mg moxifloxacin oral tablet

Protocol document:
Prot_000.pdf: 
TITLE PAGE 
Protocol 
Single-dose and Randomized, Single-center, Placebo- and 
Active-controlled, Crossover Study to Assess the Effect of Omecamtiv 
Mecarbil (OM) on QT/QTc Intervals in Healthy Subjects 
Protocol Amendment 3 Status: Final 
Protocol Amendment 3 Date: 23 August 2019 
Protocol Amendment 2 Date: 07 August 2019 
Protocol Amendment 1 Date: 19 July 2019 
Original Protocol Date: 30 May 2019 
Protocol Version 4.0 
Clinical Phase: 1 
Investigational Product: omecamtiv mecarbil (AMG 423) 
Amgen Protocol Reference Number: 20090231 
Covance Study Number: 8405952 
EudraCT Number: 2018-003157-19 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Approved
NCT Number: NCT04175808
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 2 of 80 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and members 
of the Institutional Review Board/Independent Ethics Committee/Institutional Scientific 
Review Board or equivalent. 
The information in this document cannot be used for any purpose other than the evaluation 
or conduct of the clinical investigation without the prior written consent of Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the Amgen 
Medical Information number: US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 3 of 80 
INVESTIGATOR AGREEMENT 
I have read the protocol entitled “Single-dose and Randomized, Single-center, Placebo- and 
Active-controlled, Crossover Study to Assess the Effect of Omecamtiv Mecarbil (OM) on 
QT/QTc Intervals in Healthy Subjects” (Version 4.0, dated: 23 August 2019), and agree to 
conduct the study as described herein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable national 
or regional regulations/guidelines.  
I agree to ensure that 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 Principal Investigator 
 
Date (DD Month YYYY) 
 
Approved 
 
 


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Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 5 of 80 
SYNOPSIS 
Title of study: Single-dose and randomized, single-center, placebo- and active-controlled, 
crossover study to assess the effect of omecamtiv mecarbil (OM) on QT/QTc intervals in healthy 
subjects 
Objectives: 
The primary objective of the study is: 
• 
To assess the effect of a single therapeutic (50 mg) oral dose of OM on the QT/QT interval 
corrected for heart rate (QTc) interval, relative to placebo, in healthy subjects. 
The secondary objectives of the study are: 
• 
To assess the pharmacokinetics (PK) of OM after a single oral dose to healthy subjects. 
• 
To evaluate the effect of OM on other electrocardiogram (ECG) parameters (heart rate 
[HR], PR and QRS intervals, and treatment-emergent T-wave abnormalities and presence 
of U-waves). 
• 
To evaluate the plasma concentration-effect relationship for OM on the QT/QTc interval 
in healthy subjects. 
• 
To evaluate assay sensitivity by evaluation of the positive control, a single 400-mg oral 
dose of moxifloxacin, on the QT/QTc interval in healthy subjects. 
• 
To evaluate the safety and tolerability of OM after a single oral dose to healthy subjects. 
Hypothesis: 
The hypothesis is that OM does not prolong QTc intervals after administration of a single 50-mg 
oral dose and will be safe and well tolerated in healthy subjects. 
Study design: 
This is a single-center, single-dose (Part A; PK Evaluation Period), and randomized, 3-period, 
3-treatment, crossover, single-dose (Part B) study in healthy adult subjects to determine whether 
OM prolongs the QTc after a single oral dose administration of 50 mg OM. Treatment in Part A 
will consist of a single 25-mg OM treatment (Treatment 1). Subjects whose resulting maximum 
observed plasma OM concentration (Cmax) is ≤ 350 ng/mL will be randomized into Part B, which 
consists of 3 periods wherein a single treatment is given in each period. Treatments will consist of 
placebo (Treatment A), OM 50 mg (Treatment B), or moxifloxacin 400 mg (Treatment C). All 
treatments (Part A and Part B) will be separated by a washout of at least 7 days.  
 
Part A 
All subjects will receive Treatment 1. OM treatment will be open-label. Safety and tolerability 
monitoring will be conducted throughout Part A, and blood samples will be collected to determine 
plasma OM concentrations. Safety digital ECG recordings will be reviewed by the Investigator or 
designee on Day -1, and on Day 1 at the following timepoints: predose and at 1, 4, 24, 48, and 
120 hours postdose. Pharmacokinetic blood samples for OM will be collected at the following 
timepoints on Day 1: predose and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 12 hours postdose.  
 
Subjects whose resulting Cmax is ≤ 350 ng/mL will be randomized into Part B. There will be a 
minimum of a 7-day washout between treatments in Part A and Part B. 
 
Part B 
 
After completing Part A, eligible subjects will be randomized to receive 3 treatments in 1 of 
6 sequences, as follows: 
 
 
 
 
 
Approved 
 
 


Protocol 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 6 of 80 
Sequence  Period 
1 
Period 
2 
Period 
3 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
A 
C 
B 
5 
C 
B 
A 
6 
B 
A 
C 
 
In Part B, placebo and OM treatments will be double-blinded, moxifloxacin treatment will be 
open-label, and the core ECG lab will be blinded to all treatment information. Safety and 
tolerability monitoring will be conducted throughout the study, and blood samples will be 
collected to determine plasma OM and moxifloxacin concentrations in relevant periods. 
 
In each Part B treatment period, continuous digital ECG recording will be performed for 
approximately 27 hours, from predose through at least 24 hours postdose, and up to 10 replicate 
12-lead ECGs will be extracted at the following timepoints on Day 1: -1.25, -1, and -0.75 hours 
predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours postdose. 
 
In each Part B treatment period, PK blood samples for OM and moxifloxacin will be collected at 
the following timepoints on Day 1: predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, 
and 120 hours postdose. 
Number of subjects: 
Approximately 60 to 70 subjects will be enrolled in Part A in order to have 60 subjects (10 per 
sequence) enrolled in Part B. With approximately 60 subjects in Part B, it is estimated that 
approximately 48 evaluable subjects will have data from all 3 periods in Part B. 
Diagnosis and main criteria for inclusion: 
Healthy adult females and males, aged between 18 and 50 years (inclusive) and with a body mass 
index between 18.0 and 30.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Subjects will receive the following single, oral dose under fasting conditions: 
Part A 
• 
Treatment 1: 25-mg OM oral solution  
 
Note: Individual subject PK will be measured in Part A. Only subjects with plasma OM maximum 
concentrations ≤ 350 ng/mL in Part A will be eligible to continue to Part B. 
 
Subjects will receive the following single, oral doses under fasting conditions, according to a 
randomization schedule generated by a Covance statistician: 
 
Part B 
• 
Treatment A: Placebo oral solution 
• 
Treatment B: 50-mg OM oral solution 
• 
Treatment C: 400-mg moxifloxacin oral tablet 
Duration of subject participation in the study: 
The total duration of participation in this study will be approximately 55 days, including a 
screening period of up to 28 days. 
Study endpoints: 
The primary endpoint is the placebo-corrected change from baseline in QTc interval based on the 
Fridericia correction (QTcF) (∆∆QTcF) after OM dosing. 
The following are secondary endpoints for this study: 
Approved 
 
 


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Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 7 of 80 
• 
Pharmacokinetic parameters of OM including, but not limited to, Cmax, the time of 
maximum observed concentration (tmax), apparent terminal elimination half-life (t1/2), 
apparent volume of distribution (VZ/F), apparent total plasma clearance (CL/F), area under 
the concentration-time curve (AUC) from time 0 to the last quantifiable concentration 
(AUC0-t), AUC from time 0 to infinity (AUCinf), and the percentage of AUCinf due to 
extrapolation (%AUCextrap) 
• 
∆∆QTcF after moxifloxacin dosing 
• 
Change-from-baseline heart rate, QTcF, PR and QRS intervals (∆HR, ΔQTcF, ∆PR, and 
∆QRS) after OM dosing 
• 
Concentration-QTc analysis based on ΔΔQTcF after OM dosing 
• 
Placebo-corrected ∆HR, ∆PR, and ∆QRS (∆∆HR, ∆∆PR, and ∆∆QRS) after OM dosing 
• 
Categorical outliers for QTcF, HR, PR, and QRS after OM dosing 
• 
Frequency of treatment-emergent changes in T-wave morphology and U-wave presence 
after OM dosing 
• 
Subject incidence of treatment-emergent adverse events (TEAEs) 
• 
Changes in laboratory safety tests, vital signs, and ECGs. 
Statistical methods: 
Cardiodynamic evaluation: 
The primary analysis will be based on by-timepoint analysis to evaluate the effect of OM on 
ΔΔQTcF at each postdose extraction window using a linear mixed-effect model. The effect of OM 
on ∆∆HR, ∆∆PR, and ∆∆QRS will also be evaluated using the same modeling approach. An 
analysis of categorical outliers will be performed for changes in HR, PR, QRS, QTcF, T-wave 
morphology and U-wave presence. Assay sensitivity will also be evaluated using by-timepoint 
analysis of the effect of moxifloxacin on Δ∆QTcF using the same model as for the primary 
analysis. 
Pharmacokinetics: 
Pharmacokinetic data for OM will be presented and summarized by treatment and at each 
timepoint when applicable. Graphical summaries of the data may also be presented. 
Pharmacokinetic/electrocardiography analyses: 
The relationship between OM plasma concentrations and Δ∆QTcF will be evaluated using a linear 
mixed-effects modeling approach.  
Safety: 
The number and percentage of subjects reporting any TEAEs will be tabulated by Medical 
Dictionary for Regulatory Activities system organ class and preferred term and grouped by 
treatment. Adverse events, serious adverse events, clinical laboratory evaluations, ECGs, and vital 
signs measurements will be summarized by descriptive statistics. 
Approved 
 
 


Protocol 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 8 of 80 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................12 
LIST OF ABBREVIATIONS ..................................................................................................13 
1. 
INTRODUCTION ...........................................................................................................15 
1.1. 
Study Rationale ......................................................................................................15 
1.2. 
Background ............................................................................................................15 
1.2.1. 
Disease .........................................................................................................15 
1.2.2. 
Amgen Investigational Product Background: Omecamtiv Mecarbil ...........16 
1.2.3. 
Non-Amgen Non-Investigational Product Background: Moxifloxacin .......17 
1.3. 
Benefit-Risk Assessment .......................................................................................17 
1.3.1. 
Therapeutic Context .....................................................................................17 
1.3.2. 
Key Benefits.................................................................................................17 
1.3.3. 
Risks .............................................................................................................17 
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESES.....................................................18 
2.1. 
Objectives ..............................................................................................................18 
2.2. 
Endpoints ...............................................................................................................19 
2.2.1. 
Primary Endpoints .......................................................................................19 
2.2.2. 
Secondary Endpoints ...................................................................................19 
2.3. 
Research Hypothesis ..............................................................................................19 
3. 
INVESTIGATIONAL PLAN ..........................................................................................19 
3.1. 
Overall Study Design and Plan ..............................................................................19 
3.2. 
Discussion of Study Design ...................................................................................23 
3.3. 
Selection of Doses in the Study .............................................................................24 
4. 
SELECTION OF STUDY POPULATION .....................................................................25 
4.1. 
Inclusion Criteria ...................................................................................................25 
4.2. 
Exclusion Criteria ..................................................................................................25 
4.3. 
Screen Failures and Rescreening ...........................................................................27 
4.4. 
Subject Number and Identification ........................................................................27 
4.5. 
Subject Withdrawal and Replacement ...................................................................27 
4.6. 
Study Termination .................................................................................................28 
4.7. 
Discontinuation of Study Treatment ......................................................................28 
5. 
STUDY TREATMENTS .................................................................................................29 
5.1. 
Investigational Products .........................................................................................29 
5.1.1. 
Dose Modification .......................................................................................30 
Approved 
 
 


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Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
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5.1.2. 
Guidance for Signs or Symptoms Consistent with Myocardial Ischemia 
or Infarction .................................................................................................30 
5.1.3. 
Treatment of Overdose ................................................................................31 
5.1.4. 
Medical Devices ...........................................................................................31 
5.1.5. 
Product Complaints ......................................................................................31 
5.2. 
Non-Amgen Non-investigational Product .............................................................31 
5.3. 
Study Treatment Administration ............................................................................31 
5.4. 
Randomization .......................................................................................................32 
5.5. 
Blinding..................................................................................................................32 
5.5.1. 
Site Personnel Access to Individual Treatment Assignments ......................32 
5.5.2. 
Access to Individual Treatment Assignments by Amgen or Designees ......32 
5.6. 
Treatment Compliance ...........................................................................................33 
6. 
STUDY RESTRICTIONS ...............................................................................................33 
6.1. 
PRIOR AND CONCOMITANT THERAPIES .....................................................33 
6.1.1. 
Prior Therapies .............................................................................................33 
6.1.2. 
Concomitant Therapies ................................................................................33 
6.2. 
Diet .........................................................................................................................34 
6.3. 
Smoking .................................................................................................................35 
6.4. 
Exercise ..................................................................................................................35 
6.5. 
Blood Donation ......................................................................................................35 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................35 
7.1. 
General Assessments .............................................................................................36 
7.1.1. 
Demographics ..............................................................................................36 
7.1.2. 
Medical History ...........................................................................................36 
7.1.3. 
Physical Measurements ................................................................................36 
7.2. 
Electrocardiography Assessments .........................................................................36 
7.2.1. 
Continuous 12-lead Electrocardiogram Recording ......................................36 
7.2.1.1. 
TQT Plus Extraction Technique ........................................................36 
7.2.1.2. 
Expert-Precision QT Analysis ...........................................................37 
7.2.2. 
Safety 12-Lead Electrocardiogram ..............................................................38 
7.2.3. 
Telemetry .....................................................................................................38 
7.3. 
Pharmacokinetic Assessments ...............................................................................38 
7.3.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................38 
7.3.2. 
Analytical Methodology ..............................................................................38 
7.4. 
Safety and Tolerability Assessments .....................................................................39 
7.4.1. 
Adverse Events and Serious Adverse Events: Time period and 
Frequency for Collecting and Reporting Safety Event Information ............39 
7.4.2. 
Clinical Laboratory Evaluations ..................................................................41 
7.4.3. 
Vital Signs ....................................................................................................41 
7.4.4. 
Physical Examination...................................................................................41 
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8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................42 
8.1. 
Determination of Sample Size ...............................................................................42 
8.2. 
Analysis Populations ..............................................................................................42 
8.3. 
Statistical Analyses ................................................................................................42 
8.3.1. 
Primary Analysis ..........................................................................................43 
8.3.2. 
General Considerations ................................................................................43 
8.3.3. 
Cardiodynamic ECG Assessments ..............................................................43 
8.3.3.1. 
Baseline for Cardiodynamic ECG Assessments ................................43 
8.3.3.2. 
Primary Cardiodynamic Analysis ......................................................43 
8.3.3.3. 
Secondary Cardiodynamic Analyses .................................................43 
8.3.3.4. 
Assay Sensitivity ................................................................................44 
8.3.3.5. 
Categorical Analyses .........................................................................44 
8.3.4. 
Pharmacokinetic Analyses ...........................................................................44 
8.3.5. 
Pharmacokinetic/Electrocardiography Analyses .........................................45 
8.3.5.1. 
Investigation of Hysteresis .................................................................45 
8.3.5.2. 
Appropriateness of a Linear Model ...................................................46 
8.4. 
Safety Analyses ......................................................................................................46 
8.4.1. 
Adverse Events ............................................................................................46 
8.4.2. 
Clinical Laboratory Tests .............................................................................46 
8.4.3. 
Vital Signs ....................................................................................................46 
8.4.4. 
Physical Measurements ................................................................................46 
8.4.5. 
Safety 12-Lead Electrocardiograms .............................................................46 
8.5. 
Interim Analysis .....................................................................................................47 
9. 
REFERENCES ................................................................................................................47 
10. APPENDICES .................................................................................................................49 
Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting .......................................................................................50 
Definition of Adverse Event ........................................................................................50 
Definition of Serious Adverse Event ...........................................................................51 
Recording Adverse Events, and Serious Adverse Events ............................................52 
Evaluating Adverse Events and Serious Adverse Events ............................................52 
Reporting of Serious Adverse Event ............................................................................54 
Appendix 2: Sample Storage and Destruction ...................................................................58 
Appendix 3: Clinical Laboratory Evaluations ...................................................................59 
Appendix 4: Total Blood Volume ......................................................................................60 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................61 
Appendix 6: Schedule of Assessments ..............................................................................66 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information ............................................................................................................71 
Collection of Pregnancy Information ...........................................................................73 
Approved 
 
 


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Collection of Lactation Information ............................................................................75 
Appendix 8: Hepatotoxicity: Suggested Actions and Follow-up Assessments .................78 
Drug-induced Liver Injury Reporting and Additional Assessments ............................79 
 
Approved 
 
 


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Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 12 of 80 
LIST OF TABLES AND FIGURES 
Table 1: 
Study Treatments .......................................................................................30 
Table 2: 
T-wave Morphology Categories (Assessed Manually) ..............................37 
Table 3: 
Schedule of Assessments ...........................................................................67 
 
Figure 1: 
Study Schematic.........................................................................................21 
Figure 2: 
Sample Serious Adverse Event Report Form ............................................55 
Figure 3: 
Pregnancy Notification Form .....................................................................76 
Figure 4: 
Lactation Notification Form ......................................................................77 
 
Approved 
 
 


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Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 13 of 80 
LIST OF ABBREVIATIONS 
Abbreviation Definition 
ACE 
angiotensin-converting-enzyme 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
Anti-HBc 
hepatitis B core antibody 
Anti-HBs 
hepatitis B surface antibody 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCinf 
area under the plasma concentration-time curve from time zero to infinity 
AUC0-t 
area under the plasma concentration-time curve from time zero to the last 
quantifiable concentration 
AUCinf 
area under the plasma concentration-time curve from time 0 to infinity 
AV 
atrioventricular 
BID 
twice daily 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK-MB 
creatine kinase MB fraction 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CRO 
Contract Research Organization 
CV% 
coefficient of variation 
∆∆QTcF 
time-matched change from baseline in placebo-adjusted QT interval 
corrected for heart rate based on the Fridericia correction 
DILI 
drug-induced liver injury 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCAb 
hepatitis C antibodies 
hERG 
human ether-à-go-go-related gene 
HF 
heart failure 
Approved 
 
 


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Protocol Version 4.0, 23 August 2019 
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HFrEF 
heart failure  
HIV 
human immunodeficiency virus 
HIVAb 
human immunodeficiency virus antibodies 
HR 
heart rate 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual  
IRB 
institutional review board 
IUD 
intrauterine device 
LS 
least squares 
MAD 
multiple-ascending dose 
MDRD 
Modified Diet in Renal Disease 
MRI 
magnetic resonance imaging 
OM 
omecamtiv mecarbil 
PD 
pharmacodynamic  
%AUCextrap 
percentage of area under the concentration-time curve from time 0 to 
infinity due to extrapolation 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate based on the Fridericia correction 
RBC 
red blood cell 
RR 
time interval between two successive R-waves of the QRS signal on the 
electrocardiogram 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2 
apparent terminal elimination half-life 
TBL 
total bilirubin 
TdP 
torsades de pointes 
TEAE 
treatment-emergent adverse event 
tmax 
time of the maximum observed plasma concentration 
TQT 
thorough QT 
ULN 
upper limit of normal 
WBC 
white blood cell 
Approved 
 
 


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1. INTRODUCTION 
Refer to the omecamtiv mecarbil (OM) Investigator’s Brochure (IB)1 for detailed information 
concerning the available pharmacology, toxicology, drug metabolism, clinical studies, and 
safety profile of omecamtiv mecarbil. 
1.1. 
Study Rationale 
The International Council for Harmonisation (ICH) E14 requests that non anti-arrhythmic 
drugs are tested for their QT liability and proposes that a thorough assessment is performed in 
healthy volunteers in order to determine whether the potential for QT prolongation needs to 
be studied further in the patient population. The QT interval represents the duration of 
ventricular depolarization and subsequent repolarization, and is measured from the beginning 
of the QRS complex to the end of the T-wave. A delay in cardiac repolarization creates an 
electrophysiological environment that favors the development of cardiac arrhythmias, most 
clearly torsades de pointes (TdP), but possibly other ventricular tachyarrhythmias as well. 
Most drugs that have caused TdP clearly increase both the absolute QT and the QT interval 
corrected for heart rate (QTc). Because prolongation of the QT/QTc interval is the 
electrocardiogram (ECG) finding associated with the increased susceptibility to these 
arrhythmias, an adequate investigation should include characterization of OM’s effects on the 
QT/QTc interval consistent with ICH E14 guidance.  
1.2. 
Background 
1.2.1. 
Disease 
Heart failure (HF) is a clinical syndrome marked by impaired cardiac contractility and is the 
final pathway for a diversity of diseases that afflict the heart.2 It affects over 26 million 
people worldwide, over 3.5 million people are newly diagnosed every year, and its 
prevalence notably increases with age.3 The rate of cardiovascular mortality or HF 
re-hospitalization approaches 25% to 30% at 6 months in patients hospitalized for HF.4 
Heart failure is most often caused by coronary artery disease; other common causes include 
idiopathic, hypertension, and valvular heart disease.5 In an attempt to preserve cardiac output, 
the condition progresses through stages with compensatory mechanisms characterized by 
increased sympathetic tone and peripheral vasoconstriction, and activation of various 
neurohormonal pathways. These adaptive properties provide short-term relief but can be 
damaging with long-term or prolonged activation. Patients experience dyspnea, fatigue, and 
fluid retention and may eventually develop pulmonary congestion and peripheral edema. 
Treatment goals are to improve symptoms, prolong survival, and reduce hospital 
readmissions.6,7 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 pacing8), 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. Current inotropic agents, such as β-adrenergic receptor agonists or 
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phosphodiesterase inhibitors, work indirectly by activating second messenger signaling 
pathways to increase cardiac myocyte intracellular calcium resulting in an increase in systolic 
function. However, these agents can also cause arrhythmias, increase heart rate and oxygen 
consumption, result in clinically significant hypotension, and have been associated with 
increased mortality. These adverse effects may be related to their mechanism of action of 
increasing intracellular calcium. 
In contrast to current inotropes, OM directly activates cardiac myosin without affecting 
intracellular calcium and may therefore improve systolic function without the liabilities of 
inotropes. 
1.2.2. 
Amgen Investigational Product Background: Omecamtiv Mecarbil  
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.9,10  
Omecamtiv mecarbil has been evaluated in 11 Phase 1 studies (Studies CY 1011, CY 1013, 
CY 1015, CY 1016, CY 1111, CY 1211 [20120255], 20080676, 20090229, 20090727, 
20150134, and 20160159), 4 Phase 2a studies in subjects with chronic heart failure with 
reduced ejection fraction (HFrEF; Studies CY 1121, CY 1221, CY 1124, and CY 1021), 
1 Phase 2b study in subjects with acute HF (Study 20100754), and 2 Phase 2b studies in 
subjects with HFrEF (Studies 20110151 and 20120227). In these studies, the efficacy, safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) effects of OM were 
evaluated with intravenous infusions up to 72 hours and oral dosing up to 20 weeks. 
In addition to the above studies, a Phase 3 cardiovascular outcomes study (Study 20110203 
[GALACTIC-HF], NCT 02929329) in approximately 8000 subjects is underway to evaluate 
chronic dosing of the oral MR dosage form of OM for the reduction of cardiovascular death 
and HF events (defined by an urgent, unscheduled clinic/office/emergency department visit 
or hospital admission, with a primary diagnosis of HF) in subjects with HFrEF. A second 
Phase 3 study (CY 1031 [METEORIC-HF], NCT 03759392) is also being conducted to 
assess the effect of OM on exercise tolerance in subjects with chronic HFrEF and reduced 
exercise capacity. A summary of completed and ongoing clinical studies for OM is provided 
in the IB.1 
The half maximal inhibitory concentration (IC50) for the effect of omecamtiv mecarbil on 
human ether à go-go related gene (hERG) current was estimated to be 125.5 µM. Omecamtiv 
mecarbil did not inhibit or prolong QT interval in dogs at therapeutic concentrations. 
Following oral solution administration of OM in healthy subjects, the time of maximum 
observed concentration (tmax) is approximately 0.5 hours and apparent terminal elimination 
half-life (t1/2) is approximately 21 hours. Refer to the specific section of the IB for additional 
information related to the physical, chemical, and pharmaceutical properties and 
formulations. A detailed description of the chemistry, pharmacology, efficacy, and safety of 
OM is provided in the IB.1 
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1.2.3. 
Non-Amgen Non-Investigational Product Background: Moxifloxacin 
Moxifloxacin is a broad-spectrum fluoroquinolone antibiotic that binds to and inhibits the 
hERG IKr α subunit and causes a mean increase of the QTc interval of 6 ms after a single 
400-mg oral dose. Moxifloxacin is commonly used as a positive control in thorough QT 
(TQT) studies to satisfy the requirements of ICH E14. 
Refer to the regional manufacturer package insert of AVELOX (moxifloxacin hydrochloride) 
tablets for additional information.11 
1.3. 
Benefit-Risk Assessment 
The following benefit-risk assessment supports the conduct of this trial. For more details on 
identified risks, see Appendix A of the OM IB.1 
1.3.1. 
Therapeutic Context 
This study will be conducted in healthy subjects without therapeutic intent. In particular, the 
subjects enrolled in the study would not be expected to benefit from exposure to the 
treatments used in this study.  
1.3.2. 
Key Benefits 
Subjects will not directly benefit from participating in the study. The data from the study will 
support the development of OM, which may address unmet medical need in the relevant 
patient population.  
1.3.3. 
Risks 
Myocardial ischemia and myocardial infarction have been observed in a healthy subject and 
in subjects with heart failure in clinical studies and are identified risks of OM. One healthy 
subject was reported to have signs and symptoms consistent with myocardial infarction 
following intravenous administration of 1 mg/kg/hr of OM. The subject experienced chest 
tightness, palpitations, lightheadedness, and feeling hot, in association with tachycardia, ECG 
changes, and troponin elevation. The maximum observed plasma OM concentration (Cmax) 
associated with this event was estimated to be approximately 1540 ng/mL. Echocardiography 
following this event did not demonstrate any evidence of regional wall motion abnormality 
and a contrast enhanced cardiac magnetic resonance imaging (MRI) was negative for 
myocardial infarction/scar. 
Excessive exposure to OM may result in prolongation of the systolic ejection time to an 
extent that reduces diastolic coronary filling. The reduced coronary filling could precipitate 
myocardial ischemia or infarction. Signs and symptoms of myocardial ischemia or infarction 
can include, but are not limited to, electrocardiographic changes consistent with myocardial 
ischemia (ST-segment depression), angina, chest or throat tightness, palpitations and/or 
tachycardia, lightheadedness, dizziness, hypotension, dyspnea, premature ventricular 
contractions, and troponin elevation. For more details on identified risks, see Appendix A of 
the OM IB.1 
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To mitigate the risk of myocardial ischemia or infarction in patients due to excessive 
exposure during the clinical development program, exposure to OM is controlled (to maintain 
plasma concentrations lower than 1000 ng/mL) through a PK-based dose adjustment strategy 
using an oral modified-release formulation to guide appropriate dosing (Section 3.3). 
To limit the risk of excessive exposure to healthy subjects in the current study, which utilizes 
an OM oral solution, Part A will consist of a PK Evaluation Period, in which a 25-mg dose of 
OM will be given and PK assessed by subject. The mean Cmax following a 25-mg dose is 
expected to be approximately 220 ng/mL and, assuming dose proportionality, the exposure 
following 50 mg is therefore expected to be approximately 440 ng/mL. Only those subjects 
with Cmax ≤ 350 ng/mL in Part A will be eligible to continue to Part B. Therefore, exposure in 
Part B is not expected to exceed 700 ng/mL, which is 55% lower than the predicted exposure 
that resulted in the cardiac event in 1 healthy subject.  
As a result of administration of moxifloxacin, subjects may experience the following side 
effects: temporary changes in the electrical activity of the heart, palpitations, inflammation or 
rupture of the tendons, fainting spells, dizziness or lightheadedness, allergic reactions, nerve 
damage, convulsions, low blood sugar levels, and rupture or tearing of large blood vessels. 
However, at the dose level administered in the present trial and the very limited exposure, it 
is expected that these side effects will be mild in nature. Refer to the adverse reactions 
section of the regional manufacturer package insert of Avelox.11 
Safety monitoring: safety assessments throughout the study include adverse event (AE) and 
serious adverse event (SAE) monitoring, ECGs, clinical examination, vital signs, and clinical 
chemistry.  
2. OBJECTIVES, ENDPOINTS, AND HYPOTHESES 
2.1. 
Objectives 
The primary objective of the study is: 
• To assess the effect of a single therapeutic (50 mg) oral dose of OM on the QT/QTc 
interval, relative to placebo, in healthy subjects. 
The secondary objectives of the study are: 
• To assess the PK of OM after a single oral dose to healthy subjects. 
• To evaluate the effect of OM on other ECG parameters (hear rate [HR], PR and QRS 
intervals, and treatment-emergent T-wave abnormalities and presence of U-waves). 
• To determine the plasma concentration-effect relationship for OM on the QT/QTc 
interval in healthy subjects. 
• To evaluate assay sensitivity by evaluation of the positive control, a single 400-mg 
oral dose of moxifloxacin, on the QT/QTc interval in healthy subjects. 
• To evaluate the safety and tolerability of OM after a single oral dose to healthy 
subjects. 
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2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoint is the placebo-corrected change from baseline in QT interval corrected 
for HR based on the Fridericia correction (QTcF) interval (ΔΔQTcF) after OM dosing. 
2.2.2. 
Secondary Endpoints 
The following are secondary endpoints for this study: 
• Pharmacokinetic parameters of OM including, but not limited to, Cmax, tmax, t1/2, 
apparent volume of distribution (VZ/F), apparent total plasma clearance (CL/F), area 
under the concentration-time curve (AUC) from time 0 to the last quantifiable 
concentration (AUC0-t), AUC from time 0 to infinity (AUCinf), and the percentage of 
AUCinf due to extrapolation (%AUCextrap) 
• ∆∆QTcF after moxifloxacin dosing 
• Change-from-baseline HR, QTcF, PR and QRS intervals (∆HR, ΔQTcF, ∆PR and 
∆QRS) after OM dosing 
• Concentration-QTc analysis based on ΔΔQTcF after OM dosing 
• Placebo-corrected ∆HR, ∆PR and ∆QRS (∆∆HR, ∆∆PR and ∆∆QRS) after OM 
dosing 
• Categorical outliers for QTcF, HR, PR, and QRS after OM dosing 
• Frequency of treatment-emergent changes in T-wave morphology and U-wave 
presence after OM dosing 
• Subject incidence of treatment-emergent adverse events (TEAEs) 
• Changes in laboratory safety tests, vital signs, and ECGs. 
Other noncompartmental PK parameters may be reported. In addition, plasma concentration 
will be determined and PK parameters will be calculated for moxifloxacin only if deemed 
necessary. 
2.3. 
Research Hypothesis 
The hypothesis is that OM does not prolong QTc intervals after administration of a single 
50-mg oral dose and will be safe and well tolerated in healthy subjects. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a single-dose and randomized, single-center, 3-period, 3-treatment crossover 
study in healthy adult subjects to determine whether OM prolongs the QT/QTc interval after 
a single oral dose administration of 50 mg OM. The total duration of participation in the 
study will be approximately 55 days, including the screening period. The study will be 
conducted at a single clinical site.  
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The overall duration for individual subjects may vary depending on timing of sample 
shipment and analysis for Part A of the study, to confirm eligibility for Part B. 
An overview of the study design is shown in Figure 1. 
Approved 
 
 


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Potential subjects will be asked to read and sign an Informed Consent Form (ICF). After 
informed consent is obtained, screening procedures and tests to establish subject eligibility to 
enter the study will be performed within 28 days before Day 1 in Part A (PK Evaluation 
Period). Study procedures are summarized in the Schedule of Assessments in Appendix 6. 
Adverse events and SAEs will be recorded from the time the ICF is signed.  
Approximately 60 to 70 subjects will be enrolled in Part A in order to have 60 subjects 
(10 per sequence) enrolled in Part B. With approximately 60 subjects in Part B, it is estimated 
that approximately 48 evaluable subjects will have data from all 3 periods in Part B. 
Treatment in Part A will consist of a single 25-mg OM oral dose (Treatment 1), after which 
subjects whose resulting Cmax is ≤ 350 ng/mL will be randomized into Part B. Part B consists 
of 3 periods, in which a single treatment is given in each period. Treatments in Part B will 
consist of placebo (Treatment A), OM 50 mg (Treatment B), and moxifloxacin 400 mg 
(Treatment C). All study treatments (Part A and Part B/Period 1, Period 2 and Period 3) will 
be separated by a washout of at least 7 days.  
Part A 
• Treatment 1: 25-mg OM oral solution 
A subject will be considered enrolled once he/she is deemed eligible by the Investigator and 
has received the first dose administration in Part A.  
Subjects will be admitted to the research facility on Day -1 in Part A, at which time baseline 
procedures will be performed according to the Schedule of Assessments in Appendix 6. After 
an overnight fast of at least 10 hours, subjects will be administered treatment with 250 mL of 
water. No food will be allowed for at least 4 hours postdose. Water is allowed as desired 
except for 1 hour before and after drug administration. 
Subjects will stay at the research facility until Day 3, and study assessments will be 
performed according to the Schedule of Assessments in Appendix 6. PK samples will be 
collected to determine plasma OM concentrations according to the Schedule of Assessments 
in Appendix 6. Subjects will be discharged after completion of Day 3 activities and will 
return for a safety follow-up visit on Day 6. PK results from Part A will be available prior to 
Part B. For subjects whose resulting Cmax in Part A is > 350 ng/mL, the Day 6 visit will be 
considered their End of Study (EOS) visit.  
Part B 
• Treatment A: Placebo oral solution 
• Treatment B: 50-mg OM oral solution 
• Treatment C: 400-mg moxifloxacin oral tablet  
 
 
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After completing Part A, eligible subjects will be randomized to receive 3 treatments in 
1 of 6 sequences, as follows: 
Sequence  Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
A 
C 
B 
5 
C 
B 
A 
6 
B 
A 
C 
Subjects will be admitted to the research facility on Day -1 of Period 1 in Part B, at which 
time Check-in procedures will be performed according to the Schedule of Assessments in 
Appendix 6. After an overnight fast of at least 10 hours, subjects will be administered 
treatment with 250 mL of water. No food will be allowed for at least 4 hours postdose. Water 
is allowed as desired except for 1 hour before and after drug administration. Placebo and OM 
treatments will be double-blinded and moxifloxacin treatment will be open-label. Subjects 
will receive standardized meals at approximately the same time. 
Subjects will stay at the research facility throughout Part B, and study assessments will be 
performed according to the Schedule of Assessments in Appendix 6, including continuous 
ECG recording, digital ECG extractions, and PK sample collections to determine plasma OM 
and moxifloxacin concentrations. Additionally, standard safety assessments, including 
12-lead ECGs and vital signs monitoring, will be performed and safety and tolerability 
monitoring will be conducted throughout the study. Subjects will be discharged after 
completion of Day 6 activities in Period 3.  
All study treatments will be separated by a washout period of at least 7 days (including 
between Part A and Part B). 
The EOS visit will complete a subject’s participation in this study after Period 3. If there is a 
clinically significant clinical or laboratory abnormality that requires monitoring, the subject 
will be followed until resolution of the abnormality or until it is considered stable. If possible, 
EOS procedures will be performed on subjects who withdraw early from the study. 
The primary completion date is defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the primary endpoint, for the 
purposes of conducting the primary analysis, whether the study concluded as planned in the 
protocol or was terminated early. The planned primary completion date is the date when the 
last subject has completed the assessments on Day 6 of Period 3 in Part B.  
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled).  
3.2. 
Discussion of Study Design 
The purpose of this study is to evaluate the potential for OM to cause QT prolongation. As 
OM exposure affects cardiac contractility, the primary endpoint for this study will be the 
QTcF. A supratherapeutic dose of OM is unable to be administered due to the step-wise 
titration scheme needed to optimize OM dose and safety concerns in healthy subjects. A 
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crossover design has been selected, with subjects acting as their own controls to minimize 
inter-subject variability. 
This study will be double-blinded for OM and placebo to control for bias in safety 
assessments, including safety ECGs, and open-label for moxifloxacin as the QTc effects and 
AEs of this drug are well characterized. The central ECG laboratory and ECG readers will be 
blinded to treatment sequence, timepoint, and subject. 
The anticipated Cmax resulting from the 50-mg OM dose used for the assessment of QTc 
effects will be consistent with that in Phase 3 and will be below 1200 ng/mL. However, to 
provide further assurance that subjects will not exceed 1200 ng/mL, this study incorporates 
an initial PK assessment at 25 mg to confirm that individual Cmax values do not exceed 
350 ng/mL; given the linear PK of OM, a subject with Cmax ≤ 350 ng/mL at 25 mg would be 
expected to have predicted exposure no higher than 700 ng/mL at 50 mg, and therefore below 
1200 ng/mL.  
This study will be conducted using healthy subjects to eliminate potential variables known to 
have an effect on ECG parameters (eg, concomitant drugs, diseases). Subjects will be 
randomized to treatment in an effort to ensure that baseline characteristics are evenly 
distributed across treatment sequences. The sample size in this study is driven by the need to 
perform a by-timepoint statistical analysis of the primary endpoint per the ICH E14 guidance. 
Moxifloxacin will be included as a positive control to validate the sensitivity of the assay to 
detect small increases from baseline in QTc. Following single oral doses of 400 mg 
moxifloxacin, a QTc increase of 6 ms has occurred at tmax.11 Moxifloxacin plasma samples 
will be collected and concentrations may be measured, but PK vs QTc modeling will not be 
performed, as the QT effects of moxifloxacin are well-known. 
3.3. 
Selection of Doses in the Study 
According to ICH E14, the highest therapeutic dose and a supratherapeutic dose are 
recommended for the QT/QTc study. The OM dose in ongoing Phase 3 studies is 
individualized using a PK-based titration to avoid excessive OM exposures (> 1200 ng/mL). 
The observed mean (standard deviation; SD) steady state Cmax from a Phase 2 study 
(20110151) for 25 mg BID and 50 mg BID are 193 (58.5) ng/mL and 492 (115) ng/mL, 
respectively. A supratherapeutic dose will not be evaluated due to the identified risk of 
myocardial ischemia or infarction. 
Based on Study 20160159, the 25-mg oral solution formulation resulted in a mean (SD) Cmax 
of 220 (71.2) ng/mL after a single dose administration in healthy subjects. This exposure is 
well below the 1200 ng/mL threshold and the dose is proximal to the 50-mg dose, such that it 
is anticipated to provide a very reliable prediction of the Cmax of 50 mg, given the linear PK 
of OM. 
In Part B, OM treatment will be a 50-mg single dose of oral solution. The 50-mg oral solution 
dose should achieve therapeutic concentrations (range of 300 to 700 ng/mL). Moxifloxacin 
400 mg is associated with an observed 6 ms increase in the mean placebo- and 
baseline-corrected QTc interval, which is within the range required by ICH.17  
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In summary, to attain clinically relevant concentrations, a single dose of 50 mg oral solution 
will be administered for the purpose of evaluating the proarrhythmic potential of OM as 
reflected by change in the QTc interval in healthy subjects.  
4. SELECTION OF STUDY POPULATION 
The Investigator will be expected to maintain a screening log of all potential study 
candidates, which includes limited information about the potential candidate (eg, date of 
screening).  
Before any study-specific activities/procedures may be performed, the appropriate written 
informed consent must be obtained (see Appendix 5). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, will not be provided. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria at the Screening visit or as otherwise stated: 
1. Subject has provided informed consent before initiation of any study-specific 
activities/procedures. 
2. Healthy male or healthy female subjects ≥ 18 to ≤ 50 years of age. 
3. No history or evidence of clinically relevant medical disorders as determined by the 
Investigator at Screening. 
4. Physical examination at Screening and vital signs, clinical laboratory values, and 
ECGs at Screening and Day -1 of each period are clinically acceptable to the 
Investigator. 
5. Body mass index (BMI) ≥ 18.0 kg/m2 and ≤ 30.0 kg/m2. 
6. Willing to maintain current general diet and physical activity regimen. 
4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
Screening visit unless otherwise stated: 
1. History or evidence of clinically significant disorder, condition, or disease not 
otherwise excluded that, in the opinion of the Investigator, would pose a risk to 
subject safety or interfere with the study evaluation, procedures, or completion. 
2. Any users of tobacco- or nicotine-containing products within 6 months before Day -1 
of Part A. 
3. History suggestive of esophageal (including esophageal spasm, esophagitis), gastric, 
or duodenal ulceration or bowel disease (including, but not limited to, peptic 
ulceration, gastrointestinal bleeding, ulcerative colitis, Crohn’s disease, or irritable 
bowel syndrome); or a history of gastrointestinal surgery other than uncomplicated 
appendectomy. 
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4. History or current signs or symptoms of cardiovascular disease, including but not 
limited to myocardial infarction, congenital heart disease, valvular heart disease, 
coronary revascularization, or angina. 
5. Known substance abuse (eg, alcohol, licit or illicit drugs) within 1 year prior to 
Screening. 
6. Subjects with poor peripheral venous access. 
7. Use of any medications/substances outside the allowed timeframes as specified in 
Section 6.1.2. 
8. Currently receiving treatment in another investigational device or drug study, or less 
than 3 months, or 5 half-lives if longer, prior to receiving the first dose of study drug. 
Other investigational procedures while participating in this study are excluded. 
9. Donated blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening. 
10. Subjects who were previously exposed to OM. 
11. Hepatic impairment defined by a total bilirubin (TBL) ≥ 1.2 times the upper limit of 
normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > ULN (and confirmed upon repeat). 
12. Systolic blood pressure (BP) > 140 mmHg or < 90 mmHg, or diastolic BP 
> 90 mmHg. 
13. QTcF interval > 450 msec in male or > 470 msec in female or history/evidence of 
long QT syndrome, or PR of ≥ 200 msec; or 2nd degree atrioventricular (AV) block or 
3rd degree AV block, or heart rate > 100 bpm (and confirmed upon repeat, except 2nd 
or 3rd degree AV block, which are exclusionary based on a single finding). 
14. Troponin I or creatine kinase MB fraction (CK-MB) > ULN at Screening or Check-in 
for Part A or B. 
15. Estimated glomerular filtration rate (eGFR) < 80 mL/min/1.73 m2 at Screening as 
calculated by the Modified Diet in Renal Disease (MDRD) equation; 
16. Any positive test for drugs, cotinine (tobacco or nicotine use), and/or alcohol use.  
17. Positive hepatitis panel and/or positive human immunodeficiency virus test. Subjects 
whose results are compatible with prior immunization may be included. 
18. Subject has known sensitivity to any of the products or components to be 
administered during dosing, including history of hypersensitivity to moxifloxacin or 
any member of the quinolone class of antibacterials. 
19. History of tendon rupture or connective tissue disorders. 
20. Female subjects with a positive pregnancy test.  
21. Female subjects lactating/breastfeeding or who plans to breastfeed during the study 
through 90 days after the EOS visit. 
22. Unwilling to adhere to contraceptive requirements through 90 days after the EOS visit 
(see Appendix 7).  
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23. Unwilling to abstain from sperm and ovum donation through 90 days after the EOS 
visit. 
24. Male subjects with a female partner of childbearing potential and not willing to 
inform his partner of his participation in this clinical study. 
25. Male subjects with a pregnant partner or partner planning to become pregnant while 
the subject is on study through 90 days after the EOS visit. 
26. Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and Investigator’s knowledge. 
If generic screening was performed within the specified study screening window, selected 
study-specific procedures will be repeated either at an additional Screening visit or on 
admission to the Clinical Research Unit on Day -1 of Part A.  
4.3. 
Screen Failures and Rescreening 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently enrolled in the study due to not meeting eligibility criteria. A minimal set of 
screen failure information will be collected that includes demography, screen failure details, 
eligibility criteria, medical history, prior therapies, and any serious Adverse Events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Screen failures may only be rescreened once at the discretion of the Investigator 
in consultation with the Sponsor.  
4.4. 
Subject Number and Identification 
Subjects will be given a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of dosing in Part A. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, Subjects 0101, 0102, 0103). 
Replacement subjects (Section 4.5) will be assigned a subject number corresponding to the 
number of the subject he/she is replacing plus 1000 (eg, Subject 1101 replaces Subject 0101).  
Subjects meeting the PK Evaluation criteria will continue on to Part B, and will be 
randomized to a treatment sequence and given a randomization number on Day 1 of Part B 
Period 1. 
Subjects will be identified only by subject number on all trial documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.5. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn from dosing if any of the following criteria are met: 
• change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the Investigator (or designee) 
Approved 
 
 


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• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn from dosing, the Sponsor will be notified and the date and reason(s) 
for the withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). 
If a subject is withdrawn, efforts will be made to perform all EOS assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the clinic. The Investigator (or designee) may also request that 
the subject return for an additional follow-up visit. All withdrawn subjects will be followed 
until resolution of all their AEs or until the unresolved AEs are judged by the Investigator (or 
designee) to have stabilized. 
Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of 
adverse events thought to be related to the study treatment will generally not be replaced. 
4.6. 
Study Termination 
The Sponsor may stop the study or study site participation in the study for medical, safety, 
regulatory, administrative, or other reasons consistent with applicable laws, regulations, and 
GCP. Both the Sponsor and the Investigator reserve the right to terminate the Investigator's 
participation in the study according to the Clinical Trial Agreement (CTA). The Investigator 
is to notify the institutional review board (IRB)/independent ethics committee (IEC) in 
writing of the study's completion or early termination and send a copy of the notification to 
the Sponsor. Amgen reserves the unilateral right, at its sole discretion, to determine whether 
to supply IP and by what mechanism, after termination of the study. 
In addition, the study may be terminated by the Sponsor at any time and for any reason. If the 
Sponsor decides to terminate the study, they will inform the Investigator as soon as possible. 
4.7. 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any time 
during the study but continue participation in the study. If this occurs, the Investigator is to 
discuss with the subject the appropriate processes for discontinuation from investigational 
product or other protocol-required therapies and must discuss with the subject the 
possibilities for continuation of the Schedule of Assessments (Appendix 6) including 
different options of Follow-up (eg, in person, by phone/mail, through family/friends, in 
correspondence/communication with other treating physicians, from the review of medical 
records) and collection of data, including endpoints, adverse events, and must document this 
decision in the subject’s medical records. Subjects who have discontinued investigational 
product and/or other protocol-required therapies or procedures should not be automatically 
removed from the study. Whenever safe and feasible, it is imperative that subjects remain on 
study to ensure safety surveillance and/or collection of outcome data. 
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Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• Decision by the Sponsor 
• Lost to Follow-up 
• Death 
• Protocol deviation 
• Noncompliance  
• Adverse events 
• Subject request 
• Pregnancy 
In addition, a subject must be discontinued from study treatment if either of the following 
occur: 
• QTcF > 500 ms (as confirmed by 2 ECGs taken within 1 hour) 
• Increase in QTcF > 60 ms compared to predose baseline. 
5. STUDY TREATMENTS 
Study treatment is defined as any IP, non-investigational product (non-IP), placebo, or 
medical device intended to be administered to a study subject according to the study protocol. 
Note that in several countries, IP and non-IP are referred to as investigational medicinal 
product and non-investigational medicinal product, respectively. 
5.1. 
Investigational Products 
The Investigational Product Instruction Manual (IPIM), a document external to this protocol, 
contains detailed information regarding the storage, preparation, destruction, and 
administration of each treatment shown in Table 1. 
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Table 1: 
Study Treatments 
Study 
Treatment 
Name 
Amgen Investigational 
Product: 
Omecamtiv Mecarbil (OM) 
Amgen Investigational 
Product: Placebo 
Water 
Non-Amgen Non-
Investigational Product: 
Moxifloxacin 
Dosage 
Formulation 
Oral solution 
Water 
Oral tablets 
Unit Dose 
Strength(s)/ 
Dosage Level(s) 
and Dosage 
Frequency 
25 mg (Part A); single dose 
50 mg (Part B); single dose 
 
Not applicable; single dose 
400 mg; single dose 
Route of 
Administration 
Oral 
Oral 
Oral 
Accountability 
The quantity administered, 
date administered, and lot 
number of investigational 
product is to be recorded 
on each subject's case 
report form (CRF).  
The quantity administered, 
date administered, and lot 
number of investigational 
product is to be recorded 
on each subject's CRF. 
The quantity administered, 
date administered, and lot 
number of product is to be 
recorded on each subject's 
CRF. 
Dosing 
Instructions 
The Principal 
Investigator/designee will 
administer the treatment 
after the completion of all 
predose procedures and 
after a fast of at least 
10 hours.  
The Principal 
Investigator/designee will 
administer the treatment 
after the completion of all 
predose procedures and 
after a fast of at least 
10 hours.  
The Principal 
Investigator/designee will 
administer the treatment 
after the completion of all 
predose procedures and 
after a fast of at least 
10 hours. One tablet should 
be taken with 8 oz. of 
water. Tablet should not be 
broken or chewed. 
All supplies of IP, both bulk and subject-specific, will be stored in accordance with the 
manufacturer’s or pharmacy’s instructions. Until dispensed to the subjects, the study drugs 
will be stored at the study site in a location that is locked with restricted access. 
5.1.1. 
Dose Modification 
Dose modification is not permitted with this study. 
5.1.2. 
Guidance for Signs or Symptoms Consistent with Myocardial Ischemia or 
Infarction 
If a subject experiences clinical signs or symptoms consistent with myocardial ischemia or 
infarction, the subject should receive immediate medical attention according to the 
institution’s usual standard of care. A series of troponin samples should be analyzed at the 
local laboratory if possible. If possible, a series of samples for CK-MB should be collected 
for analysis by the local laboratory, and a series of 12-lead ECGs should be collected until the 
symptoms have reverted or a diagnosis has been established. Amgen will be notified of any 
subject experiencing clinical signs or symptoms of myocardial ischemia or infarction. 
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5.1.3. 
Treatment of Overdose 
Excessive exposure to OM may result in prolongation of the systolic ejection time to an 
extent that reduces diastolic coronary filling. The reduced coronary filling could precipitate 
myocardial ischemia or infarction. 
No antidote for OM currently exists. In the event of an overdose, health care providers should 
be especially vigilant for signs and symptoms of myocardial ischemia and should treat as 
clinically indicated. 
5.1.4. 
Medical Devices  
No investigational medical device(s) will be used in this study. 
Other non-investigational medical devices may be used in the conduct of this study as part of 
standard care. Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by the Sponsor (except, for 
example, if required by local regulation).  The investigator will be responsible for obtaining 
supplies of these devices.   
5.1.5. 
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 or device after it is released for distribution to market or clinic by either Amgen 
(Sponsor) or by distributors and partners for whom Amgen manufactures the material. This 
includes any investigational product (OM) provisioned and/or repackaged/modified by the 
Sponsor. 
Any product complaints associated with an IP (OM) supplied by Amgen (Sponsor) are to be 
reported according to the instructions provided in the IPIM. 
5.2. 
Non-Amgen Non-investigational Product 
Moxifloxacin hydrochloride non-IP will be used in this study (see Section 1.2.3).  
5.3. 
Study Treatment Administration 
For each treatment period, subjects will fast overnight from food (not including water) for at 
least 10 hours. Each dose of study treatment (moxifloxacin, OM, placebo) will be 
administered orally. Except as part of the dose administration, subjects will restrict their 
consumption of water for 1 hour predose and for 1 hour postdose; at all other times during the 
study, subjects may consume water ad libitum. Subjects will continue fasting for at least 
4 hours postdose. 
Subjects will be dosed in numerical order while standing. As soon as possible after dosing, 
subjects will be instructed to lie down supine or semi-recumbent and will remain supine or 
semi-recumbent for 2 hours after treatment administration, except as necessitated by the 
study procedures or occurrence of an AE. 
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All study treatments will be separated by a washout period of at least 7 days (including 
between Part A and Part B). 
Additional details on the study treatment administration will be provided in the IPIM. 
5.4. 
Randomization 
A subject number will be assigned at the time of dosing in Part A. Subjects meeting the PK 
Evaluation criteria will continue on to Part B, and will be randomized to a treatment sequence 
on Day 1 of Part B Period 1. The randomization date is to be documented in the subject’s 
medical record and on the enrollment eCRF. A computer-generated randomization schedule 
and emergency code-break envelopes will be provided to the clinical site. Randomization 
details will be included in the randomization specification. 
5.5. 
Blinding 
This is a partially double-blind study. Part A will be open-label. In Part B, placebo and OM 
treatments will be double-blinded, moxifloxacin treatment will be open-label, and the core 
ECG lab will be blinded to all treatment information. Except for the moxifloxacin treatment 
in one of 3 periods in Part B, treatment assignment will be blinded to all subjects, site 
personnel, the Medical Monitor, Clinical Research Associate(s), as described below. The 
bioanalytical lab and Amgen Clinical Pharmacology Modeling Simulation group will be 
unblinded, and there will additionally be an unblinded Clinical Research Associate. 
5.5.1. 
Site Personnel Access to Individual Treatment Assignments  
A subject’s assigned treatment sequence in Part B is to only be unblinded by the Investigator 
when knowledge of the treatment other than moxifloxacin in any given period is essential for 
the further management of the subject on this study or may potentially impact the safety of 
the subject. Unblinding at the study site for any other reason will be considered a protocol 
deviation. It is encouraged that the Study Manager be notified before the blind is broken 
unless the Investigator believes that identification of the study treatment is required for a 
medical emergency. If this is not possible, the Study Manager must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and CRF, as applicable. 
5.5.2. 
Access to Individual Treatment Assignments by Amgen or Designees 
Blinded individuals will not have access to unblinded information until the study is formally 
unblinded. Unblinding and potentially unblinding information is not to be distributed to the 
study team, investigators, or subjects before the study being formally unblinded (eg, the 
formal unblinding may occur at the final analysis rather than during the primary analysis) 
except as specified (eg, Section 5.5.1). 
The bioanalytical laboratory will be unblinded and receive the randomization schedule to 
facilitate analysis of the required concentration samples. 
If an SAE or significant event occurs in a subject (eg, suspected unexpected serious adverse 
reaction [SUSAR]) and the Sponsor determines that knowledge of the subject’s treatment 
sequence may be necessary to protect the safety of other subjects in this or other studies of 
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OM, the Sponsor (or designee) may be unblinded to that subject’s assigned treatment 
sequence following the same procedures as in Section 5.5.1. 
5.6. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered under the supervision of suitably qualified study site 
staff. 
• Immediately after dose administration, visual inspection of the mouth and hands will 
be performed for each subject. 
• At each dosing occasion, a predose and postdose inventory of OM, placebo, and 
moxifloxacin will be performed. 
6. STUDY RESTRICTIONS 
6.1. 
PRIOR AND CONCOMITANT THERAPIES  
6.1.1. 
Prior Therapies 
Prior therapies that were being taken/used from 30 days before enrollment through the first 
dose of study treatment will be recorded. 
6.1.2. 
Concomitant Therapies 
Concomitant therapies are to be recorded from first dose of IP through the EOS, during each 
visit and as specified in the Schedule of Assessments in Appendix 6. Any concomitant 
medication use reported throughout the study will be recorded in the source documents and 
the eCRF. The therapy name, indication, dose, unit, frequency, route, start date, and stop date 
will be recorded.  
The following medications/substances are prohibited for the periods stated: 
Medication/Substance 
Typea,b 
Examples (including, 
but not limited to) 
Restriction 
Period Start 
Restriction 
Period End 
Over-the-counter or 
prescription 
medications 
Antacids, H2-blockers, 
proton pump inhibitors, 
inhibitors of CYP3A4, 
CYP2D6 or 
P-glycoprotein (P-gp), 
aspirin, non-steroidal 
anti-inflammatory drugs 
(NSAIDS) 
Within 14 days or 
5 half-lives 
(whichever is 
longer) prior to 
receiving the dose 
in Part A 
EOS visit 
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Substances known to 
affect drug metabolism 
(CYP inducers) 
Rifampin, corticosteroids, 
anticonvulsants 
Within 30 days or 
5 half-lives 
(whichever is 
longer) prior to 
receiving the dose 
in Part A 
EOS visit 
Substances known to 
affect drug metabolism 
(Inhibitors of CYP3A4 
or P-gp) 
Ketoconazole, 
itraconazole, human 
immunodeficiency virus 
(HIV) protease inhibitors, 
nefazodone, cyclosporine, 
erythromycin, 
clindamycin, tetracycline, 
clarithromycin 
Within 14 days or 
5 half-lives 
(whichever is 
longer) prior to 
receiving the dose 
in Part A 
EOS visit 
Substances known to 
affect drug metabolism 
(Inhibitors of 
CYP2D6) 
Fluoxetine, paroxetine, 
bupropion, quinidine, 
cinacalcet 
Within 14 days or 
5 half-lives 
(whichever is 
longer) prior to 
receiving the dose 
in Part A 
EOS visit 
a 
Acetaminophen (up to 2 g per day) for analgesia and hormone replacement therapy (eg, estrogen, thyroid) 
will be allowed. 
b 
All herbal medicines (eg, St. John’s wort), vitamins, and supplements consumed by the subject within the 
30 days before receiving the first dose of OM, and continuing use, if applicable, will be reviewed by the 
Investigator. 
Subjects will refrain from use of any prescription or nonprescription medications/products 
during the study until the EOS visit, unless the Investigator (or designee) and/or Sponsor 
have given their prior consent. Throughout the study, the Investigator may prescribe any 
concomitant medications or treatments deemed necessary to provide adequate supportive 
care. 
6.2. 
Diet 
While confined at the clinical site, subjects will receive a standardized diet at scheduled times 
that do not conflict with other study-related activities. The clinical site will provide 
standardized meals, in addition to light snacks and drinks to the subjects during the 
in-residency period. The timing and composition of the meals for individual subjects should 
be the same between periods. For safety laboratory tests, subjects will be fasted at least 
8 hours before collection of blood samples at Check-in for Parts A and B. Subjects will fast 
overnight at least 10 hours prior to dose administration, and will continue fasting for at least 
4 hours after. 
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Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Day -1 of Part A until after the EOS visit. 
Caffeine-containing foods and beverages will not be allowed from 7 days before each visit 
(including Screening) and while confined to the research unit. 
Subjects must refrain from alcohol consumption within 48 hours before Check-in for each 
period and while confined to the research unit. For the remainder of the study, the use of 
alcohol by subjects should be limited to no more than 1 unit per day for females and 2 units 
per day for males (1 unit being equivalent to 12 ounces of regular beer, 5 ounces of wine, or 
1.5 ounces of 80 proof distilled spirits). 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine -containing products within 
6 months prior to Screening until the EOS visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 72 hours before each blood 
collection for clinical laboratory tests. Subjects should otherwise maintain their normal level 
of physical activity during this time (ie, will not begin a new exercise program nor participate 
in any unusually strenuous physical exertion). 
6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 3 months prior to Screening, 
plasma from 2 weeks prior to Screening, and platelets from 6 weeks prior to Screening until 
3 months after the EOS visit. 
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and the other procedures to be performed at the same timepoint. 
The order of priority for scheduling procedures around a timepoint is (in descending order of 
priority): 
• dosing 
• continuous ECG extraction window 
• pharmacokinetic blood samples  
• safety assessments 
• any other procedures. 
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7.1. 
General Assessments 
7.1.1. 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in order 
to study their possible association with subject safety and treatment effectiveness. 
7.1.2. 
Medical History 
At timepoints specified in Appendix 6, the Investigator or designee will collect a complete 
medical and surgical history. Medical history will include information on the subject’s 
concurrent medical conditions and any events occurring prior to the first dose of study 
treatment. All findings will be recorded on the medical history eCRF. 
7.1.3. 
Physical Measurements 
Height (in centimeters) and weight (in kilograms) should be measured without shoes. Body 
mass index should be calculated using the following formula:  
BMI (kg/m2) = weight (kg)/[height (cm)/100]2 
7.2. 
Electrocardiography Assessments 
7.2.1. 
Continuous 12-lead Electrocardiogram Recording 
In Part B, continuous 12-lead digital ECG recording will be performed as specified in 
Appendix 6. The continuous 12-lead digital ECG data will be stored onto SD memory cards. 
The ECGs to be used in the analyses will be selected by predetermined timepoints as defined 
in Appendix 6 and will be read centrally by ERT. 
The following principles will be followed in ERT’s core laboratory: 
• ECG analysts are blinded to the subject, visit, and treatment allocation. 
• Baseline and on-treatment ECGs for a particular subject will be over-read on the same 
lead and will be analyzed by the same reader. 
The primary analysis lead is lead II. If lead II is not analyzable, then the primary lead of 
analysis will be changed to another lead for the entire subject data set. 
The 12-lead ECGs will be extracted in up to 10 replicates at the predefined timepoints with 
subjects resting for at least 10 minutes prior to and 5 minutes after each nominal time. 
7.2.1.1. 
TQT Plus Extraction Technique 
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous recordings 
using the ‘TQT Plus method’, a computer-assisted and statistical process utilized by ERT. 
The method enables extraction of ECGs with the lowest HR variability and noise within the 
protocol-specified extraction time window (eg, the HR and QT changes from beat to beat in 
the range of < 10%). At each protocol-specified timepoint, 10 ECG replicates will be 
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extracted from a 5-minute “ECG window” (typically, the last 5 minutes of the 15-minute 
period when the subject is maintained in a supine or semi-recumbent quiet position). 
7.2.1.2. 
Expert-Precision QT Analysis 
Expert-precision QT analysis will be performed on all analyzable (non-artifact) beats in the 
10 ECG replicates. Statistical quality control procedures are used to review and assess all 
beats and identify “high” and “low” confidence beats using several criteria, including: 
• QT or QTc values exceeding or below certain thresholds (biologically unlikely). 
• Time interval between 2 successive R-waves of the QRS signal on the 
electrocardiogram (RR) values exceeding or below certain thresholds (biologically 
unlikely). 
• Rapid changes in QT, QTc or RR from beat to beat. 
Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” will be performed using COMPAS software. 
All low-confidence beats will be reviewed manually and adjudicated using pass-fail criteria. 
The final QC assessment will be performed by a cardiologist. The beats found acceptable by 
manual review will be included in the analysis. The median QT, QTc, and RR value from 
each extracted replicate will be calculated, and then the mean of all available medians from a 
nominal timepoint will be used as the subject’s reportable value at that timepoint. 
Categorical T-wave morphology analysis (Table 2) and the measurement of PR and QRS 
intervals will be performed manually in 3 of the 10 ECG replicates at each timepoint. Each 
fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) will 
be electronically marked. 
Table 2: 
T-wave Morphology Categories (Assessed Manually) 
Category 
Description 
Normal T-wave 
Any T-wave not meeting any criterion below 
Flat T-waves 
T amplitude < 1 mm (either positive or negative) including flat 
isoelectric line 
Notched T-wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on 
ascending or descending arm of the positive T-wave 
Biphasic 
T-wave that contains a second component with an opposite 
phase that is at least 0.1 mV deep (both positive and 
negative/positive and polyphasic T-waves included) 
Normal T-wave (-) 
T amplitude that is negative, without biphasic T-wave or 
notches 
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Category 
Description 
Notched T-wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on 
descending or ascending arm of the negative T-wave 
In addition to the T-wave categorical analysis, the presence of abnormal U-waves is to be 
noted. 
7.2.2. 
Safety 12-Lead Electrocardiogram 
Standard safety 12-lead ECGs will be recorded at the times indicated in the Schedule of 
Assessments in Appendix 6 in each treatment period after the subject has been supine or 
semi-recumbent and at rest for at least 5 minutes to detect any immediate ECG effects for 
subject safety. These ECGs will be viewed by the Investigator locally, with the Investigator 
only blinded to OM or placebo treatment. 
Any on-therapy ECG with a QTcF > 500 ms (as defined by automatically measured intervals) 
should be confirmed by a second ECG taken within 1 hour. If the second safety ECG 
confirms a QTcF > 500 ms, the subject should be discontinued from the study. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests that a more detailed assessment of 
ECGs is required. 
7.2.3. 
Telemetry 
Cardiac rhythm monitoring will be done by telemetry at the times indicated in Appendix 6. 
7.3. 
Pharmacokinetic Assessments 
7.3.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples for analysis of plasma OM and moxifloxacin concentrations will be obtained 
from all subjects in each treatment period of this study to ensure uniform study conditions. 
Analyses for OM will be performed on samples from subjects who receive OM and analyses 
for moxifloxacin may be performed (if needed) on samples from subjects who receive 
moxifloxacin. No analysis of blood samples taken from subjects during the placebo treatment 
period is planned. All other samples will be saved for analysis if needed. 
Blood samples (approximately 1 × 4 mL) for OM and for moxifloxacin (approximately 
1 × 2 mL) will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments in Appendix 6. Procedures for collection, processing, and shipping 
of PK blood samples will be detailed in a separate document. 
7.3.2. 
Analytical Methodology 
Plasma concentrations of OM and potentially moxifloxacin will be determined using a 
validated analytical procedure. Specifics of the analytical method will be provided in separate 
Bioanalytical Reports. 
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7.4. 
Safety and Tolerability Assessments 
7.4.1. 
Adverse Events and Serious Adverse Events: Time period and Frequency for 
Collecting and Reporting Safety Event Information     
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF until the 
subject’s completion of the study. Subjects will be observed for any signs or symptoms and 
asked about their condition by open questioning, such as “How have you been feeling since 
you were last asked?”, at least once each day while resident at the study site and at each study 
visit. Subjects will also be encouraged to spontaneously report AEs occurring at any other 
time during the study. 
Adverse Events 
Adverse events possibly related to any study procedures are reported from signing of the ICF. 
All other AEs are reported after the first dose of study treatment. The Investigator is 
responsible for ensuring that all AEs observed by the Investigator or reported by the subject 
that occur from signing of the ICF or after the first dose of study treatment as specified 
above, through the end of the study are reported using the appropriate eCRF. 
The AE grading scale to be used in this study will be the Amgen Standard Grading Scale and 
is described in Appendix 1.   
The investigator is responsible for ensuring that all AEs observed by the investigator or 
reported by the subject from first dose of study treatment through the last dose of study 
treatment or through the end of study visit, whichever is later, are recorded/reported using 
the appropriate eCRF.   
Serious Adverse Events 
The investigator is responsible for ensuring that all SAEs observed by the investigator or 
reported by the subject that occur after signing of the ICF through 30 days after the last dose 
of study treatment, are recorded/ reported using the appropriate eCRF and recorded/reported 
on the paper-based Serious Adverse Event Report Form (described in Appendix 1).  
All SAEs will be collected, recorded and reported to Amgen (Sponsor) within 24 hours of the 
investigator’s knowledge of the event. The investigator will submit any updated SAE data to 
Amgen (Sponsor) within 24 hours of it being available.   
Any AEs and remedial action required will be recorded in the subject’s source data. The 
nature, time of onset, duration, and severity will be documented, together with the 
Investigator’s (or designee’s) opinion of the relationship to study drug. 
Serious Adverse Events After the Protocol-Required Reporting Period  
There is no requirement to monitor study subjects for SAEs following the protocol-required 
reporting period or after end of study. However, these SAEs can be reported to Amgen. Per 
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local requirements in some countries, investigators are required to report SAEs that they 
become aware of after end of study. If SAEs are reported, the investigator is to report them to 
the Sponsor within 24 hours following the investigator’s knowledge of the event using the 
paper-based Serious Adverse Event Report Form.  
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the Sponsor’s safety database as clinical trial cases and handled accordingly 
based on relationship to investigational product (OM).  
Method of Detecting Adverse Events and Serious Adverse Events  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. All AEs and SAEs will be followed, where possible, until 
resolution, stabilization, until the event is otherwise explained, or the subject is lost to follow-
up. This will be completed at the Investigator’s (or designee’s) discretion. 
All new information for previously reported SAEs must be sent to Amgen within 24 hours 
following knowledge of the new information. If specifically requested, the investigator may 
need to provide additional follow-up information, such as discharge summaries, medical 
records, or extracts from the medical records. Information provided about the SAE must be 
consistent with that recorded on the appropriate eCRF. 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of an SAE, this 
information must be submitted to the Sponsor. 
Prompt notification by the investigator to the sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Individual safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators 
as necessary. 
An investigator who receives an individual safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
Part B of the study - to comply with worldwide reporting regulations for SAEs, the treatment 
assignment of subjects who develop serious, unexpected, and related AEs may be unblinded 
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by Amgen before submission to regulatory authorities. Aggregate analyses may also be 
unblinded by the Safety Assessment Team, as appropriate. Investigators will receive 
notification of related SAE reports sent to regulatory authorities in accordance with local 
requirements. 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the Sponsor’s safety surveillance and 
signal management processes. 
7.4.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 3. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a pregnancy test will be performed at the times 
indicated in the Schedule of Assessments in Appendix 6. 
The Investigator (or designee) is responsible for reviewing laboratory test results and 
recording any clinically relevant changes occurring during the study in the appropriate CRF. 
The Investigator (or designee) must determine whether an abnormal value in an individual 
study subject represents a clinically significant change from the subject’s baseline values. In 
general, abnormal laboratory findings without clinical significance (based on the 
Investigator's [or designee’s] judgment) are not to be recorded as AEs. However, laboratory 
value changes that require treatment or adjustment in current therapy are considered AEs. 
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded as 
AEs. 
7.4.3. 
Vital Signs 
Supine (or semi-recumbent) BP, supine (or semi-recumbent) pulse rate, and oral body 
temperature will be assessed at the times indicated in the Schedule of Assessments in 
Appendix 6. Vital signs may also be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests that a more detailed assessment of 
vital signs is required. 
Vital signs measurements will be taken singly and will be repeated once if outside the 
relevant clinical reference range. 
Subjects must be supine or semi-recumbent for at least 5 minutes before BP and pulse rate 
measurements. 
7.4.4. 
Physical Examination 
A full physical examination and symptom-directed physical examination will be performed at 
the timepoints specified in the Schedule of Assessments in Appendix 6. 
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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
With approximately 60 enrolled subjects, it is estimated that approximately 48 evaluable 
subjects will have data from all 3 periods in Part B.  
Based on the calculation of the sample size for a TQT study12, assuming a 1-sided 5% 
significance level and a within-subject standard deviation (SD) of 7 msec for ΔQTcF, and a 
true mean difference of 3 msec in ΔQTcF between OM and placebo, a sample size of 
48 evaluable subjects would be expected to provide 99.5% power to demonstrate that the 
upper bounds of all the 2-sided 90% confidence intervals (CIs) on ΔΔQTcF will fall below 
10 msec for up to 8 timepoints. With the within-subject SD of 8 msec and other similar 
assumptions, the power will decrease to 96.5%.  
Determination of sample size for assay sensitivity: 
Assuming a 1-sided 5% significance level and a within-subject SD of 7 msec for ΔQTcF, a 
sample size of 48 evaluable subjects will provide a power of 99.9% to exclude a mean 
difference of 5 msec in ΔQTcF between moxifloxacin and placebo groups from the lower 
bound of the 2-sided 90% CI on ΔΔQTcF at at least 1 of the 3 prespecified timepoints. With 
the within-subject SD of 8 msec and other similar assumptions, the power will decrease to 
99%. 
8.2. 
Analysis Populations 
The full analysis set (FAS) includes all randomized subjects who have received at least 
1 dose of each study treatment (OM, moxifloxacin, and placebo).  
The PK population will include all subjects who received at least 1 dose of OM and have 
evaluable PK data. Any subject who experiences emesis within 4 hours of dosing or diarrhea 
within 24 hours of dosing may be excluded from the PK analysis. 
The QT/QTc analysis set will include all subjects in FAS with measurements at baseline as 
well as on-treatment with at least 1 postdose timepoint with a valid ΔQTcF value in Part B. 
The QT/QTc analysis set will be used for the by-timepoint and categorical analyses of 
cardiodynamic ECG parameters. 
The PK/QTc analysis set will include all subjects who are in both the QT/QTc and PK 
analysis sets with at least 1 pair of postdose PK and QTcF data from the same timepoint. The 
PK/QTc analysis set will be used for the concentration-QTc analysis in Part B. 
The safety analysis set will include all subjects who receive at least 1 dose of study treatment. 
8.3. 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock. 
Below is a summary of the timing and methods for the planned statistical analyses. To 
preserve study integrity, the final analysis will be conducted and reported following the EOS, 
as defined in Section 3.1. 
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8.3.1. 
Primary Analysis 
Primary analysis will be conducted after 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 locked. Based on the locked data, cardiodynamic, PK, and safety 
analyses will be performed. 
8.3.2. 
General Considerations 
Summary statistics for continuous variables will include number of subjects, mean, median, 
SD or standard error, minimum, and maximum. For categorical variables, frequency and 
percentage will be given.  
Safety data will be analyzed and reported by treatment (OM, placebo, or moxifloxacin). 
Statistical inferences will be provided for analyses of primary endpoints. Unless specified 
otherwise, all statistical tests are 2-sided with a significance level of 0.05; no statistical 
inference and imputation will be conducted for analyses of safety endpoints. 
8.3.3. 
Cardiodynamic ECG Assessments 
The Cardiac SAP will provide details on the planned electrocardiography analyses. 
8.3.3.1. 
Baseline for Cardiodynamic ECG Assessments 
For all continuous ECG parameters from each period, baseline will be the average of the 
measured ECG intervals from the 3 predose timepoints (-1.25, -1, and -0.75 hours) for the 
respective period. 
8.3.3.2. 
Primary Cardiodynamic Analysis 
The primary analysis of the QT/QTc data will be the “by-timepoint” analysis for QTcF, based 
on a linear mixed-effects model with ΔQTcF as the dependent variable; period, sequence, 
time (categorical), treatment (OM, moxifloxacin, and placebo), and time-by-treatment 
interaction as fixed effects; and baseline QTcF as a covariate. An unstructured covariance 
matrix will be specified for the repeated measures at timepoints for subject within-treatment 
period. If the model with an unstructured covariance matrix fails to converge, other 
covariance matrices such as compound symmetry and autoregressive will be considered. The 
model will also include a subject-specific random effect. If the fixed effects for period and/or 
sequence should prove to be nonsignificant (ie, if the p-value > 0.1), these effects may be 
removed from the model and the analysis will be repeated without those covariates. From this 
analysis, the least squares (LS) mean and 2-sided 90% CI will be calculated for the contrast 
“OM versus placebo” at each postdose timepoint, separately. If the upper bound of the CI lies 
below 10 msec for all postdose timepoints, OM will be concluded not to have a significant 
effect on QT interval prolongation. 
8.3.3.3. 
Secondary Cardiodynamic Analyses 
For HR, PR, and QRS intervals, the analysis will be based on the change-from-baseline 
post-dosing (ΔHR, ΔPR, and ΔQRS). The same model will be used as described for QTcF in 
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the by-timepoint analysis. The LS mean, standard error, and 90% CI from the statistical 
modeling for both change-from-baseline and placebo-corrected change-from-baseline values 
will be listed in tables and graphically displayed. 
8.3.3.4. 
Assay Sensitivity 
The analysis to show assay sensitivity will be based on the change-from-baseline post-dosing 
QTcF of moxifloxacin. The same model will be used as described for the primary analysis. 
For the timepoints 2, 3, and 4 hours after dose administration, the contrast in treatment 
ΔΔQTcF = “moxifloxacin – placebo” will be tested against the 1-sided null hypothesis 
ΔΔQTcF ≤ 5 msec at the 5% level. Multiplicity will be controlled using the Hochberg 
procedure.13 If after this procedure QTc (ΔΔQTcF) is significantly larger than 5 msec for at 
least 1 timepoint, assay sensitivity will be considered shown. In addition, 2-sided 90% CIs 
will be obtained for the contrast at all timepoints and used in the figures. 
8.3.3.5. 
Categorical Analyses 
The results for categorical outliers, T-wave morphology, and U-wave presence will be 
summarized in frequency tables with counts and percentages for both number of subjects and 
number of timepoints. For categorical outliers, the number (percentage) of subjects as well as 
timepoints that had increases in absolute QTcF values > 450 and ≤ 480 msec, > 480 and 
≤ 500 msec, or > 500 msec, and changes from predose baseline of > 30 and ≤ 60 msec, or 
> 60 msec; increase in PR from predose baseline > 25% to a PR > 200 msec; increase in QRS 
from predose baseline > 25% to a QRS > 120 msec; decrease in HR from predose baseline 
> 25% to a HR < 50 bpm; and increase in HR from predose baseline >25% to a HR > 100 
bpm will be determined. For T-wave morphology and U-wave presence, the analyses will be 
focused on change from baseline (ie, treatment-emergent changes). 
Outliers for HR and PR, QRS, QT, and QTc intervals will be summarized. New ECG 
morphological changes will be summarized. “New” means not present on any baseline ECG 
and becomes present on at least 1 on-treatment ECG. 
8.3.4. 
Pharmacokinetic Analyses 
The plasma PK parameters of OM will be calculated using standard noncompartmental 
methods. Plasma concentrations and PK parameters for OM and potentially plasma 
concentrations for moxifloxacin will be summarized by descriptive statistics. No formal 
statistical analyses are planned. 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of OM: 
Cmax 
maximum observed concentration 
tmax  
time to maximum observed concentration 
AUC0-t 
area under the concentration-time curve from time 0 to the time of the 
last quantifiable concentration 
AUCinf 
area under the concentration-time curve from time 0 to infinity 
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%AUCextrap 
percentage of AUCinf that is due to extrapolation 
t1/2 
apparent terminal elimination half-life 
CL/F 
apparent total plasma clearance  
VZ/F 
apparent volume of distribution 
Other PK parameters may also be calculated. Moxifloxacin plasma samples may be assayed 
and PK parameters will be calculated only if deemed necessary. 
8.3.5. 
Pharmacokinetic/Electrocardiography Analyses 
The Cardiac SAP will provide details on the planned PK/electrocardiography analyses. 
The concentration-QTc analysis, based on ΔΔQTcF, will be reported separately. That is, for 
the placebo adjustment, the individual ΔQTcF for placebo calculated at a specific timepoint is 
subtracted from ΔQTcF for the same subject on OM at the same timepoint to generate 
ΔΔQTcF. The relationship between OM plasma concentration and ΔΔQTcF will be 
investigated by linear mixed-effects modeling with ΔΔQTcF as the dependent variable, 
time-matched concentration of OM as the explanatory variate, centered baseline QTcF 
(ie, baseline QTcF for individual subject subtracting the population mean baseline QTcF for 
all subjects in the same period) as an additional covariate, a fixed intercept, and subject as a 
random effect for both intercept and slope, when applicable.  
The geometric mean of the individual Cmax values for subjects on each of the active dose 
groups will be determined, respectively. The predicted population average ΔΔQTcF (ie, slope 
estimate × concentration + intercept) and its corresponding 2-sided 90% CI at the observed 
geometric mean Cmax of OM will be obtained.  
The plot of the observed median-quantile OM concentrations and associated mean ΔΔQTcF 
(2-sided 90% CI) together with the regression line presenting the predicted ΔΔQTcF (2-sided 
90% CI; as described by Tornøe et al)14 will be used to evaluate the adequacy of the model fit 
to the assumption of linearity and the impact on quantifying the exposure response. For 
evaluation of the heart rate-corrected QT interval, a scatter plot and a quantile plot of QTcF 
and RR intervals by treatment with regression line and a linear mixed-effects line (90% CI), 
respectively, will also be given. Additional exploratory analyses (via graphical displays 
and/or model fitting) will include accounting for a delayed effect (hysteresis) and the 
justification for the choice of PD model (linear versus nonlinear) as follows.  
8.3.5.1. 
Investigation of Hysteresis 
Hysteresis will be assessed based on joint graphical displays of the LS mean difference 
between ΔQTcF under OM and under placebo (ΔΔQTcF) for each postdose timepoint and the 
mean concentrations of OM at the same timepoints. In addition, hysteresis plots will be given 
for LS mean ΔΔQTcF and the mean concentrations. If a QT effect (∆∆QTcF) > 10 msec 
cannot be excluded from the by-timepoint analysis and if a delay between peak ∆∆QTcF and 
peak plasma concentration in the plot (ΔΔQTcF versus OM) of more than 1 hour is observed, 
other C-QTc models, such as a model with an effect compartment, may be explored. With the 
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provision stated above, hysteresis will be assumed if the curve of hysteresis plot shows a 
counterclockwise loop. 
8.3.5.2. 
Appropriateness of a Linear Model 
To assess the appropriateness of a linear model, normal Q-Q plots for the standardized 
residuals and random effects, and plots of standardized residuals versus concentration and 
versus fitted values and versus centered baseline QTcF will be produced. The scatter plots of 
standardized residuals versus concentration and versus centered baseline QTcF by LOESS 
fitting (ie, locally weighted scatter plot smoothing as described by Cleveland)15 will also be 
produced with optimal smoothing parameters selected by the Akaike information criterion 
with a correction.16 A scatter plot of observed concentration and ΔΔQTcF with LOESS line 
(90% CI) and linear regression line will also be provided to check the assumption of linear 
concentration-QTc relationship. If there is an indication that a linear model is inappropriate, 
additional models will be fitted, in particular, an Emax model. 
The concentration-QTc analysis will then be repeated for the model found to best 
accommodate the nonlinearity detected. 
8.4. 
Safety Analyses 
8.4.1. 
Adverse Events 
The number and percentage of subjects reporting any TEAEs will be tabulated by Medical 
Dictionary for Regulatory Activities system organ class and preferred term. Tables of fatal 
AEs, SAEs, AEs leading to withdrawal from IP or other protocol-required therapies, and 
significant TEAEs will also be provided. Subject-level data may be provided instead of tables 
if the subject incidence is low. 
8.4.2. 
Clinical Laboratory Tests 
Key safety laboratory endpoints will be summarized in descriptive statistics. Details will be 
provided in the SAP. 
8.4.3. 
Vital Signs 
The analyses of vital signs, including systolic BP, diastolic BP, pulse, and temperature, will 
be summarized using the descriptive statistics at each scheduled timepoint. 
8.4.4. 
Physical Measurements 
The analyses of height, weight, and BMI measurements will include summary statistics at 
baseline. 
8.4.5. 
Safety 12-Lead Electrocardiograms 
Summaries over time and/or changes from baseline over time will be provided for all safety 
ECG parameters. Subjects’ maximum change from baseline in QTcF will be categorized and 
the number and percentage of subjects in each group will be summarized. Subjects’ 
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maximum post-baseline values will also be categorized and the number and percentage of 
subjects in each group will be summarized. 
8.5. 
Interim Analysis 
No interim analyses are planned for this study. 
9. REFERENCES 
1. Omecamtiv mecarbil (AMG 423) Investigator’s Brochure. Edition 14.1. Thousand Oaks, 
CA: Amgen Inc.; 26 October 2018. 
2. Hilfiker-Kleiner D, Landmesser U, Drexler H. Molecular mechanisms in heart failure. 
Focus on cardiac hypertrophy, inflammation, angiogenesis, and apoptosis. J Am Coll 
Cardiol. 2006;48: Suppl A:A56-66. 
3. López-Sendón J. The heart failure epidemic. Medicographia. 2011;33:363-369. 
4. Konstam M, Gheorghiade M, Burnett J, et al. Effects of oral tolvaptan in patients 
hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 
2007;297:1319-31. 
5. Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of 
hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. 
J Am Coll Cardiol. 2014;63:1123-33. 
6. Yancy C, Jessup M, Bozkurt B, et al. ACCF/AHA guideline for the management of heart 
failure: A report on the American College of Cardiology Foundation/American Heart 
Association Task Force on practice guidelines. Circ. 2013;128:e240-e327. 
7. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure. Eur Heart J. 2016;37:2129-2200/ 
Corrigendum in Eur Heart J. 2017; ehx158. doi: 10.1093/eurheartj/ehx158. 
8. Krum H, Teerlink JR. Medical therapy for chronic heart failure. Lancet. 
2011;378:713-21. 
9. 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;378:667-75. 
10. Malik FI, Hartman JJ, Elias KA, et al. Cardiac myosin activation: a potential therapeutic 
approach for systolic heart failure. Science. 2011;331:1439-43. 
11. Avelox [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2016. 
12. Zhang J and Machado SG. Statistical issues including design and sample size calculation 
in thorough QT/QTc studies. J Biopharm Stat. 2008;18(3):451-67. 
13. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988;75:800-02. 
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14. Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin Pharmacol. 2011;51(7):1035-42. 
15. Cleveland WS. Robust locally weighted regression and smoothing scatter plots. J Amer 
Statist Assoc. 1979;74(368):829-36. 
16. Hurvich, CM, Simonoff, JS, and Tsai, CL. Smoothing parameter selection in 
nonparametric regression using an improved Akaike information criterion. J Roy Statist 
Soc Ser B. 1998;60(2):271-93. 
17. ICH E14. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs. May 2005. Available: 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/the-clinical-
evaluation-of-qtqtc-interval-prolongation-and-proarrhythmic-potential-for-non-
antiarrh.html. 
 
 
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10. APPENDICES 
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Appendix 1: Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
• An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.  
• Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device or 
procedure. 
Events Meeting the Adverse Event Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the Investigator (ie, not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/serious adverse event (SAE) unless it is an intentional overdose taken with 
possible suicidal/self-harming intent. Such overdoses are to be reported regardless of 
sequelae. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE event if they fulfill the definition of an AE or SAE. Also, 
“lack of efficacy” or “failure of expected pharmacological action” also constitutes an 
AE or SAE. 
Events NOT Meeting the Adverse Event Definition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
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Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
• The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are an AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE is to be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which 
may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
• Medical or scientific judgment is to be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the subject or may require medical or surgical intervention to 
prevent 1 of the other outcomes listed in the above definition. These events are 
typically to be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
 
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Recording Adverse Events, and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
• When an AE or SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant adverse event/serious adverse event 
information in the Event case report form (CRF). 
o Additionally, the Investigator is required to report a fatal event on the appropriate 
CRF. 
• The Investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to Amgen investigational product (IP): (OM/placebo), 
Non-Amgen protocol-required therapy (Moxifloxacin) and/or study-mandated 
procedures; and 
o Action taken. 
• If the severity of an AE changes from the date of onset to the date of resolution, 
record as a single event with the worst severity on the appropriate CRF.  
• It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to Sponsor in lieu of completion of the appropriate CRF page. 
• If specifically requested, the Investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records. In this case, all subject identifiers, with the exception of the subject 
number, will be blinded on the copies of the medical records before submission to 
Amgen. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study. The assessment of severity will be based on:  
The Amgen Standard Grading Scale as show below: 
Grade 
Definition 
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MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVEREa 
Incapacitating, with inability to work or do usual activity 
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between IP (OM/placebo), 
protocol-required therapy (Moxifloxacin) and/or study-mandated procedure and each 
occurrence of AE/SAE. 
• Relatedness means that there are facts or reasons to support a relationship between IP 
and the event. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report. However, it is very important that 
the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of Adverse Event and Serious Adverse Event 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Amgen to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• If a subject is permanently withdrawn from IP/protocol-required therapies because of 
an SAE, this information must be submitted to Amgen. 
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• 
If a subject dies during participation in the study or during a recognized 
follow-up period, the Investigator will provide Amgen with a copy of any 
post-mortem findings including histopathology.  
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data to Amgen within 24 hours of 
receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Paper Case Report Form (SAER Form) 
• Facsimile transmission of the Serious Adverse Event Report Form (see Figure 2) is 
the preferred method to transmit this information. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the Serious Adverse Event Report Form sent 
by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the Serious Adverse Event Report Form within the designated 
reporting time frames. 
 
 
 
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Figure 2: 
Sample Serious Adverse Event Report Form 
 
 
 
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Appendix 2: Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Assessments (Appendix 6) 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 before 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.  
Since the evaluations are not expected to benefit the subject directly or to alter the treatment 
course, the results of any exploratory studies are not placed in the subject’s medical record 
and are not to be made available to the subject, members of the family, the personal 
physician, or other third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by contacting 
the Investigator. Following the request from the subject, the Investigator is to provide the 
Sponsor with the required study and subject number so that any remaining samples and any 
other components from the cells can be located and destroyed. Samples will be destroyed 
once all protocol-defined procedures are completed. However, information collected from 
samples before 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 Appendix 5 for subject confidentiality. 
Approved 
 
 


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Appendix 3: Clinical Laboratory Evaluations 
Clinical chemistrya: 
Hematologya: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Urea 
Uric acid 
Hematocrit 
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination 
Serologyb: 
Drug screenc: 
 
Hepatitis B core antibody 
Hepatitis B surface antigen 
Hepatitis B surface antibody 
Hepatitis C antibody 
Human immunodeficiency virus 
(HIV-1 and HIV-2) antibodies 
Including, but not limited to: 
Amphetamines/methamphetami
nes 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Cotinine 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Alcohol breath test 
 
Hormone panel - females 
only: 
Other tests: 
 
Follicle-stimulating hormoneb 
(postmenopausal females only) 
Serum pregnancy test (human 
chorionic gonadotropin)d 
Urine pregnancy teste 
Troponin I 
Creatine kinase-MBf 
 
 
a Blood samples for clinical chemistry and hematology. 
b Only analyzed at Screening. 
c Only analyzed at Screening and at Check-in of each period. 
d Performed at Screening for all females. 
e Performed for all females at each Check-in and the Follow-up/End of Study visit. A positive urine pregnancy test will be 
confirmed with a serum pregnancy test. 
f CK-MB at post-baseline timepoints also to be collected if possible in the event of a suspected coronary event. 
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Appendix 4: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Serology 
3.5 
1 
3.5 
Safety laboratory tests 
7.5 
7 
52.5 
OM pharmacokinetics 
4 
27 
108 
Moxifloxacin 
pharmacokinetics 
2 
16 
32 
Placebo blood samplinga 
4 
16 
64 
Troponin-I sampling 
2.5 
16 
40 
Total: 
300 
a 
Blood samples will be collected but not analyzed for the placebo treatment period. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will be less than 500 mL. 
Any blood sample collected according to the Schedule of Assessments 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. 
Approved 
 
 


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Appendix 5: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated. A copy of the 
written approval of the protocol and ICF must be received by the Sponsor (Amgen Inc.) 
before recruitment of subjects into the study and shipment of Amgen investigational product 
(IP). 
Amgen may amend the protocol at any time. Any protocol amendments will require EC and 
regulatory authority (as locally required) approval before implementation of changes made to 
the study design, except for changes necessary to eliminate an immediate hazard to study 
subjects or any nonsubstantial changes, as defined by regulatory requirements. The 
Investigator must send a copy of the approval letter from the EC and amended protocol 
Investigator’s Signature page to Amgen before implementation of the protocol amendment at 
their site. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the EC. 
• Obtaining annual EC approval/renewal throughout the duration of the study. Copies 
of the Investigator’s reports and the EC continuance of approval must be sent to 
Amgen. 
• Notifying the EC of serious adverse events (SAE) or other significant safety findings 
as required by EC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR; if applicable), ICH guidelines, 
the EC, European regulation 536/2014 for clinical studies, and all other applicable 
local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
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Informed Consent 
An initial sample ICF will be provided for the Investigator (or designee) to prepare the 
informed consent document to be used at his or her site. Updates to the sample ICF are to be 
communicated formally in writing from the Study Manager to the Investigator. The written 
ICF is to be prepared in the language(s) of the potential study participant population. 
The Investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any IP(s) is/are 
administered and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative (defined as an individual or other body authorized under applicable 
law to consent, on behalf of a prospective subject, to the subject’s participation in the clinical 
study) will then be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, and the EC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
The Investigator is also responsible for asking the subject if the subject has a primary care 
physician and if the subject agrees to have his/her primary care physician informed of the 
subject’s participation in the clinical study unless it is a local requirement. The Investigator 
shall then inform the primary care physician. If the subject agrees to such notification, the 
Investigator is to inform the subject’s primary care physician of the subject’s participation in 
the clinical study. If the subject does not have a primary care physician and the Investigator 
will be acting in that capacity, the Investigator is to document such in the subject’s medical 
record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent discussion. 
Subject withdrawal of consent or discontinuation from study treatment and/or procedures 
must also be documented in the subject’s medical records. 
Subjects must be re-consented to the most current version of the ICF during their 
participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a copy 
of the ICF must be provided to the subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the Investigator must provide an impartial witness to read the ICF to the 
subject and must allow for questions. Thereafter, both the subject and the witness must sign 
the ICF to attest that informed consent was freely given and understood. (Refer to ICH E6 
GCP guideline, Section 4.8.9). 
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A subject who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date. 
Subject Data Protection 
The Investigator must ensure that the subject’s confidentiality is maintained for documents 
submitted to Amgen. 
A subject will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  
On the electronic case report form (eCRF) demographics page, in addition to the unique 
subject identification number, include the age at time of enrollment. 
For SAEs reported to Amgen, subjects are to be identified by their unique subject 
identification number and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in confidence by 
the Investigator, except as described below. 
In compliance with 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/EC direct access to review the subject’s original medical records for verification of 
study-related procedures and data. Direct access includes examining, analyzing, verifying, 
and reproducing any records and reports that are important to the evaluation of the study.  
The Investigator is obligated to inform and obtain the consent of the subject to permit such 
individuals to have access to his/her study-related records, including personal information. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential information of 
the Sponsor. The Investigator (or designee) agrees not to disclose such information in any 
way without prior written permission from the Sponsor. 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 permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. 
• All data collected at the Clinical Research Unit is recorded on source documents prior 
to entry in the eCRF. The Investigator must maintain accurate documentation (source 
data) that supports the information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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• The Sponsor or Contract Research Organization (CRO) is responsible for the data 
management of this study including quality checking of the data. Predefined, agreed 
risks, monitoring thresholds, quality tolerance thresholds, controls, and mitigation 
plans will be documented in a risk management register. Additional details of quality 
checking to be performed on the data may be included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in the study site archive for at least 5 years after 
the end of the study unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the Sponsor. No records may be transferred to another location or 
party without written notification to the Sponsor. 
Investigator Documentation Responsibilities 
The Investigator is to maintain a list of appropriately qualified persons to whom he/she has 
delegated study duties. All persons authorized to make entries and/or corrections on CRFs 
will be included on the Delegation of Authority Form. 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to the Sponsor or CRO electronically, will be integrated with the subject’s eCRF 
data in accordance with the Data Management Plan. 
An eCRF must be completed for each subject who is enrolled in the study, according to the 
eCRF completion instructions. The Sponsor or CRO will review the supporting source 
documentation against the data entered into the eCRFs to verify the accuracy of the electronic 
data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for medical, 
safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement. The Investigator is to 
Approved 
 
 


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notify the Independent Ethics Committee in writing of the study’s completion or early 
termination and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen IP(s) by an extension protocol 
or as provided for by the local country’s regulatory mechanism. However, Amgen reserves 
the unilateral right, at its sole discretion, to determine whether to supply Amgen IP(s) and by 
what mechanism, after termination of the study and before the product(s) is/are available 
commercially 
Publications 
To coordinate dissemination of data from this study, the Investigator will obtain input and 
assistance from Amgen staff as appropriate. 
Authorship of any publications resulting from this study will be determined on the basis of 
the Uniform Requirement for Manuscripts Submitted to Biomedical Journals International 
Committee of Medical Journal Editors Recommendations for the Conduct of Reporting, 
Editing, and Publications of Scholarly Work in Medical Journals, which states: Authorship 
credit is to be based on: (1) substantial contributions to conception and design, acquisition of 
data, or analysis and interpretation of data; (2) drafting the article or revising it critically for 
important intellectual content; (3) final approval of the version to be published; and (4) 
agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript. These individuals must fully 
meet the criteria for authorship defined above. Acquisition of funding, collection of data, or 
general supervision of the research group, alone, does not justify authorship. All persons 
designated as authors must qualify for authorship, and all those who qualify are to be listed. 
Each author must have participated sufficiently in the work to take public responsibility for 
appropriate portions of the content. 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. 
Approved 
 
 


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Appendix 6: Schedule of Assessments 
Approved 
 
 


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Table 3: 
Schedule of Assessments 
Activity 
Screening 
 
Part A 
 
Follow-
up/EOSb 
Day 
Within -28 
days of Day 1 -1 
1 
2 
3 
6 
Time (hours)a 
 
 
Predose 0.25 
0.5 
0.75 
1 
2 
3 
4 
6 
8 
12 
24 
48 
120 
Clinical Research Unit 
Residency 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
 
Outpatient Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG – standard safety 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Vital signs (BP, HR) 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Vital signs (temp) 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventse 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY PROCEDURES 
Clinical chemistry 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFRg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test (females only)h 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FSH (females only)i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponin I 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
CK-MB 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug, alcohol, and cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Activity 
Screening 
 
Part A 
 
Follow-
up/EOSb 
Day 
Within -28 
days of Day 1 -1 
1 
2 
3 
6 
Time (hours)a 
 
 
Predose 0.25 
0.5 
0.75 
1 
2 
3 
4 
6 
8 
12 
24 
48 
120 
Clinical Research Unit 
Residency 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
 
Outpatient Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIVAb, HBsAg, anti-HBs, anti-
HBc, HCAb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OM plasma PKj 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
TREATMENTk 
OM 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK EVALUATION 
 
Determine subject eligibility for 
Part B of study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
Abbreviations: AE = adverse event; anti-HBs = hepatitis B surface antibody; anti-HBc = hepatitis B core antibody; BMI = body mass index; BP = blood pressure; CK-MB = creatine kinase MB 
fraction; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = End of Study; FSH = follicle-stimulating hormone; HBsAg = hepatitis B surface antigen; 
HCAb = hepatitis C antibody; HIVAb = human immunodeficiency virus antibody; HR = heart rate; ICF = Informed Consent Form; MDRD = Modified Diet in Renal Disease; OM = omecamtiv 
mecarbil; PK = pharmacokinetic; Temp = temperature; SAE = serious adverse event.  
a 
Time (in hours) is relative to treatment administration.  
b 
Subjects will return to the clinic on Day 6 for safety evaluations. For subjects with maximum OM plasma concentrations > 350 ng/mL, the completion of these procedures will be 
considered the End of Study (EOS). Subjects who withdraw or early terminate prior to Day 6 should also return for Day 6 procedures, if possible. 
c 
Subjects may be discharged from the unit after all assessments are completed.  
d 
Medical history since Screening. 
e 
Adverse events (AEs) are collected from the time of the first dose of study treatment until EOS. Events occurring prior to dosing will be reported as baseline signs and symptoms or 
medical history, as applicable.  
f 
Serious adverse events (SAEs) are collected from the time the ICF is signed until 30 days after the last dose. 
g 
eGFR will be calculated using the MDRD equation. 
h 
Serum pregnancy test at Screening. Urine pregnancy tests will be used on Day -1 and at Follow-up/EOS. 
i  
FSH must be measured for all females to confirm postmenopausal status. 
j   
Pharmacokinetic (PK) samples should be collected within 5 minutes. Samples collected outside of this window should still be collected and recorded as protocol deviations. 
k   
Treatment will be administered after all predose procedures are completed and after at least a 10-hour fast. 
l 
Subjects with maximum plasma OM concentrations ≤ 350 ng/mL will be eligible to continue to Part B. Due to logistics of sample shipping and analysis, this may occur after Day 6 
(but prior to Part B). 
 
Approved 
 
 


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Activity 
Part B: Treatment Periods 1 – 3 
End of 
period/
Studyb 
Day in Period 1 
-1 
1 
2 
3 
4 
5 
6 
Day in Period 2 
-1 
1 
2 
3 
4 
5 
6 
Day in Period 3 
-1 
1 
2 
3 
4 
5 
6 
(EOS) 
Time (hours)a 
 
-1.25 
-1 
-0.75 Predose 0.25 0.5 0.75 
1 
1.5 
2 
3 
4 
8 
12 
24 
48 
72 
96 
120 
Clinical Research Unit Residency 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GENERAL AND SAFETY ASSESSMENTS 
Randomization 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (BP, HR) 
X 
 
 
 
Xi 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
Vital signs (temp) 
X 
 
 
 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
ECG – standard safety 
X 
 
 
 
Xi 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
Xd 
ECGe – extraction windows 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
ECG – telemetry monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Physical exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse eventsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY PROCEDURES 
Clinical chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Pregnancy test (females only)h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Troponin I 
Xn 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Xd 
CK-MB 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug, alcohol, and cotinine screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OM plasma PKl 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Moxifloxacin plasma PKl 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TREATMENTj,k 
OM, Moxifloxacin, or Placebo 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 70 of 80 
BMI = body mass index; BP = blood pressure; CK-MB = creatine kinase MB fraction; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; 
FSH = follicle-stimulating hormone; anti-HBs = hepatitis B surface antibody; anti-HBc = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCAb = hepatitis C antibody; HIVAb = 
human immunodeficiency virus antibody; HR = heart rate; OM = omecamtiv mecarbil; PK = pharmacokinetic; Temp = temperature.  
a 
Time (in hours) is relative to treatment administration during each period.  
b 
Subjects may be discharged from the unit after all assessments are completed in Period 3. Subjects who withdraw or terminate early should have EOS procedures performed, if 
possible.  
c 
Subjects will be randomized to a treatment sequence prior to dosing in Period 1. 
d 
Assessment to be performed at EOS only or if a subject is withdrawn early from the study. 
e  
ECGs will be extracted from the continuous 12-lead digital ECG recording as noted. The recording will be performed for approximately 27 hours in total. Subjects should lie down in 
a quiet room for at least 10 minutes before and 5 minutes after each extraction at the timepoints listed.  
f 
Adverse events (AEs) are collected from the time of the first dose of study treatment to EOS. Events occurring prior to the first dose in Part B but after dosing in Part A will be 
reported as occurring in Part A. 
g 
Serious adverse events (SAEs) are collected from the time the ICF is signed until 30 days after the last dose. 
h 
Urine pregnancy tests will be used on Day -1 of each dosing period and at EOS. 
i   
Predose vital signs measurements and safety ECGs are to be performed prior to the start of continuous cardiac monitoring. 
j   
Treatments will be separated by a washout period of ≥ 7 days.  
k   
Treatment will be administered after all predose procedures are completed and after at least a 10-hour fast. 
l   
Pharmacokinetic (PK) samples should be collected within 5 minutes after the completion of the digital ECG extraction window through 24 hours postdose and within ± 2 hours of the 
digital ECG extraction windows after 24 hours postdose. Samples collected outside of this window should still be collected and recorded as protocol deviations.  
n 
Collect only on Day -1 of Period 1. 
 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 71 of 80 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 
All subjects must receive pregnancy prevention counseling and be advised of the risk to the 
fetus if they conceive a child during treatment and for 90 days after the Follow-up visit. 
Additional medications given during the study may alter the contraceptive requirements. The 
Investigator must discuss these contraceptive changes with the subject. 
Definitions 
Women of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche.  
Women of Non-Child-Bearing Potential:  
1. Surgically sterile: Females who are permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history and/or 
medical records. Surgical sterilization to have occurred a minimum of 6 weeks, or 
at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhea should not be induced by 
a medical condition such as anorexia nervosa, hypothyroid disease or polycystic 
ovarian disease, or by extreme exercise. It should not be due to concomitant 
medications that may have induced the amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormones, anti-estrogens, or selective estrogen 
receptor modulators. 
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance  
Female Subjects  
Female subjects who are of nonchildbearing potential will not be required to use 
contraception. Female subjects of childbearing potential must be willing to use 1 highly 
effective method of contraception and a barrier method (male or female) from the time of 
signing the Informed Consent Form (ICF) until 90 days after the Follow-up visit.  
Primary (highly effective) methods of contraception include:  
• Hormonal injection (as prescribed) 
• Combined oral contraceptive pill or progestin/progestogen-only pill associated with 
inhibition of ovulation (as prescribed) 
• Combined hormonal patch (as prescribed) 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 72 of 80 
• Combined hormonal vaginal ring (as prescribed) 
• Surgical method performed at least 3 months prior to the Screening visit 
o Bilateral tubal ligation with confirmation of surgical success 
o Regulatory approved hysteroscopic bilateral tubal occlusion with confirmation 
of occlusion of the fallopian tubes 
• Hormonal implant 
• Hormonal or non-hormonal intrauterine device (IUD or IUS) 
• Vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject) 
Secondary (barrier) methods of contraception include: 
• Male condom with spermicide 
• Female condom with spermicide 
• Over-the-counter sponge with spermicide 
• Cervical cap with spermicide (as prescribed) 
• Diaphragm with spermicide (as prescribed).  
Female subjects of childbearing potential should refrain from donation of ova from the time 
of signing the ICF until 90 days after the EOS visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception by female partner from Check-in until 90 days 
after the Follow-up visit. Acceptable methods of contraception for female partners include:  
• Hormonal injection 
• Combined oral contraceptive pill or progestin/progestogen-only pill 
• Combined hormonal patch 
• Combined hormonal vaginal ring 
• Surgical method (bilateral tubal ligation or regulatory approved hysteroscopic 
bilateral tubal occlusion) 
• Hormonal implant 
• Hormonal or non-hormonal IUD 
• Over-the-counter sponge with spermicide 
• Cervical cap with spermicide 
• Diaphragm with spermicide. 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 73 of 80 
Male subjects are required to refrain from donation of sperm from the time of signing the ICF 
until 90 days after the EOS visit. 
Sexual Abstinence  
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a 
subject who is abstinent at the time of signing the ICF becomes sexually active they must 
agree to use contraception as described previously. 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the EOS visit.  
Same-sex Relationships 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 
Subjects in same-sex relationships at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the EOS visit. 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
• The Investigator will collect pregnancy information on any female subject who 
becomes pregnant while taking protocol-required therapies through 90 days after the 
Follow-up visit. 
• Information will be recorded on the Pregnancy Notification Form (see Figure 3). The 
form must be submitted to Amgen Global Patient Safety within 24 hours of learning 
of a subject’s pregnancy. (Note: Sites are not required to provide any information on 
the Pregnancy Notification Form that violates the country or regions local privacy 
laws). 
• After obtaining the female subject’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 90 days after the 
Follow-up visit. This information will be forwarded to Amgen Global Patient Safety. 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 74 of 80 
• Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
• While pregnancy itself is not considered to be an adverse event (AE) or serious 
adverse event (SAE), any pregnancy complication or report of a congenital anomaly 
or developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an AE or SAE. Note that an elective termination with no information 
on a fetal congenital malformation or maternal complication is generally not 
considered an AE but still must be reported to the Sponsor as a pregnancy exposure 
case. 
• If the outcome of the pregnancy meets a criterion for immediate classification as an 
SAE (eg, female subject experiences a spontaneous abortion, stillbirth, or neonatal 
death, or there is a fetal or neonatal congenital anomaly) the Investigator will report 
the event as an SAE. 
• Any SAE occurring as a result of a post-study pregnancy, which is considered 
reasonably related to the study treatment by the Investigator, will be reported to 
Amgen Global Patient Safety. While the Investigator is not obligated to actively seek 
this information in former study subjects, he or she may learn of an SAE through 
spontaneous reporting.  
• Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
 
Male Subjects with Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
• In the event a male subject fathers a child during treatment, and for an additional 
90 days after the Follow-up visit, the information will be recorded on the Pregnancy 
Notification Form. The form (see Figure 3) must be submitted to Amgen Global 
Patient Safety within 24 hours of the site’s awareness of the pregnancy. (Note: Sites 
are not required to provide any information on the Pregnancy Notification Form that 
violates the country or regions local privacy laws). 
• The Investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
• After obtaining the female partner’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the pregnancy 
questionnaires. This information will be forwarded to Amgen Global Patient Safety. 
• Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
• Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 75 of 80 
Collection of Lactation Information 
• The Investigator will collect lactation information on any female subject who 
breastfeeds while taking protocol-required therapies through 90 days after the 
Follow-up visit. 
• Information will be recorded on the Lactation Notification Form (Figure 4) and 
submitted to Amgen Global Patient Safety within 24 hours of the Investigator’s 
knowledge of event. 
• Study treatment will be discontinued if the female subject breastfeeds during the 
study. 
• With the female subject’s signed authorization for release of mother and infant health 
information, the Investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 90 days after the Follow-up visit. 
 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 76 of 80 
Figure 3: 
Pregnancy Notification Form 
 
 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 77 of 80 
Figure 4: 
Lactation Notification Form 
 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 78 of 80 
Appendix 8: Hepatotoxicity: Suggested Actions and Follow-up Assessments 
Subjects with normal hepatic function at Screening who experience aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) elevations > 3x upper limit of 
normal (ULN) or subjects with elevated values before drug exposure who have a 2-fold 
increase above baseline values (as specified in the Guidance for Industry Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation, July 2009) are to undergo clinical assessments and 
a period of “close observation” until abnormalities return to normal or to the subject’s 
baseline level as described below. 
 
Clinical Assessments and Observation 
Assessments that are to be performed during this period include:  
• Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
• In cases of total bilirubin (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.  
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL. 
The following are to be considered depending on the clinical situation: 
• Complete blood count with differential to assess for eosinophilia 
• Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
• Serum acetaminophen (paracetamol) levels 
• 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 nonprescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
o Viral serologies 
o Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral 
blood smear 
• Appropriate liver imaging if clinically indicated 
• Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
• Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist). 
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 79 of 80 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the Investigator. The “close 
observation period” is to continue for a minimum of 4 weeks after discontinuation of all IP(s) 
and protocol-required therapies. 
The potential drug-induced liver injury (DILI) event and additional information such as 
medical history, concomitant medications and laboratory results must be captured in the 
corresponding CRFs. 
Important alternative causes for elevated AST/ALT and/or TBL values include, but are not 
limited to: 
• Hepatobiliary tract disease 
• Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
• Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
• Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, 
indinavir, atazanavir) 
• Alpha-one antitrypsin deficiency 
• Alcoholic hepatitis 
• Autoimmune hepatitis 
• Wilson’s disease and hemochromatosis 
• Nonalcoholic fatty liver disease including steatohepatitis 
• Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, ie cases of AST or ALT > 3x ULN 
and concurrent TBL > 2x ULN or INR > 1.5 (for subjects not on anticoagulation therapy) 
without evidence of alternative cause of the elevations, require the following: 
• The event is to be reported to Amgen as an SAE within 24 hours of discovery or 
notification of the event (ie, before additional etiologic investigations have been 
concluded) 
• The appropriate Case Report Form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen.  
Approved 
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Protocol Version 4.0, 23 August 2019 
Page 80 of 80 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Appendix 1. 
Approved 
 
 


Protocol Amendment 3 
CONFIDENTIAL 
Covance Study: 8405952 
Sponsor Reference: 20090231 
 
Final, 23 August 2019 
Page 1 of 4 
Summary of Amended Protocol Changes 
Single-dose and Randomized, Single-center, Placebo- and Active-controlled, Crossover 
Study to Assess the Effect of Omecamtiv Mecarbil (OM) on QT/QTc Intervals in 
Healthy Subjects 
Protocol Amendment 3 Status: Final 
Protocol Amendment 3 Date: 23 August 2019 
Protocol Amendment 2 Date: 07 August 2019 
Protocol Amendment 1 Date: 19 July 2019 
Original Protocol Date: 30 May 2019 
 
Clinical Phase: 1 
Investigational Product: omecamtiv mecarbil (AMG 423) 
 
Amgen Protocol Reference Number: 20090231 
Covance Study Number: 8405952 
EudraCT Number: 2018-003157-19 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
________________________________________ 
The protocol is being amended to reflect the additional blood volume needed for 
troponin-I sample collections due to a change in analysis method (CPS Labs instead of 
I-Stat method). Additionally, the blood volume table in Appendix 4 is being updated to 
reflect the total number of troponin I sample collections. 
Other changes include: the protocol version and date were updated throughout the protocol to 
reflect the amendment status, the Confidentiality Statement was updated for consistency with 
other studies in the development program, the volume of water to be given with dosing was 
Approved 
 
 


Protocol Amendment 3 
CONFIDENTIAL 
Covance Study: 8405952 
Sponsor Reference: 20090231 
 
Final, 23 August 2019 
Page 2 of 4 
updated to 250 mL for consistency with the Investigational Product Instruction Manual, and 
the Medical Monitor was clarified to be the out-of-hours contact for clinic staff. 
A detailed summary of changes is presented below: 
Title Page 
The title page was updated to reflect the new protocol version and effective date.  
Confidentiality Statement 
Previously read:  
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and members 
of the institutional review board/independent ethics committee/institutional scientific 
review board or equivalent. 
The information in this document cannot be used for any purpose other than the evaluation 
or conduct of the clinical investigation without the prior written consent of Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the Amgen 
Medical Information number: US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; European/UK sites, +44(0) 1223 436441; Amgen’s general number in 
the US, 1-805-447-1000. 
Now reads:  
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 Institutional Review Board/Independent Ethics Committee/Institutional 
Scientific Review Board or equivalent. 
The information in this document cannot be used for any purpose other than the evaluation 
or conduct of the clinical investigation without the prior written consent of Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the Amgen 
Medical Information number: US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; European/UK sites, +44(0) 1223 436441; Amgen’s general number in 
the US, 1-805-447-1000. 
Approved 
 
 


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Protocol Amendment 3 
CONFIDENTIAL 
Covance Study: 8405952 
Sponsor Reference: 20090231 
 
Final, 23 August 2019 
Page 4 of 4 
Appendix 4: Total Blood Volume 
Previously read:  
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Serology 
3.5 
1 
3.5 
Safety laboratory tests 
7.5 
7 
52.5 
OM pharmacokinetics 
4 
27 
108 
Moxifloxacin 
pharmacokinetics 
2 
16 
32 
Placebo blood samplinga 
4 
16 
64 
Troponin-I sampling 
1 
13 
13 
Total: 
273 
 
Now reads:  
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Serology 
3.5 
1 
3.5 
Safety laboratory tests 
7.5 
7 
52.5 
OM pharmacokinetics 
4 
27 
108 
Moxifloxacin 
pharmacokinetics 
2 
16 
32 
Placebo blood samplinga 
4 
16 
64 
Troponin-I sampling 
12.5 
1316 
1340 
Total: 
273300 
 
Approved 
 
 


Protocol Amendment 2 
CONFIDENTIAL 
Covance Study: 8405952 
Sponsor Reference: 20090231 
 
Final, 07 August 2019 
Page 1 of 3 
 
Summary of Amended Protocol Changes 
Single-dose and Randomized, Single-center, Placebo- and Active-controlled, Crossover 
Study to Assess the Effect of Omecamtiv Mecarbil (OM) on QT/QTc Intervals in 
Healthy Subjects 
Protocol Amendment 2 Status: Final 
Protocol Amendment 2 Date: 07 August 2019 
Protocol Amendment 1 Date: 19 July 2019 
Original Protocol Date: 30 May 2019 
 
Clinical Phase: 1 
Investigational Product: omecamtiv mecarbil (AMG 423) 
 
Amgen Protocol Reference Number: 20090231 
Covance Study Number: 8405952 
EudraCT Number: 2018-003157-19 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
________________________________________ 
The protocol is being amended to comply with MHRA requirement to clarify in the 
appropriate protocol section that a subject must be discontinued from study treatment 
if QTcF > 500 ms (as confirmed by 2 ECGs taken within 1 hour) or if increase in QTcF 
> 60 ms compared to predose baseline is observed.  
The protocol version and date were also updated throughout the protocol to reflect the 
amendment status. 


Protocol Amendment 1 
CONFIDENTIAL 
Covance Study: 8405952 
Sponsor Reference: 20090231 
 
Final, 19 July 2019 
Page 1 of 6 
Summary of Amended Protocol Changes 
Single-dose and Randomized, Single-center, Placebo- and Active-controlled, Crossover 
Study to Assess the Effect of Omecamtiv Mecarbil (OM) on QT/QTc Intervals in 
Healthy Subjects 
Protocol Amendment 1 Status: Final 
Protocol Amendment 1 Date: 19 July 2019 
Original Protocol Date: 30 May 2019 
Clinical Phase: 1 
Investigational Product: omecamtiv mecarbil (AMG 423) 
 
Amgen Protocol Reference Number: 20090231 
Covance Study Number: 8405952 
EudraCT Number: 2018-003157-19 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
________________________________________ 
The protocol is being amended primarily in response to MHRA recommendations to 
further ensure selection of healthy subjects and to ensure the safety and privacy of 
study subjects. Major changes include: 
1.  Additional troponin-I sample collections have been added to Parts A and B of the 
study corresponding with safety electrocardiograms (ECGs) at the following Day 1 
timepoints: predose and 1, 4, and 24 hours postdose. An additional standard safety 
ECG was added at 1 hour postdose on Day 1 of Part B, and a troponin-I sample 
collection was added to End of Study (EOS) or early withdrawal in Part B. These 
samples will be analyzed and reviewed along with the other safety data as described 
in the protocol to ensure selection of healthy subjects and to protect subject safety. 


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PI

SAP_001.pdf: 
TITLE PAGE 
Statistical Analysis Plan 
Single-dose and Randomized, Single-center, Placebo- and Active-
controlled, Crossover Study to Assess the Effect of Omecamtiv Mecarbil 
(OM) on QT/QTc Intervals in Healthy Subjects 
SAP Version: 1 
SAP Status: Final 
SAP Date: 10 December 2019 
Investigational Product: Omecamtiv mecarbil (AMG 423) 
Protocol Reference: 20090231 
Covance Study: 8405952 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Study Site: 
Leeds Covance CRU, Springfield House, 
Hyde Street, Leeds, LS2 9LH 
UK 
Principal Investigator: 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
Page 2 of 23
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PI


SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 2 of 21 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
2.1 Primary Objectives ........................................................................................................... 6 
2.2 Secondary Objectives ....................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 7 
3.1. Primary Endpoints ........................................................................................................... 7 
3.2. Secondary Endpoints ....................................................................................................... 7 
3.3. Research Hypothesis ....................................................................................................... 8 
4. STUDY DESIGN................................................................................................................... 8 
5. SAMPLE SIZE JUSTIFICATION ...................................................................................... 10 
6. STUDY TREATMENTS ..................................................................................................... 11 
7. DEFINITIONS OF POPULATIONS .................................................................................. 12 
7.1. All Subjects Population ................................................................................................. 12 
7.2. Safety Population .......................................................................................................... 12 
7.3. Pharmacokinetic Population ......................................................................................... 12 
7.4. QT/QTc Analysis Set .................................................................................................... 12 
7.5. PK/QTc Analysis Set .................................................................................................... 12 
8. STATISTICAL METHODOLOGY .................................................................................... 12 
8.1. General .......................................................................................................................... 12 
8.1.1. Calculation of the Summary Statistics ................................................................... 13 
8.1.2. Repeat and Unscheduled Readings ........................................................................ 13 
8.2. Subject Disposition and Population Assignment .......................................................... 14 
8.3. Screening Demographics .............................................................................................. 14 
8.4. Prior and Concomitant Medication ............................................................................... 14 
8.5. Pharmacokinetic Assessments ...................................................................................... 14 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 14 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 17 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 17 
8.6. Safety and Tolerability Assessments ............................................................................ 18 
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SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 3 of 21 
8.6.1. Adverse Events ....................................................................................................... 18 
8.6.2. Clinical Laboratory Parameters .............................................................................. 19 
8.6.3. Vital Signs Parameters ........................................................................................... 20 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 20 
8.6.5. Other Assessments ................................................................................................. 20 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 20 
9. INTERIM ANALYSES ....................................................................................................... 20 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 20 
11. REFERENCES .................................................................................................................. 20 
12. APPENDICES ................................................................................................................... 21 
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SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 4 of 21 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]) 
AUC 
area under the plasma concentration-time curve 
AUCinf 
area under the plasma concentration-time curve from time zero to  
infinity 
AUC0-t 
area under the plasma concentration-time curve from time zero to the 
last quantifiable concentration 
CI 
confidence interval 
CL/F 
apparent total plasma clearance 
Cmax 
maximum plasma concentration 
CK-MB 
creatine kinase MB fraction 
CSR 
Clinical study report 
CV 
coefficient of variation 
ΔHR 
Change-from-baseline HR interval 
ΔPR 
Change-from-baseline PR interval 
ΔQRS 
Change-from-baseline QRS interval 
ΔQTcF 
Change-from-baseline QTcF interval 
ΔΔHR 
Placebo-corrected ΔHR 
ΔΔPR 
Placebo-corrected ΔPR 
ΔΔQRS 
Placebo-corrected ΔQRS 
ΔΔQTcF 
time-matched change from baseline in placebo-adjusted QT interval 
corrected for heart rate based on the Fridericia correction interval 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
ERT 
eResearch Technology Inc. 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation  
OM 
omecamtiv mecarbil 
%AUCextrap 
percentage of area under the concentration-time curve from time 0 to 
infinity due to extrapolation 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 
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SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 5 of 21 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell 
RR 
time interval between two successive R-waves of the QRS signal on the 
electrocardiogram 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time of the maximum observed plasma concentration 
TQT 
thorough QT 
Vz/F 
apparent volume of distribution 
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SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 6 of 21 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol for AMG 423 study 
20090231 (Final Version dated 30 May 2019, Amendment 1 dated 19 July 2019, Amendment 
2 dated 07 August 2019, and Amendment 3 dated 23 August 2019) and electronic case report 
form. 
This SAP describes the planned analysis of the pharmacokinetic (PK) and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document. A 
separate SAP concerning QT/QTc and PK/QTc analysis will be provided by eResearch 
Technology Inc. (ERT). 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Amgen Inc. A limited amount of information about this study 
(eg, objectives, study design) is given to help the reader’s interpretation. This SAP must be 
finalized prior to the lock of the clinical database for this study. When the SAP and TFL 
shells are approved, they will serve as the template for this study’s CSR. 
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Amgen Inc. and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2 
The document history is presented in Appendix 1. 
2. STUDY OBJECTIVES 
2.1 Primary Objectives 
The primary objective of the study is: 
 To evaluate the effect of a single therapeutic (50 mg) oral dose of omecamtiv 
mecarbil (OM) on the QT/QTc interval, relative to placebo, in healthy subjects. 
2.2 Secondary Objectives 
The secondary objectives of the study are: 
 To assess the PK of OM after a single oral dose to healthy subjects. 
 To evaluate the effect of OM on other ECG parameters (hear rate [HR], PR and QRS 
intervals, and treatment-emergent T-wave abnormalities and presence of U-waves). 
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Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
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 To evaluate the plasma concentration-effect relationship for OM on the QT/QTc 
interval in healthy subjects. 
 To evaluate assay sensitivity by evaluation of the positive control, a single 400-mg 
oral dose of moxifloxacin, on the QT/QTc interval in healthy subjects. 
 To evaluate the safety and tolerability of OM after a single oral dose to healthy 
subjects. 
3. STUDY ENDPOINTS 
3.1. Primary Endpoints 
The primary endpoint is the placebo-corrected change from baseline in QTc interval based on 
the Fridericia correction (QTcF) interval (ΔΔQTcF) after OM dosing. 
3.2. Secondary Endpoints 
The secondary endpoints of the study are: 
 Pharmacokinetic parameters of OM including, but not limited to, Cmax, tmax, t1/2, 
apparent volume of distribution (VZ/F), apparent total plasma clearance (CL/F), area 
under the concentration-time curve (AUC) from time 0 to the last quantifiable 
concentration (AUC0-t), AUC from time 0 to infinity (AUCinf), and the percentage of 
AUCinf due to extrapolation (%AUCextrap) 
 ΔΔQTcF after moxifloxacin dosing 
 Change-from-baseline HR, QTcF, PR and QRS intervals (ΔHR, ΔQTcF, ΔPR and 
ΔQRS) after OM dosing 
 Concentration-QTc analysis based on ΔΔQTcF after OM dosing 
 Placebo-corrected ΔHR, ΔPR and ΔQRS (ΔΔHR, ΔΔPR and ΔΔQRS) after OM 
dosing 
 Categorical outliers for QTcF, HR, PR, and QRS after OM dosing 
 Frequency of treatment-emergent changes in T-wave morphology and U-wave 
presence after OM dosing 
 Subject incidence of treatment-emergent adverse events (TEAEs) 
 Changes in laboratory safety tests, vital signs, and ECGs. 
Other noncompartmental PK parameters may be reported. In addition, plasma concentration 
will be determined and PK parameters will be calculated for moxifloxacin only if deemed 
necessary. 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
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3.3. Research Hypothesis 
The hypothesis is that OM does not prolong QTc intervals after administration of a single 50-
mg oral dose and will be safe and well tolerated in healthy subjects. 
4. STUDY DESIGN 
This is a single-center, single-dose (Part A; PK Evaluation Period), and randomized, 3-
period, 3-treatment, crossover, single-dose (Part B) study in healthy adult subjects to 
determine whether OM prolongs the QTc after a single oral dose administration of 50 mg 
OM. The total duration of participation in the study will be approximately 55 days, including 
the screening period of up to 28 days. 
The overall duration for individual subjects may vary depending on timing of sample 
shipment and analysis for Part A of the study, to confirm eligibility for Part B. 
A schematic of the study design is presented in Figure 1. 
Figure 1: Study Design 
 
Note: All study treatments will be separated by a washout period of 7 days (including 
between Part A and Part B). 
Potential subjects will be asked to read and sign an Informed Consent Form (ICF). After 
informed consent is obtained, screening procedures and tests to establish subject eligibility to 
enter the study will be performed within 28 days before Day 1 in Part A (PK Evaluation 
Period). Study procedures are summarized in the protocol. Adverse events and SAEs will be 
recorded from the time the ICF is signed.  
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SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 9 of 21 
Approximately 60 to 70 subjects will be enrolled in Part A in order to have 60 subjects (10 
per sequence) enrolled in Part B. With approximately 60 subjects in Part B, it is estimated 
that approximately 48 evaluable subjects will have data from all 3 periods in Part B. 
Treatment in Part A will consist of a single 25-mg OM oral dose (Treatment 1), after which 
subjects whose resulting Cmax is ≤ 350 ng/mL will be randomized into Part B. Part B consists 
of 3 periods, in which a single treatment is given in each period. Treatments in Part B will 
consist of placebo (Treatment A), OM 50 mg (Treatment B), and moxifloxacin 400 mg 
(Treatment C). All study treatments (Part A and Part B/Period 1, Period 2 and Period 3) will 
be separated by a washout of at least 7 days. 
Part A 
 Treatment 1: 25-mg OM oral solution 
A subject will be considered enrolled once he/she is deemed eligible by the Investigator and 
has received the first dose administration in Part A. 
Subjects will be admitted to the research facility on Day -1 in Part A, at which time baseline 
procedures will be performed according to the Schedule of Assessments in protocol. After an 
overnight fast of at least 10 hours, subjects will be administered treatment with 250 mL of 
water. No food will be allowed for at least 4 hours postdose. Water is allowed as desired 
except for 1 hour before and after drug administration. 
Subjects will stay at the research facility until Day 3, and study assessments will be 
performed according to the Schedule of Assessments in protocol. PK samples will be 
collected to determine plasma OM concentrations according to the Schedule of Assessments 
in protocol. Subjects will be discharged after completion of Day 3 activities and will return 
for a safety follow-up visit on Day 6. PK results from Part A will be available prior to Part B. 
For subjects whose resulting Cmax in Part A is > 350 ng/mL, the Day 6 visit will be 
considered their End of Study (EOS) visit. 
Part B 
 Treatment A: Placebo oral solution 
 Treatment B: 50-mg OM oral solution 
 Treatment C: 400-mg moxifloxacin oral tablet 
After completing Part A, eligible subjects will be randomized to receive 3 treatments in 1 of 6 
sequences, as follows: 
Sequence 
Period 1 
Period 2 
Period 3 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
A 
C 
B 
5 
C 
B 
A 
6 
B 
A 
C 
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SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 10 of 21 
Subjects will be admitted to the research facility on Day -1 of Period 1 in Part B, at which 
time Check-in procedures will be performed according to the Schedule of Assessments in 
protocol. After an overnight fast of at least 10 hours, subjects will be administered treatment 
with 250 mL of water. No food will be allowed for at least 4 hours postdose. Water is 
allowed as desired except for 1 hour before and after drug administration. Placebo and OM 
treatments will be double-blinded and moxifloxacin treatment will be open-label. Subjects 
will receive standardized meals at approximately the same time. 
Subjects will stay at the research facility throughout Part B, and study assessments will be 
performed according to the Schedule of Assessments in protocol, including continuous ECG 
recording, digital ECG extractions, and PK sample collections to determine plasma OM and 
moxifloxacin concentrations. Additionally, standard safety assessments, including 12-lead 
ECGs and vital signs monitoring, will be performed and safety and tolerability monitoring 
will be conducted throughout the study. Subjects will be discharged after completion of Day 
6 activities in Period 3. 
All study treatments will be separated by a washout period of at least 7 days (including 
between Part A and Part B). 
The EOS visit will complete a subject’s participation in this study after Period 3. If there is a 
clinically significant clinical or laboratory abnormality that requires monitoring, the subject 
will be followed until resolution of the abnormality or until it is considered stable. If possible, 
EOS procedures will be performed on subjects who withdraw early from the study. 
The primary completion date is defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the primary endpoint, for the 
purposes of conducting the primary analysis, whether the study concluded as planned in the 
protocol or was terminated early. The planned primary completion date is the date when the 
last subject has completed the assessments on Day 6 of Period 3 in Part B. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
5. SAMPLE SIZE JUSTIFICATION 
With approximately 60 enrolled subjects, it is estimated that approximately 48 evaluable 
subjects will have data from all 3 periods in Part B. 
Based on the calculation of the sample size for a TQT study 3, assuming a 1-sided 5% 
significance level and a within-subject standard deviation (SD) of 7 msec for ΔQTcF, and a 
true mean difference of 3 msec in ΔQTcF between OM and placebo, a sample size of 48 
evaluable subjects would be expected to provide 99.5% power to demonstrate that the upper 
bounds of all the 2-sided 90% confidence intervals (CIs) on ΔΔQTcF will fall below 10 msec 
for up to 8 timepoints. With the within-subject SD of 8 msec and other similar assumptions, 
the power will decrease to 96.5%. 
Determination of sample size for assay sensitivity: 
Assuming a 1-sided 5% significance level and a within-subject SD of 7 msec for ΔQTcF, a 
sample size of 48 evaluable subjects will provide a power of 99.9% to exclude a mean 
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SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 11 of 21 
difference of 5 msec in ΔQTcF between moxifloxacin and placebo groups from the lower 
bound of the 2-sided 90% CI on ΔΔQTcF at at least 1 of the 3 prespecified timepoints. With 
the within-subject SD of 8 msec and other similar assumptions, the power will decrease to 
99%. 
6. STUDY TREATMENTS
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 1.  
Table 1: 
Presentation of Study Treatment in TFLs 
Study Treatment 
Part A 
Study Treatment Name 
Treatment Abbreviation 
25-mg OM oral solution
25-mg OM
Part B 
Study Treatment Name 
Treatment Abbreviation 
Treatment Order in TFLs 
Treatment A: 
Placebo oral solution 
Placebo 
1 
Treatment B: 
50-mg OM oral solution
50-mg OM
2 
Treatment C: 
400-mg moxifloxacin oral
tablet 
Moxifloxacin 
3 
The study treatment sequence names, abbreviations,  and ordering of Part B to be used in the 
TFLs are presented in Table 2.
Table 2: 
Presentation of Part B Study Treatment Sequences in TFLs 
Study Treatment Sequence 
Abbreviation 
Order in TFLs 
 Sequence 1 
Placebo/50-mg OM/Moxifloxacin 
1 
 Sequence 2 
50-mg OM/Moxifloxacin/Placebo
2 
 Sequence 3 
Moxifloxacin/Placebo/50-mg OM 
3 
 Sequence 4 
Placebo/Moxifloxacin/50-mg OM 
4 
 Sequence 5 
Moxifloxacin/50-mg OM/Placebo 
5 
 Sequence 6 
50-mg OM/Placebo/Moxifloxacin
6 
All treatments described above are the planned treatments. The TFLs will reflect the actual 
treatments received, and dose levels will be displayed in increasing order. 
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SAP 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 12 of 21 
7. DEFINITIONS OF POPULATIONS 
Any protocol deviations will be considered prior to database lock for their importance and 
taken into consideration when assigning subjects to populations.  
The full analysis set will include all subjects who received at least 1 dose of study treatment 
(Omecamtiv Mecarbil, placebo or moxifloxacin).  
The completer analysis set will include subjects in the full analysis set who completed all 
study treatment administrations and have non-missing values for the primary endpoint. 
7.1. All Subjects Population 
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol. 
7.2. Safety Population 
The safety population will include all subjects who received at least 1 dose of study treatment 
(Omecamtiv Mecarbil, placebo or moxifloxacin) and have at least 1 postdose safety 
assessment. 
7.3. Pharmacokinetic Population 
The PK population for Part A or Part B will consist of all subjects who received at least 1 
dose of OM and have evaluable PK data. Any subject who experiences emesis within 4 hours 
of dosing or diarrhea within 24 hours of dosing may be excluded from the PK analysis. 
7.4. QT/QTc Analysis Set 
The QT/QTc analysis set will include all subjects in FAS with measurements at baseline as 
well as on-treatment with at least 1 postdose timepoint with a valid ΔQTcF value in Part B. 
The QT/QTc analysis set will be used for the by-timepoint and categorical analyses of 
cardiodynamic ECG parameters. This analysis set will be present in the ERT report. 
7.5. PK/QTc Analysis Set 
The PK/QTc analysis set will include all subjects who are in both the QT/QTc and PK 
analysis sets with at least 1 pair of postdose PK and QTcF data from the same timepoint. The 
PK/QTc analysis set will be used for the concentration-QTc analysis in Part B. This analysis 
set will be present in the ERT report. 
8. STATISTICAL METHODOLOGY 
8.1. General 
Listings will be provided for all data captured in the database, with the exception of medical 
history. Listings will include all subjects assigned to the all subjects population and include 
data up to the point of study completion or discontinuation. Any subject who discontinued the 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 13 of 21 
study will be identified accordingly in the listings. Summaries and statistical analyses will 
include the subjects assigned to the relevant population based on data type. 
Data analysis will be performed using the SAS® statistical software package Version 9.4. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 and CDISC ADaM Implementation 
Guide Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilized to ensure 
compliance with CDISC standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations. 
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses and any parameter derivations. 
8.1.1. Calculation of the Summary Statistics 
For continuous data the following rules will be applied: 
●Missing values will not be imputed, unless specifically stated otherwise.
●Unrounded data will be used in the calculation of summary statistics.
●If number of subjects with valid observations (n) <3, summary statistics will not be
calculated, with the exception of n, minimum, and maximum.
●As Early Termination data is not associated with any scheduled timepoint, it will be
excluded from all calculations of summary statistics.
For categorical data the following rules will be applied: 
●If the categories of a parameter are ordered (eg, adverse event severity), all categories
between the possible minimum and maximum categories will be included, even if n = 0
for a given category. If the categories are not ordered (eg, race), only those categories
for which there is at least 1 subject represented will be included.
●Missing values will not be imputed, with the exception of adverse events where the
‘worst-case’ approach will be taken (see Section 8.6.1), or unless specifically stated
otherwise. A ‘missing’ category will be included for any parameter for which
information is missing. This will ensure that the population size totals are consistent
across different parameters.
8.1.2. Repeat and Unscheduled Readings 
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 
be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the original value will be defined as an unscheduled value. 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 14 of 21 
The original value will be replaced by the last associated repeat value in all calculations. 
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations. 
8.2. Subject Disposition and Population Assignment 
Subject disposition and population assignment will be listed. 
A summary table will be provided, based on the all subject population. 
8.3. Screening Demographics  
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed. 
A summary table will be provided, based on the safety population. 
8.4. Prior and Concomitant Medication 
Prior medication will be defined as medication that starts within 30 days prior to enrollment 
and ends prior to the first dose. Concomitant medication will be defined as medication that 
starts after the first dose or starts but does not end prior to the first dose. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version March 2019 (or later if upversioned 
during the study). Prior and concomitant medications will be listed. 
8.5. Pharmacokinetic Assessments  
8.5.1. Pharmacokinetic Analysis 
The following pharmacokinetic parameters will be determined where possible from the 
plasma concentrations of OM using non-compartmental methods performed using Phoenix 
WinNonlin (Certara USA, Inc.) version 8.1 or higher: 
Parameter 
Definition 
AUClasta 
Area under the concentration-time curve from time 0 to the time of last 
quantifiable concentration (tlast) 
AUCinfa 
Area under the concentration-time curve from time 0 to infinity 
Cmax 
Maximum observed concentration 
tmax 
Time to maximum observed concentration 
t1/2 
Apparent terminal elimination half-life 
CL/F 
Apparent total plasma clearance 
Vz/F 
Apparent volume of distribution  
a 
AUCs will be calculated using the linear trapezoidal linear interpolation rule. 
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Version 1, Final, 10 December 2019 
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The following parameters will be listed only: 
Parameter 
Definition 
%AUCextrap 
Percentage of AUCinf that is due to extrapolation  
λz 
Apparent elimination rate constant 
R2 
Correlation coefficient of terminal elimination phase 
Number of points 
Number of data points included in determination of λz 
Start of exponential fit 
Lower limit of the terminal phase 
End of exponential fit 
Upper limit of the terminal phase 
 
Additional pharmacokinetic parameters may be determined where appropriate. Moxifloxacin 
plasma samples may be assayed and PK parameters (same as for OM) will be calculated only 
if deemed necessary. 
Pharmacokinetic analysis will, where possible, be carried out using actual postdose times 
recorded in the raw data. If actual times are missing, nominal times may be used with sponsor 
approval.  
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
Cmax and tmax will be obtained directly from the plasma concentration-time profiles.  
For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case 
that multiple peaks are of equal magnitude, the earliest tmax will be reported.  
8.5.1.1. Criteria for handling concentrations below the limit of quantification in 
Pharmacokinetic analysis 
Concentration values that are below the level of quantification (BLQ) will be set to zero, with 
defined exceptions as follows: 
 Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
 If there are late positive concentration values following 2 BLQ concentration values 
in the apparent terminal phase, these values will be evaluated. If these values are 
considered to be anomalous, they will be set to missing. 
 If an entire concentration-time profile is BLQ, the profile will be excluded from the 
PK analysis. 
 If a predose concentration is missing, it will be set to 0 by default. 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 16 of 21 
8.5.1.2. Criteria for the Calculation of an Apparent Terminal Elimination Rate 
Constant and Half-Life 
8.5.1.2.1. Number of Data Points 
At least three data points will be included in the regression analysis and should not include 
Cmax. 
8.5.1.2.2. Goodness of Fit 
When assessing terminal elimination phases, the R2 value will be used as a measure of the 
goodness of fit of the data points to the determined line.  
Regression-based parameters (AUCinf, %AUCextrap, t1/2, CL/F, and Vz/F) will only be 
calculated if the R2 value of the regression line is greater than or equal to 0.8. 
8.5.1.2.3. Period of Estimation 
The time span used for the estimation of apparent terminal elimination rate constant, where 
possible, will be over at least two half-lives.  
Where an elimination half-life is estimated over a time span of less than two half-lives, it will 
be flagged in the data listings at the discretion of the Pharmacokineticist, and the robustness 
of the value should be discussed in the study report. 
8.5.1.3. Calculation of AUC 
 The minimum requirement for the calculation of AUC will be the inclusion of at 
least three consecutive plasma concentrations above the lower limit of quantification 
(LLOQ), with at least one of these concentrations following Cmax.  
 AUCinf values where the percentage extrapolation is less than or equal to 20% will 
be reported. AUCinf values where the percentage extrapolation is greater than 20% 
will be listed but flagged and excluded from descriptive statistics. Parameters 
derived using AUCinf (CL/F and Vz/F) will also be flagged and excluded from 
descriptive statistics when the percentage extrapolation is greater than 20%. 
8.5.1.4. Anomalous Values 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data and 
study report. 
Positive predose value(s) greater than 5% of Cmax may be excluded from the summary 
statistics of PK tables and statistical analysis at the discretion of the Pharmacokineticist. 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 17 of 21 
8.5.2. Presentation of Pharmacokinetic Data 
8.5.2.1. Presentation of Pharmacokinetic Plasma Drug Concentration Data 
The following rules will be applied if there are values that are BLQ or if there are missing 
values (e.g., no result [NR]) in a plasma concentration data series to be summarized. 
 For the calculation of summary statistics, BLQ values will be set to zero. 
 If an embedded BLQ value is considered anomalous within the concentration time 
profile, this value will be excluded from the summary statistics. 
 Where there is NR, these will be set to missing. 
 If there are less than three values in the data series, only the min, max and N will be 
presented. The other summary statistics will be denoted as not calculated (NC). BLQ 
is considered a value. 
 If all the values are BLQ, then the arithmetic mean, arithmetic SD, median, min and 
max will be presented as zero, and the geometric mean and geometric CV will be 
denoted as NC. 
 If the value of the arithmetic mean or median is below the lower limit of 
quantification, these values will be presented as zero and the geometric mean and 
geometric CV will be denoted as NC. 
8.5.2.2. Presentation of Pharmacokinetic Parameters 
For the calculation of summary statistics of PK parameters, all non-reportable and NC values 
in a data series will be set to missing. 
The AUC values will be set to NC if they were calculated using fewer than three 
concentrations, and/or three concentrations if the last is Cmax. 
8.5.3. Pharmacokinetic Statistical Methodology 
All PK concentrations and parameters will be listed. 
Summary tables, mean (+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by treatment and time postdose will be provided for plasma PK 
concentrations. All figures will be produced on both linear and semi-logarithmic scales. The 
+SD bars will be only displayed on the linear scale. 
Summary tables by treatment will be provided for all PK parameters, with the exception of 
regression-related PK parameters. Separate summary tables by treatment and time interval 
will be provided for excretion parameters and cumulative excretion parameters. 
The analyses for this study will be performed in 2 parts. 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 18 of 21 
8.5.3.1. Part A Methodology 
Part A will evaluate 25-mg OM oral solution and is designed to determine the subject 
eligibility for Part B. Dose escalation will proceed when a safety review with an acceptable 
safety profile has been completed by the Safety Review Committee. 
No formal statistical analysis on the safety data. 
8.5.3.2. Part B Methodology 
Part B of the study is designed to assess the ECG effects to determine plasma OM and 
moxifloxacin concentrations. 
All QT/QTc-related statistical analysis will be conducted by ERT and reported in a separate 
SAP and TFL shells report.  
Real-time safety ECG assessments will be performed by the study physician. No formal 
statistical analysis on the safety data. 
8.6. Safety and Tolerability Assessments 
8.6.1. Adverse Events 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 22.0 (or higher if upversioned during the study). 
A TEAE will be defined as an adverse event that starts during or after the first dose, or starts 
prior to the first dose and increases in severity after the first dose.  
A treatment-related TEAE will be defined as a TEAE with a relationship of possibly related 
or related to the study treatment, as determined by the investigator. 
All adverse events will be listed. In addition to the data recorded in the database, the listings 
will include derived onset time and duration. Onset time will be calculated from the time of 
the last dose for TEAEs only. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories: 
● TEAEs (overall, serious, leading to discontinuation and leading to death) by treatment 
● TEAEs by severity and treatment 
● Treatment-related TEAEs (overall, serious, leading to discontinuation and leading to 
death) by treatment 
● Treatment-related TEAEs by severity and treatment 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 19 of 21 
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following: 
● System organ class, preferred term, and treatment 
● Preferred term and treatment 
For the adverse event data the following rules will apply: 
● For the derivation of TEAE status: If the start date/time of an adverse event is 
incomplete or missing, an adverse event will be assumed to be a TEAE, unless the 
incomplete start date/time or the end date/time indicates an adverse event started prior 
to the first dose. 
● For the derivation of treatment-related TEAE status: If the study treatment relationship 
for a TEAE is missing, a TEAE will be assumed to be a treatment-related TEAE. 
● For the derivation of onset time: If the start date/time of an adverse event is missing, 
onset time will not be calculated. If the start date/time of an adverse event is 
incomplete, where possible, the minimum possible onset time will be calculated and 
presented in ‘≥DD:HH:MM’ format (eg, if the date/time of the last dose is 
01MAY2019/08:00 and recorded start date/time of an adverse event is 03MAY2019, 
then the minimum possible onset time will be calculated by assuming the an adverse 
event started at the first hour and minute of 03MAY2019 [03MAY2019/00:00], thus 
will be presented as onset time ≥01:16:00 in the listing). 
● For the derivation of duration: If the end date/time of an adverse event is missing, 
duration will not be calculated. If the start or end date/time of an adverse event is 
incomplete, where possible, the maximum possible duration will be calculated and 
presented in ‘≤DD:HH:MM’ format (eg, if the start of an adverse event date/time is 
01MAY2019/08:00 and its recorded end date/time is 03MAY2019, then the maximum 
possible duration will be calculated by assuming the adverse event ended at the last 
hour and minute of 03MAY2019 [03MAY2019/23:59], thus will be presented as 
duration ≤02:15:59 in the listing). 
● For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE 
will be counted under the maximum severity possible. 
● For the calculation of summary statistics: If a subject experienced multiple TEAEs with 
the same preferred term for the same treatment, this will be counted as 1 TEAE for that 
treatment under the maximum severity recorded. 
8.6.2. Clinical Laboratory Parameters 
All clinical laboratory parameters will be listed; any value outside the clinical reference range 
will be flagged. Separate listings will be provided for any parameter for which there is any 
individual subject value outside the respective clinical reference range.  
Summary tables by timepoint will be provided for clinical chemistry and hematology 
parameters. 
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Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 20 of 21 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags and calculation of summary statistics, <x and ≤x values will be set 
to 0, whereas >x and ≥x values will be set to x. 
8.6.3. Vital Signs Parameters 
All vital signs parameters will be listed; any value outside the clinical reference range will be 
flagged.  
Summary tables will be provided for all vital signs parameters. 
8.6.4. 12-lead Electrocardiogram Parameters 
All 12-lead ECG parameters will be listed; any value outside the clinical reference range will 
be flagged.  
Summary tables by timepoint will be provided for all 12-lead ECG parameters. 
8.6.5. Other Assessments 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only. 
Medical history will not be listed. 
8.6.6. Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
9. INTERIM ANALYSES 
No interim analyses are planned for this study. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
There were no significant changes from the protocol-specified analyses. 
11. REFERENCES 
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998. 
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
3. Zhang J and Machado SG. Statistical issues including design and sample size calculation 
in thorough QT/QTc studies. J Biopharm Stat. 2008;18(3):451-67. 
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SAP 
CONFIDENTIAL 
Covance Study: 8405952 
Protocol Reference: 20090231 
Version 1, Final, 10 December 2019 
Page 21 of 21 
12. APPENDICES 
Appendix 1: 
Document History 
Document Version, Status, Date 
Summary/Reason for Changes 
Version 1, Final, 10 December 2019 
Not applicable; the first version 
 
 
Page 22 of 23


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Approval Signatures
Document Name:
161-09-csr-20090231-statistical-met
Document Number: CLIN-000097281
Document Version: 1
Document Approvals
Reason for Signing: Functional Area
Name: 
Date of Signature: 10-Sep-2020 19:18:03 GMT+0000
PI