A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction
Phase: PHASE3
Conditions: Obstructive Hypertrophic Cardiomyopathy (oHCM)
Sponsor: Cytokinetics

Protocol: CY 6031 
 
 
Title: A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to 
Evaluate the Eﬃcacy and Safety of CK-3773274 in Adults with Symptomatic 
Hypertrophic Cardiomyopathy and Left Ventricular Outﬂow Tract Obstruction 
 
 
NCT05186818 
 
 
Approval Date: 08 December 2023 
 

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PROTOCOL CY 6031 
 
 
A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL TO EVALUATE THE EFFICACY AND 
SAFETY OF CK­3773274 IN ADULTS WITH SYMPTOMATIC 
HYPERTROPHIC CARDIOMYOPATHY AND LEFT VENTRICULAR 
OUTFLOW TRACT OBSTRUCTION 
 
Protocol Version and Date: 
Amendment 04 dated 08 December 2023 
Previous Version(s): 
Amendment 03 dated 03 January 2023 
Amendment 02 dated 10 December 2021 
Amendment 01 dated 17 August 2021 
Original Protocol 26 July 2021 
Product: 
CK-3773274 (aficamten) 
Regulatory Authority 
Identifier Number(s): 
IND 138814 
EudraCT Number 2021-003536-92 
Sponsor: 
Cytokinetics, Inc. 
350 Oyster Point Blvd. 
South San Francisco, CA 94080, USA 
 
This document contains confidential information, which should not be copied, referred to, 
released or published without documented approval from Cytokinetics, Inc. 
 
 

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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CY 6031 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-blind, 
Placebo-controlled Trial to Evaluate the Efficacy and Safety of 
CK-3773274 in Adults with Symptomatic Hypertrophic 
Cardiomyopathy and Left Ventricular Outflow Tract 
Obstruction 
Protocol Version and Date: 
Amendment 04 dated 08 December 2023 
 
Principal Investigator Commitment 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to the Code of Federal Regulations (21 CFR § 312) and 
International Council for Harmonisation (ICH) E6(R2) Good Clinical Practice (GCP) guidelines, 
as well as with any and all applicable federal, state and/or local laws and regulations, and agree 
to conduct this trial in accordance with the protocol referenced herein. 
 
Investigator Name: 
 
Date:  
Investigator Signature: 
 
 
 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 04 
08 December 2023 
Amendment 03 
03 January 2023 
Amendment 02 
10 December 2021 
Amendment 01 
17 August 2021 
Original Protocol 
26 July 2021 
Amendment 04 (08 December 2023) 
The main purpose of this amendment is as follows: 
• To add a safety endpoint that contextualizes observations of LVEF <50% with clinically 
relevant associated findings. 
• To update the definition of full analysis set. 
• To update the testing hierarchy to use a closed testing procedure with pre-specified 
testing order to test the secondary endpoints once the primary endpoint achieves 
statistical significance. 
Table 1: 
Protocol Amendment 04 Summary of Changes 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3. Objectives and Endpoints  
Added the safety endpoint 
of incidence of LVEF 
<50% with signs and 
symptoms of heart failure 
(concomitant adverse 
event of heart failure or 
dyspnea) and/or increase 
in NT-proBNP from 
baseline 
This additional safety 
endpoint contextualizes 
an observation of LVEF 
<50% with clinically 
relevant associated 
findings  
 
 
1.1 Synopsis 
9.3 Populations For Analyses  
Updated full analysis set 
definition to include all 
randomized patients  
Per FDA’s 
recommendation  

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Table 1: 
Protocol Amendment 04 Summary of Changes (Continued) 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
9.4.1.1 Multiplicity Adjustment 
Revised testing hierarchy; 
and made editorial 
updates  
The testing hierarchy was 
simplified from a parallel 
gatekeeping method to a 
closed testing procedure. 
This adjustment allows 
for the examination of 
secondary endpoints at 
two-sided alpha level of 
0.05 once the primary 
endpoint achieves 
statistical significance at 
the prespecified 
sequential testing order 
 

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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2 
PROTOCOL APPROVAL PAGE ...................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Schema ........................................................................................................................19 
1.3. 
Schedule of Activities .................................................................................................20 
1.4. 
Key Contacts ...............................................................................................................23 
2. 
INTRODUCTION ......................................................................................................24 
2.1. 
Trial Rationale ............................................................................................................24 
2.2. 
Background .................................................................................................................24 
2.2.1. 
Hypertrophic Cardiomyopathy ...................................................................................24 
2.2.2. 
CK-3773274 ...............................................................................................................25 
2.3. 
Benefit/Risk Assessment ............................................................................................25 
2.3.1. 
Risk Assessment .........................................................................................................25 
2.3.1.1. 
Mitigation Strategy .....................................................................................................26 
2.3.2. 
CK-3773274 Benefit Assessment ...............................................................................27 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................28 
4. 
TRIAL DESIGN .........................................................................................................31 
4.1. 
Overall Design ............................................................................................................31 
4.1.1. 
Number of Sites ..........................................................................................................31 
4.1.2. 
Number of Patients .....................................................................................................31 
4.1.3. 
Replacement of Patients .............................................................................................31 
4.1.4. 
Trial Duration .............................................................................................................31 
4.1.5. 
CMR Imaging Sub-Study ...........................................................................................32 
4.2. 
Scientific Rationale for Trial Design ..........................................................................32 
4.3. 
Justification for Dose ..................................................................................................32 
4.4. 
End of Study Definition ..............................................................................................32 

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5. 
STUDY POPULATION .............................................................................................33 
5.1. 
Inclusion Criteria ........................................................................................................33 
5.2. 
Exclusion Criteria .......................................................................................................34 
5.3. 
Lifestyle Considerations .............................................................................................36 
5.4. 
Screen Failures ............................................................................................................36 
6. 
INVESTIGATIONAL PRODUCT ............................................................................38 
6.1. 
Investigational Product(s) Administered ....................................................................38 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................38 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................39 
6.4. 
Investigational Product Compliance ...........................................................................40 
6.5. 
Concomitant Therapy .................................................................................................40 
6.5.1. 
Drug-Drug Interactions ...............................................................................................40 
6.5.2. 
Rescue Medicine .........................................................................................................41 
6.6. 
Dose Modifications .....................................................................................................41 
6.6.1. 
Scheduled Dose Titrations ..........................................................................................41 
6.6.1.1. 
Week 2 Visit ...............................................................................................................41 
6.6.1.2. 
Week 4 Visit ...............................................................................................................41 
6.6.1.3. 
Week 6 Visit ...............................................................................................................42 
6.6.1.4. 
Week 8 Visit ...............................................................................................................42 
6.6.2. 
Dose Reductions .........................................................................................................42 
6.6.3. 
LVEF Safety Threshold ..............................................................................................42 
6.6.4. 
Hepatotoxicity Stopping and Rechallenge Rules .......................................................43 
6.7. 
Access to Investigational Product after the End of the Study ....................................43 
7. 
TEMPORARY INTERRUPTION OF INVESTIGATIONAL PRODUCT, 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT, AND 
PATIENT CONSENT WITHDRAWAL ...................................................................44 
7.1. 
Temporary IP Interruption ..........................................................................................44 
7.2. 
Permanent Discontinuation of IP ................................................................................44 
7.2.1. 
Management of Patients after Permanent Discontinuation of IP ................................45 
7.3. 
Discontinuation from Trial Procedures ......................................................................45 
7.4. 
Patient Consent Withdrawal .......................................................................................46 
7.5. 
Lost to Follow up ........................................................................................................46 
8. 
TRIAL ASSESSMENTS AND PROCEDURES .......................................................47 

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8.1. 
Visit Schedule .............................................................................................................47 
8.1.1. 
Screening Visit ............................................................................................................48 
8.1.2. 
Day 1 ...........................................................................................................................48 
8.1.3. 
Weeks 2 through 20 ....................................................................................................48 
8.1.4. 
Week 24: End of Treatment Visit ...............................................................................48 
8.1.5. 
Week 28: End of Study Visit ......................................................................................49 
8.1.6. 
Early Discontinuation Visit ........................................................................................49 
8.1.7. 
Unscheduled Visit .......................................................................................................49 
8.2. 
Efficacy Assessments .................................................................................................49 
8.2.1. 
Cardiopulmonary Exercise Testing ............................................................................49 
8.2.2. 
Echocardiography .......................................................................................................50 
8.2.3. 
Cardiac Magnetic Resonance .....................................................................................51 
8.2.4. 
New York Heart Association Functional Classification .............................................51 
8.2.5. 
Clinical Global Impression Scale ...............................................................................52 
8.2.6. 
Patient-Reported Outcomes ........................................................................................52 
8.3. 
Safety Assessments .....................................................................................................52 
8.3.1. 
Physical Examinations ................................................................................................52 
8.3.2. 
Height and Weight ......................................................................................................52 
8.3.3. 
Vital Signs ..................................................................................................................53 
8.3.4. 
Electrocardiograms .....................................................................................................53 
8.3.5. 
Laboratory Assessments .............................................................................................53 
8.4. 
Adverse Events and Serious Adverse Events .............................................................54 
8.4.1. 
Adverse Events ...........................................................................................................54 
8.4.1.1. 
Definition of Adverse Event .......................................................................................54 
8.4.1.2. 
Definition of Serious Adverse Event ..........................................................................54 
8.4.1.3. 
Intensity of Adverse Events ........................................................................................55 
8.4.1.4. 
Relationship to Investigational Product ......................................................................56 
8.4.1.5. 
Relationship to Trial Procedures ................................................................................56 
8.4.1.6. 
Reporting of AEs ........................................................................................................56 
8.4.1.7. 
Reporting Procedures for SAEs ..................................................................................57 
8.4.1.8. 
Follow-up of AEs and SAEs .......................................................................................57 
8.4.1.9. 
Regulatory Reporting ..................................................................................................58 
8.4.1.10. 
Pregnancy and Breastfeeding .....................................................................................58 

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8.5. 
Treatment of Overdose ...............................................................................................59 
8.6. 
Pharmacokinetics ........................................................................................................60 
8.7. 
Genetics ......................................................................................................................60 
8.8. 
Serum for Biomarker Analysis ...................................................................................61 
8.9. 
Serum and Plasma Collection for Future Analyses ....................................................61 
8.10. 
Immunogenicity Assessments ....................................................................................61 
9. 
STATISTICAL CONSIDERATIONS .......................................................................62 
9.1. 
Statistical Hypotheses .................................................................................................62 
9.2. 
Sample Size Determination ........................................................................................62 
9.3. 
Populations for Analyses ............................................................................................62 
9.4. 
Statistical Analyses .....................................................................................................63 
9.4.1. 
General Considerations ...............................................................................................63 
9.4.1.1. 
Multiplicity Adjustment ..............................................................................................63 
9.4.2. 
Primary Endpoint(s) ....................................................................................................63 
9.4.3. 
Secondary Endpoint(s) ................................................................................................64 
9.4.4. 
Exploratory Endpoint(s) .............................................................................................65 
9.4.5. 
Safety Analysis ...........................................................................................................66 
9.4.5.1. 
Adverse Events ...........................................................................................................66 
9.4.5.2. 
Serious Adverse Events ..............................................................................................66 
9.4.6. 
Pharmacokinetic Endpoints ........................................................................................67 
9.4.7. 
Patient Disposition ......................................................................................................67 
9.4.8. 
Demographics and Other Baseline Characteristics .....................................................67 
9.4.9. 
Investigational Product Exposure ...............................................................................67 
9.4.10. 
Concomitant Medications ...........................................................................................67 
9.4.11. 
Clinical Laboratory Parameters ..................................................................................67 
9.4.12. 
Vital Signs ..................................................................................................................67 
9.4.13. 
Electrocardiogram .......................................................................................................67 
9.5. 
Data Monitoring Committee .......................................................................................68 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................69 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ......................69 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................69 
10.1.2. 
Financial Disclosure ...................................................................................................69 

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10.1.3. 
Informed Consent Process ..........................................................................................69 
10.1.4. 
Data Protection ...........................................................................................................70 
10.1.5. 
Committees Structure .................................................................................................70 
10.1.6. 
Data Quality Assurance ..............................................................................................71 
10.1.7. 
Source Documents ......................................................................................................71 
10.1.8. 
Trial and Site Start and Closure ..................................................................................71 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................73 
10.3. 
Appendix 3: Contraceptive Guidance .........................................................................74 
10.4. 
Appendix 4: Genetics .................................................................................................76 
10.5. 
Appendix 5: Liver Safety: Actions and Follow-up Assessments ...............................77 
10.6. 
Appendix 6: Abbreviations .........................................................................................81 
10.7. 
Appendix 7: Protocol Amendment History ................................................................84 
11. 
REFERENCES ...........................................................................................................85 
 
LIST OF TABLES 
Table 1: 
Protocol Amendment 04 Summary of Changes ...........................................................4 
Table 2: 
Trial Objectives and Endpoints ..................................................................................28 
Table 3: 
Investigational Products ..............................................................................................38 
Table 4: 
Echocardiogram Criteria for Scheduled Dose Titrations ............................................42 
Table 5: 
CY 6031 Visit Windows .............................................................................................47 
Table 6: 
CY 6031 Echocardiographic LV Parameters to be Measured ....................................51 
Table 7: 
Summary of PK Time Points ......................................................................................60 
Table 8: 
Analysis Sets ...............................................................................................................62 
Table 9: 
Protocol-Required Safety Laboratory Assessments ...................................................73 
Table 10: List of Abbreviations ..................................................................................................81 
 
LIST OF FIGURES 
Figure 1: 
Statistical Testing Hierarchy for Trial Endpoints .......................................................18 
Figure 2: 
Trial Schema ...............................................................................................................19 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Investigational Product(s) (IP): CK-3773274  
Name of Active Ingredient(s): CK-3773274 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy 
and Safety of CK-3773274 in Adults with Symptomatic Hypertrophic Cardiomyopathy and Left 
Ventricular Outflow Tract Obstruction 
Phase of Development: Phase 3 
Rationale: 
Hypertrophic cardiomyopathy (HCM) is a disease of the cardiac sarcomere for which the fundamental 
pathophysiologic abnormality is myocardial hypercontractility leading to cardiac hypertrophy. In 
patients with obstructive HCM (oHCM), dynamic left ventricular outflow tract (LVOT) obstruction 
creates a high-pressure outflow tract gradient during systole. Patients with oHCM often develop signs 
and symptoms of heart failure. 
CK-3773274 is a small molecule cardiac myosin inhibitor being developed as a chronic, oral treatment 
for patients with HCM. CK-3773274 is designed to reduce the hypercontractility that underlies the 
pathophysiology of HCM. Selective inhibition of cardiac myosin with CK-3773274 may yield potential 
advantages over current therapies for oHCM by directly reducing myocardial hypercontractility and 
addressing the fundamental cause of this sarcomeric disease. 
In the Phase 2 trial, CY 6021 (REDWOOD-HCM), patients with oHCM received up to three doses of 
CK-3773274 or placebo (randomized 2:1) in a dose escalating manner using echocardiography to guide 
dose titration. Two cohorts of approximately 20 patients each were enrolled and treated for 10 weeks. 
Doses in the first cohort were 5, 10, 15 mg once daily; the second cohort studied 10, 20, and 30 mg 
once daily. In both cohorts, CK-3773274 significantly and substantially reduced the LVOT gradient 
(LVOT-G) in a dose and exposure dependent manner. A third cohort of 13 patients with symptomatic 
oHCM taking standard of care therapy plus disopyramide were enrolled and treated for 10 weeks. 
Doses were 5, 10, 15mg once daily. CK3773274 again significantly substantially reduced LVOT-G in 
a dose and exposure dependent manner. There were no treatment interruptions or discontinuations, nor 
any treatment related serious adverse events. The results from this trial support progression of 
CK-3773274 to Phase 3 given the association between reductions in LVOT-G and improvements in 
patient symptoms and function. 
This trial will evaluate the effects of treatment with CK-3773274 over a 24-week period on 
cardiopulmonary exercise capacity and health status in patients with symptomatic oHCM. 
Objectives and Endpoints: 
Objectives 
Endpoint(s) 
Primary 
To evaluate the effect of CK-3773274 
on exercise capacity in patients with 
symptomatic oHCM 
• Change in peak oxygen uptake (pVO2) by cardiopulmonary 
exercise testing (CPET) from baseline to Week 24 

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Secondary 
To evaluate the effect of CK-3773274 
on patient health status  
• Change in Kansas City Cardiomyopathy Questionnaire – 
Clinical Summary Score (KCCQ-CSS) from baseline to 
Week 12 and Week 24 
To evaluate the effect of CK-3773274 
on New York Heart Association 
(NYHA) Functional Classification 
• Proportion of patients with ≥1 class improvement in NYHA 
Functional Class from baseline to Week 12 and Week 24 
To evaluate the effect of CK-3773274 
on post-Valsalva left ventricular 
outflow tract gradients (LVOT-G)  
• Change in post-Valsalva LVOT-G from baseline to 
Week 12 and Week 24  
• Proportion of patients with post-Valsalva LVOT-G 
<30 mmHg at Week 12 and Week 24 
To evaluate the effect of CK-3773274 
on duration of eligibility for septal 
reduction therapy 
• Duration of eligibility for septal reduction therapy (SRT) 
during the 24-week treatment period in patients who were 
eligible for SRT at baseline.  
To evaluate the effect of CK-3773274 
on exercise capacity  
• Change in total workload during CPET from baseline to 
Week 24 
Safety 
To evaluate the safety and tolerability 
profile of CK-3773274 in patients with 
symptomatic oHCM 
• 
Incidence of reported major adverse cardiac events 
(cardiovascular [CV] death, cardiac arrest, non-fatal 
stroke, non-fatal myocardial infarction, CV 
hospitalization) 
• 
Incidence of new onset persistent atrial fibrillation 
• 
Incidence of appropriate implantable cardiac 
defibrillator (ICD) discharges and aborted sudden 
cardiac death  
• 
Incidence of left ventricular ejection fraction (LVEF) 
<50% 
• 
Incidence of LVEF <50% with at least one of the 
following:  
o Signs and symptoms of heart failure 
(concomitant adverse event of heart failure 
or dyspnea), AND/OR 
o Increase in NT-proBNP (≥30% increase), 
relative to results from the most recent 
previous visit and above the upper limit of 
normal, at the time of LVEF assessment 
<50%  
• 
Incidence of treatment emergent adverse events 

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Exploratory 
To evaluate the effect of CK-3773274 
on exercise capacity and functional 
class 
• Compared with baseline, proportion of patients at Week 24 
achieving either: 
− Change from baseline of ≥1.5 mL/kg/min in pVO2 AND 
≥1 class improvement in NYHA Functional Class 
OR 
− Change from baseline of ≥3.0 mL/kg/min in pVO2 
AND no worsening of NYHA Functional Class 
To evaluate the effect of CK-3773274 
on patient response over time 
• Proportion of patients with improvement in KCCQ-CSS 
≥5 points at Weeks 12 and 24 
• Proportion of patients with resting LVOT-G <30 mmHg, 
post-Valsalva LVOT-G <50 mmHg, and NYHA Functional 
Class I at Weeks 12 and 24 
• Proportion of patients with resting LVOT-G <30 mmHg, 
post-Valsalva LVOT-G <50 mmHg, and ≥1 class 
improvement in NYHA Functional Class at Weeks 12 and 
24 
To evaluate the effect of CK-3773274 
on septal reduction therapy eligibility 
• Proportion of patients who are eligible for septal reduction 
therapy at Week 24 among patients who were eligible for 
septal reduction therapy at baseline 
To evaluate the effect of CK-3773274 
on other CPET parameters 
Change from baseline to Week 24 in: 
• Ventilatory efficiency (VE/VCO2 slope) 
• Circulatory power (VO2 × systolic BP) 
• Ventilatory anaerobic threshold (VAT) 
To evaluate the effect of CK-3773274 
on health status and health-related 
quality of life as measured by PRO 
questionnaire 
• Change from baseline to Week 24 in individual responses 
to the EuroQol 5-dimension 5-level instrument (EQ-5D-5L) 
To evaluate the effect of CK-3773274 
on health status and quality of life 
related to chest pain-like angina 
• Change from baseline to Week 24 in summary and domain 
scores for the Seattle Angina Questionnaire-7 (SAQ-7) 
To evaluate the effect of CK-3773274 
on cardiac function and structure  
• Change from baseline to Week 24 in echocardiographic 
measurements of cardiac structure and of systolic function 
including: 
− LVEF 
− Left ventricular end-systolic and end-diastolic volumes 
(LVESV and LVEDV, respectively) 
− Left atrial volume 
To evaluate the effect of CK-3773274 
on biomarker levels  
• Change from baseline values in NT-pro-BNP, hs-cardiac-
TnI and other biomarkers through Week 24 
To evaluate the effect of CK-3773274 
on left ventricular mass, function, and 
• Change from baseline to Week 24 in CMR measurements 
of: 

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structure by cardiac magnetic 
resonance (CMR) imaging  
− Left ventricular (LV) mass index 
− LVEF 
− Septal, free wall, and maximal wall thickness 
− Left atrial volume index 
− LVESV 
− LVEDV 
To assess the pharmacokinetics of 
CK-3773274 and its metabolites 
• Pharmacokinetic parameters through Week 24 
Overall Design: 
This is a Phase 3 randomized, placebo-controlled, double-blind, multi-center trial in patients with 
symptomatic oHCM. Approximately 270 eligible patients will be randomized in a 1:1 ratio to receive 
CK-3773274 or placebo. Doses of 5, 10, 15, or 20 mg or matching placebo will be administered in an 
escalating manner using echocardiography to guide dose titration. Randomization will be stratified by 
use of beta-blockers and CPET exercise modality. 
The trial will comprise three periods. The screening period will be up to 6 weeks in duration. The 
double-blind placebo-controlled treatment period will last 24 weeks. Following the final dose of 
investigational product (IP), there will be a 4-week safety follow-up period. IP will be administered 
orally once daily. During the initial six weeks of the treatment period, IP doses will be individually 
titrated at Weeks 2, 4, and 6 using echocardiography. Dose escalation at the Weeks 2, 4, and 6 visits 
will occur only if a patient has a post-Valsalva LVOT-G ≥30 mmHg and a biplane LVEF ≥55%. An 
echocardiogram will be performed at each subsequent visit during the trial and the dose down-titrated if 
necessary. The primary endpoint of pVO2 will be measured by CPET at screening and at end of 
treatment (Week 24). Patients background oHCM therapy will be individually optimized according to 
local practice. 
A CMR imaging sub-study will be open to approximately 100 patients who consent to participate. 
Trial Center(s): 
This trial will take place at approximately 120 sites worldwide. 
Number of Patients: 
Approximately 270 patients will be randomized to CK-3773274 or placebo. 

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Key Eligibility Criteria: 
The key eligibility criteria are below. A full listing of eligibility criteria can be found in Section 5. 
Inclusion Criteria 
• Males and females between 18 and 85 years of age, inclusive, at screening. 
• Body mass index <35 kg/m2. 
• Diagnosed with HCM per the following criteria: 
− Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and 
− Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of:  
a. ≥15 mm in one or more myocardial segments OR 
b. ≥13 mm in one or more wall segments and a known-disease-causing gene mutation or 
positive family history of HCM 
• Has resting LVOT-G ≥30 mmHg and post-Valsalva LVOT G ≥50 mmHg during screening as 
determined by the echocardiography core laboratory. 
• LVEF ≥60% at screening as determined by the echocardiography core laboratory. 
• NYHA Functional Class II or III at screening. 
• Hemoglobin ≥10g/dL at screening. 
• Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the screening CPET per the 
core laboratory. 

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• Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on stable doses for 
>6 weeks prior to randomization and anticipate remaining on the same medication regimen during 
the trial. Patients treated with disopyramide must also be concomitantly treated with a beta blocker 
and/or calcium channel blocker. 
Exclusion Criteria 
Any of the following criteria will exclude potential patients from the trial: 
• Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics 
oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis). 
• Significant valvular heart disease (per investigator judgment). 
− Moderate-severe valvular aortic stenosis. 
− Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve. 
• History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time during their 
clinical course. 
• Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations). 
• Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal 
ablation) or has plans for either treatment during the trial period. 
• Documented paroxysmal atrial fibrillation during the screening period. 
• Paroxysmal or permanent atrial fibrillation is only excluded IF: 
− rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation procedure, 
or antiarrhythmic therapy) has been required ≤6 months prior to screening 
− rate control and anticoagulation have not been achieved for at least 6 months prior to screening. 
• History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to 
screening. 
• Has received prior treatment with CK-3773274 or mavacamten. 
Exclusion Criteria for CMR sub-study 
• Inability to tolerate CMR. 
• Has an implantable cardioverter-defibrillator (ICD). 
• Has a cardiac pacemaker. 
Data Monitoring Committee: 
An independent Data Monitoring Committee (DMC) will be established for this trial to formally 
review the accumulating data periodically in order to assess risk to patients during the conduct of the 
trial. Details regarding the scope of responsibilities, meetings and communication procedures, as well 
as information requirements will be outlined in the DMC Charter. The DMC will have access to actual 
treatment assignments and patient-level data from the clinical trial database. 

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Statistical Methods: 
Sample Size Calculation: assuming a difference in change from baseline in pVO2 of 1.5 mL/kg/min for 
CK-3773274 compared to placebo, a standard deviation (SD) of 3.5 mL/kg/min, and 10% of patients 
missing change from baseline data of the primary endpoint, a sample size of 270 patients 
(approximately 135 randomized to CK-3773274 and 135 randomized to placebo) provides more than 
90% power to detect the difference in pVO2 change from baseline to Week 24 with a 2-sided type I 
error of 0.05. 
During the study, the aggregate pooled missing data rate and overall pooled SD for the change from 
baseline in pVO2 at Week 24 will be monitored periodically in a blinded fashion. If the pooled SD is 
larger than expected, Cytokinetics may consider increasing the sample size once in order to maintain 
the intended power. 
Unless specified otherwise, efficacy analyses will be performed on the full analysis set (FAS), which 
includes all randomized patients. The primary analysis will test the null hypothesis that there is no 
treatment difference in the primary endpoint between patients randomized to placebo and those 
randomized to CK-3773274 in the FAS. Change from baseline in pVO2 will be analyzed using an 
ANCOVA model with treatment group, randomization stratification factors, baseline pVO2 and 
baseline weight as covariates. 
For preservation of the overall type I error rate at two-sided 0.05 for the primary and secondary 
endpoints will be tested in the following specified order using a closed testing procedure. First, the 
primary endpoint is tested first at two-sided 0.05. If the primary endpoint achieves statistical 
significance at two-sided p<0.05, then the secondary endpoints will be tested at two-sided 0.05, with 
their testing being in the sequential order of KCCQ-CSS change from baseline, proportion of patients 
with >1 NYHA functional class improvement, post-Valsalva LVOT-G change from baseline, 
proportion of patients with post-Valsalva LVOT-G < 30 mm Hg, and duration of SRT eligibility for 
participants who are SRT eligible at baseline, for each after 24 weeks of treatment; then KCCQ-CSS 
change from baseline, proportion of patients with ≥1 NYHA functional class improvement, post-
Valsalva LVOT-G change from baseline, and proportion of patients with post-Valsalva LVOT-G < 30 
mmHg, for each after 12 weeks of treatment; and lastly change from baseline to Week 24 in total 
workload. SRT eligibility is defined as resting or post-Valsalva LVOT-G ≥ 50 mmHg AND NYHA 
Functional Class ≥ 3. See Figure 1 for illustration of the testing order. The detailed description of 
testing sequence will be provided in the Statistical Analysis Plan. 

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1.2. 
Schema 
Figure 2: 
Trial Schema 
 
 
 

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1.3. 
Schedule of Activities 
Trial Procedure 
Screeninga 
(≤ 42 days) Day 1 Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 
EOTb 
(Week 24) 
EOSc 
(Week 28) 
EDd 
Visit Window 
Up to 
42 days 
prior to 
Day 1 
N/A 
+ 3 
days 
+ 3 
days 
+ 3 
days 
+ 3 
days 
± 3 
days 
± 7 
days 
± 7 
days 
± 7 
days 
+ 7 
days 
As soon as 
possible after 
withdrawal 
GENERAL PROCEDURES AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Enrollment in IWRS 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height/weighte 
X 
 
 
 
 
 
 
 
 
X 
 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Adverse events/serious adverse 
eventsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (triplicate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CPET 
X 
 
 
 
 
 
 
 
 
X 
 
 
CMR imaging sub-studyh 
X 
 
 
 
 
 
 
 
 
X 
 
 
Focused Echo (LVOT-G + 
LVEF)i 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Full Echocardiogrami 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
CENTRAL LABORATORY ASSESSMENTS 
Laboratory assessments 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
CMR substudy Hematocritj 
X 
 
 
 
 
 
 
 
 
X 
 
 
Pregnancy test (WOCBP 
only)k  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NT-pro-BNP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Trial Procedure 
Screeninga 
(≤ 42 days) Day 1 Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 
EOTb 
(Week 24) 
EOSc 
(Week 28) 
EDd 
Visit Window 
Up to 
42 days 
prior to 
Day 1 
N/A 
+ 3 
days 
+ 3 
days 
+ 3 
days 
+ 3 
days 
± 3 
days 
± 7 
days 
± 7 
days 
± 7 
days 
+ 7 
days 
As soon as 
possible after 
withdrawal 
hs-cTnI 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplesl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Other biomarker samplesm 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Serum and Plasma Collection 
for Future Analyses 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Genotype samplen 
 
X 
 
 
 
 
 
 
 
 
 
 
PT-INRo 
X 
 
 
 
 
 
 
 
 
 
 
 
PATIENT-REPORTED OUTCOMES AND FUNCTIONING ASSESSMENTS 
NYHA Functional 
Classification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KCCQp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5Lp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI 
 
 
 
 
 
 
 
 
 
X 
X 
X 
PGI-Cp 
 
 
 
 
 
 
 
 
 
X 
 
X 
SAQ-7p 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
INVESTIGATIONAL PRODUCT 
IP dose administration at siteq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
 
IP dispensation 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
IP dose titrationr 
 
 
X 
X 
X 
 
 
 
 
 
 
 
IP dose adjustments 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
CGI = Clinical Global Impression scale; CMR = cardiac magnetic resonance imaging; CPET = cardiopulmonary exercise testing; ECG = electrocardiogram; 
Echo = echocardiogram; ED = early discontinuation; EOS = end of study; EOT = end of treatment; EQ-5D-5L = EuroQol 5-dimension 5-level instrument; hs-
cTnI = high sensitivity cardiac troponin I; IP = investigational product; IWRS = interactive web response system; KCCQ = Kansas City Cardiomyopathy 
Questionnaire; NT-proBNP = n-terminal prohormone brain natriuretic peptide; NYHA = New York Heart Association; SAQ-7 = Seattle Angina Questionnaire-7, 
PGI-C = Patient Global Impression of Change scale; PK = pharmacokinetic; WOCBP = women of childbearing potential; PT-INR = prothrombin 
time/international normalized ratio; UNS DILI = unscheduled drug-induced liver injury 
a The CPET must be completed within four weeks but not less than one week prior to randomization. 

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b If a patient is temporarily unable to exercise on the treadmill or bicycle (whichever modality was used at baseline) due to an adverse event (eg, ankle sprain, 
upper respiratory infection, migraine), but not due to HCM symptoms, or if the site is unable to perform CPET (eg, equipment malfunction), then the Week 24 
visit may be postponed by up to 4 weeks. The patient should continue to receive IP until the visit. Sites should contact patients shortly before the Week 24 visit 
and confirm their ability to perform CPET. If necessary, the Week 24 visit may be split across two consecutive days within the visit window. If the visit is split, 
all assessments, except the CPET, should occur on the first day of the split visit. The CPET should occur on the second day of the split visit. Dosing will occur 
on site on both split visit days. 
c The EOS visit (Week 28) will occur 4 weeks after last dose. It is not required for patients who discontinue IP >4 weeks prior to the Week 24. 
d Patients who withdraw from the trial IP should complete an early discontinuation visit as soon as possible if they no longer wish to be part of the study. 
An EOS visit should be performed 4 weeks after their final IP dose if possible. 
e Height is measured at the Screening visit only. 
f Vital signs include heart rate, respiratory rate, and blood pressure. Oxygen Saturation only done at Screening. 
g Only SAEs and non- serious AEs considered related to trial procedures are collected during the screening period until initiation of IP (Day 1). Any medical 
occurrence not related to a trial procedure during this period should be collected as medical history. 
h A CMR imaging sub-study will be open to approximately 100 patients who consent to participate. The baseline CMR imaging should be done prior to 
randomization. The EOT CMR should be performed after the Week 20 visit, but prior to the last dose of IP at Week 24.CMR should occur after CPET if the 
assessments are performed on the same day. 
i Echocardiograms will be done prior to dosing on Day 1 and 2 hours after dosing in the clinic at other time points. 
j Must be done within 24 hours of CMR. 
k Only for WOCBP. Serum pregnancy test at Screening visit. A urine pregnancy test may be performed locally at all other required timepoints. If a urine 
pregnancy test is positive, a serum pregnancy test should be performed. 
l When PK collection and an echocardiogram are scheduled for the same time point, PK collection should be completed prior to the echocardiogram. 
m Other biomarkers are referenced in Table 9. 
n A genotype sample will be collected on Day 1 from patients who provide consent. 
o PT-INR should also be taken at UNS DILI visits in addition to the screening visit. 
p All PROs, KCCQ, ED-5D-5L, SAQ-7, and PGI-C, should be done prior to other assessments. 
q On clinic visit days after Day 1, patients should take IP after the blood draw. At the Week 24 visit, patients should take their final dose of IP before the CPET. 
r See Section 6.6. 
s See Section 7.1. 

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1.4. 
Key Contacts 
Sponsor’s Trial Contact: 
Edward Robbie 
Manager, Clinical Operations 
Email:  CY6031ClinicalOperations@cytokinetics.com 
Phone:  +1 (650) 624-3046 
Fax:  
+1 (650) 624-3225 
Sponsor’s Medical Monitor: 
Daniel Jacoby, MD  
Senior Medical Director, Clinical Research, 
Cardiovascular 
Email:  CY6031MedicalMonitor@cytokinetics.com 
Mobile:  +1 (650) 410-0096 
Fax:  
+1 (650) 624-3225 
Serious Adverse Event Reporting: Cytokinetics Drug Safety 
Email:  CY6031DrugSafety@cytokinetics.com 
Fax:  
+1 (650) 243-4199 
 

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2. 
INTRODUCTION  
This is a Phase 3 trial of CK-3773274, a small molecule, allosteric inhibitor of cardiac myosin 
being developed as a chronic oral treatment for patients with hypertrophic cardiomyopathy 
(HCM). 
2.1. 
Trial Rationale 
The development of a targeted therapeutic drug that directly reduces myocardial contractility in 
the sarcomere may yield potential advantages over current therapies for obstructive hypertrophic 
cardiomyopathy (oHCM) because it potentially addresses the underlying pathophysiology of 
HCM. CK-3773274 is a cardiac myosin inhibitor with potential to reduce left ventricular outflow 
tract (LVOT) obstruction and improve symptoms in patients with hyperdynamic ventricular 
contractility in oHCM. 
This trial is intended to establish the efficacy and safety of CK-3773274 with respect to 
improvements in exercise capacity and patient symptoms, as well as reduction in left ventricular 
outflow tract gradient (LVOT-G) in patients with oHCM. 
2.2. 
Background 
2.2.1. 
Hypertrophic Cardiomyopathy 
HCM results from pathogenic genetic mutations, often affecting the genes encoding the proteins 
of the cardiac sarcomere, such as myosin (Maron, B. J. 2018). Histologic features include 
myofibrillar disarray, myocyte hypertrophy and interstitial fibrosis. Clinically, HCM is 
characterized by left ventricular (LV) hypertrophy unexplained by loading conditions and a 
nondilated LV with preserved or increased ejection fraction (Gersh 2011). Imaging studies of 
patients with HCM show hypertrophied LV walls, enhanced ventricular contractility, normal 
end-diastolic LV volume, reduced end-systolic volume, impaired diastolic compliance and often 
left atrial enlargement (Marian 2017). From population-based insurance claims and national 
health system data, the prevalence of clinically identified individuals with HCM in the US and 
EU is approximately 1:2000 and 1:3195 (Maron, M. S. 2016; Husser 2018; Magnusson 2017; 
Pujades-Rodriguez 2018). 
Approximately 70% of patients with phenotypic HCM will demonstrate an element of LVOT 
obstruction (Maron, M. S. 2006). The mechanisms for developing obstruction are well defined 
and involve a complex interplay between alterations in ventricular flow between asymmetric 
septal hypertrophy and the mitral valve leaflets. The result is abnormal systolic contact with the 
mitral valve leaflets (most commonly the anterior leaflet) and the development of an LVOT 
gradient (LVOT-G). By nature, oHCM is a dynamic condition with variable systolic gradients. In 
the setting of reduced afterload or reduced preload, symptoms change depending on the gradient 
and often worsen during exertion. Additional clinical manifestations of HCM include an elevated 
risk for ventricular fibrillation and sudden cardiac death; heart failure syndrome due to diastolic 
dysfunction; chest pain due to microvascular ischemia; palpitations and stroke due to atrial 
fibrillation; syncope and presyncope due to either ventricular arrhythmias or an abnormal blood 
pressure response to exercise; and, in a minority of patients, progression to systolic heart failure. 

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Contemporary management strategies for oHCM have resulted in the majority of patients 
achieving normal or near-normal longevity and improved morbidity; however, there has been 
little progress with the development of novel pharmacotherapies. Current medical treatment 
consists of beta-blockers, verapamil, diltiazem and disopyramide as recommended in the 2014 
European Society of Cardiology and in the 2020 American College of Cardiology Foundation / 
American Heart Association guidelines for the diagnosis and management of HCM. For patients 
with advanced symptomatic disease unresponsive to medications, septal reduction therapies 
(surgical myectomy or percutaneous alcohol ablation of the septum) can provide effective 
LVOT-G reduction (Elliott 2014; Gersh 2011; Ponikowski 2016; Ommen 2020). A subgroup of 
patients, who have been resuscitated from sudden cardiac death or who are at risk of sudden 
cardiac death, may undergo placement of an implantable cardioverter defibrillator (ICD) 
(Kristensen 2014). For those patients with HCM with end-stage disease who have both 
significant systolic impairment and diastolic dysfunction, cardiac transplantation may be the only 
treatment option (Gersh 2011). Disease-related mortality is most often attributable to sudden 
cardiac death, heart failure, and embolic stroke. 
Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 
and MYBPC3, encoding β-myosin heavy chain and myosin-binding protein C, respectively, are 
the two most common genes involved, together accounting for approximately 50% of the HCM 
families (Elliott 2014). Mechanistically, mutations in HCM appear to increase the net power 
generation in the sarcomere in vitro (Chuan 2012; Sommese 2013; Spudich 2016; Toepfer 2019). 
The findings in these studies are consistent with the underlying myocardial pathophysiology of 
the LV in patients with HCM being hypercontractile with diminished compliance (Wilson 1967). 
These nonclinical investigations have enhanced our understanding of the molecular pathogenesis 
of HCM and have stimulated efforts designed to identify cardiac myosin modulators that can 
target the underlying mechanism of hypercontractility in oHCM. 
2.2.2. 
CK­3773274 
CK-3773274, a small molecule allosteric inhibitor of cardiac myosin, is being developed as a 
chronic oral treatment for patients with HCM. CK-3773274 is designed to reduce the 
hypercontractility that underlies the pathophysiology of HCM in the cardiac sarcomere. The 
intended pharmacologic effect is reduction in force produced by the cardiac sarcomere resulting 
in less LVOT obstruction and improved diastolic function in patients with oHCM. 
CK-3773274 has been studied in a Phase 1 study of healthy adult participants and a Phase 2 
study of patients with oHCM. This Phase 3 trial will assess the efficacy and safety of 
CK-3773274 in patients with oHCM. 
Please refer to the Investigator’s Brochure for detailed information on the nonclinical and 
clinical studies of CK-3773274. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Excessive exposures to CK-3773274 may result in an excess of the intended pharmacodynamic 
(PD) effect, namely a decrease in LV systolic function, resulting in decreases in stroke volume 
and cardiac output with compensatory increases in heart rate. In nonclinical toxicology studies, 

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sustained depression of cardiac function led to increases in heart weight and dilatation of the 
cardiac chambers (Section 2.2.2). These adverse cardiac effects are consistent with the 
anticipated physiological response to an excessive PD effect of CK-3773274. 
In the first-in-human CY 6011 study, short-term decreases in cardiac function produced no 
changes in the vital signs or electrocardiograms (ECGs) of the participants. The effect of 
CK-3773274 on left ventricular ejection fraction (LVEF) reversed within 24-48 hours (single 
ascending dose and multiple ascending dose cohorts) of discontinuation of dosing. The 
participants who had decreases in LVEF to <50% remained asymptomatic until their cardiac 
function returned to the normal LVEF range. 
In the first three cohorts of the Phase 2 trial, CY 6021 (REDWOOD-HCM), there were no 
adverse events of decreased LVEF reported, however, a decline in LVEF < 50% per core 
laboratory evaluation was reported for 2 of 41 participants in the aficamten group, and no 
participants in the placebo group. The decline in LVEF was asymptomatic in both patients and 
returned to above 50% at the next observed time point 2 weeks later. One of these participants 
underwent per-protocol dose reduction from 20 mg to 10 mg daily and completed the treatment 
period without dose interruption. The second participant who completed study treatment was 
noted to have an LVEF of 49.3% at Week 10 (end of treatment visit). There were no reports of 
post-baseline LVEF < 40%. 
Together these findings indicate that the treatment effect of CK-3773274 is well tolerated and 
readily reversible with either a reduction of dose or discontinuation of treatment. 
2.3.1.1. 
Mitigation Strategy 
The main mitigation strategy will be facilitated by an individualized dose titration scheme based 
on each patient’s PD response to CK-3773274 with application of prespecified 
echocardiographic criteria, including LVEF thresholds for dose escalation, down-titration, and 
drug discontinuation. 
Patients enrolled in this trial will be required to have an LVEF ≥60% prior to randomization, as 
confirmed by the central echocardiography laboratory. A low starting dose of 5 mg and a 
maximum dose of 20 mg were chosen as these were found to be well-tolerated in the Phase 2 
study (CY 6021) of patients with oHCM and effective at reducing the LVOT-G without 
adversely impacting overall LVEF. Dose escalation will be performed on an individualized basis 
only if the following criteria are met: both post-Valsalva LVOT-G ≥30 mmHg and biplane 
LVEF ≥55%. Importantly, in contrast to CY 6021, the lower limit of LVEF for dose escalations 
will be increased from 50% to 55% to provide a safety margin from the threshold of LVEF 
(<50%) that will trigger dose reduction. If the LVEF is <50% at any time, the dose of 
CK-3773274 will be down-titrated, and if the LVEF is <40% at any time, CK-3773274 will be 
temporarily interrupted. 
An independent Data Monitoring Committee (DMC) will be established for this trial to formally 
review the accumulating data periodically in order to assess the risk to patients during the 
conduct of the trial. DMC members will include echocardiologists and HCM experts and will 
have access to treatment assignments and patient-level data in support of safety oversight. 

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2.3.2. 
CK­3773274 Benefit Assessment 
The development of a targeted therapeutic drug that directly reduces myocardial contractility in 
the sarcomere may yield potential clinical benefit for patients with oHCM by trying to address 
the underlying pathophysiology of HCM. CK-3773274 is a cardiac myosin inhibitor with the 
potential to reduce LVOT obstruction and thereby reduce symptoms in patients with 
hyperdynamic ventricular contractility in oHCM. 
In the Phase 2 trial, CY 6021 (REDWOOD-HCM), patients with oHCM received up to three 
doses of CK-3773274 or placebo (randomized 2:1) in a dose escalating manner using 
echocardiography to guide dose titration. Two cohorts of 21 (14 CK-3773274 and 7 placebo) and 
20 patients (14 CK-3773274 and 6 placebo) each were enrolled and treated for 10 weeks. Doses 
in the first cohort were 5, 10, 15 mg once daily; the second cohort studied 10, 20, and 30 mg 
once daily. In both cohorts, CK-3773274 significantly and substantially reduced the LVOT 
gradient (LVOT-G) in a dose and exposure dependent manner. The majority of patients treated 
with CK-3773274 (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved the target goal of 
treatment, defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg at 
Week 10 compared to placebo (7.7%). A third cohort of 13 patients taking disopyramide plus 
either a calcium-channel blocker or beta-blocker were enrolled and treated for 10 weeks. Doses 
were 5, 10, 15 mg once daily. CK-3773274 significantly and substantially reduced LVOT-G in 
dose and exposure dependent manner. Ten patients (77%) achieved complete or partial LVOT-G 
response at Week 10. Complete response was defined as rest and post-Valsalva LVOT-G 
<30 mmHg and <50 mmHG respectively. Partial response was defined as either rest LVOT-G 
≥30mmHg with Valsalva LVOT-G <50 mmHG, or rest LVOT-G <30 mmHg with post-Valsalva 
LVOT-G ≥50 mmHg . Eleven of 13 (85%) achieved improvement in NYHA class by ≥1 class. 
Given that the LVOT-G is the primary cause of symptoms in patients with oHCM, participation 
in this trial may afford those randomized to CK-3773274 symptom reduction and increased 
exercise capacity. Patient contributions to the performance of this trial may yield a new 
therapeutic modality for the treatment of their disease. 

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3. 
OBJECTIVES AND ENDPOINTS 
Table 2: 
Trial Objectives and Endpoints 
Objectives 
Endpoint(s) 
Primary 
To evaluate the effect of CK-3773274 
on exercise capacity in patients with 
symptomatic oHCM 
• Change in peak oxygen uptake (pVO2) by cardiopulmonary 
exercise testing (CPET) from baseline to Week 24 
Secondary 
To evaluate the effect of CK-3773274 
on patient health status  
• Change in Kansas City Cardiomyopathy Questionnaire – 
Clinical Summary Score (KCCQ-CSS) from baseline to 
Week 12 and Week 24 
To evaluate the effect of CK-3773274 
on New York Heart Association 
(NYHA) Functional Classification 
• Proportion of patients with ≥1 class improvement in NYHA 
Functional Class from baseline to Week 12 and Week 24 
To evaluate the effect of CK-3773274 
on post-Valsalva left ventricular 
outflow tract gradients (LVOT-G)  
• Change in post-Valsalva LVOT-G from baseline to 
Week 12 and Week 24 
• Proportion of patients with post-Valsalva LVOT-G 
<30 mmHg at Week 12 and Week 24 
To evaluate the effect of CK-3773274 
on duration of eligibility for septal 
reduction therapy 
• Duration of eligibility for septal reduction therapy (SRT) 
during the 24-week treatment period in patients who were 
eligible for SRT at baseline.  
To evaluate the effect of CK-3773274 
on exercise capacity  
• Change in total workload during CPET from baseline to 
Week 24 
Safety 
To evaluate the safety and tolerability 
profile of CK-3773274 in patients with 
symptomatic oHCM 
• Incidence of reported major adverse cardiac events 
(cardiovascular [CV] death, cardiac arrest, non-fatal stroke, 
non-fatal myocardial infarction, CV hospitalization) 
• Incidence of new onset persistent atrial fibrillation 
• Incidence of appropriate implantable cardiac defibrillator 
(ICD) discharges and aborted sudden cardiac death  
• Incidence of left ventricular ejection fraction (LVEF) <50% 
• Incidence of LVEF <50% with at least one of the 
following:  
o Signs and symptoms of heart failure (concomitant 
adverse event of heart failure or dyspnea), AND/OR 
o Increase in NT-proBNP (≥30% increase), relative to 
results from the most recent previous visit and above 
the upper limit of normal, at the time of LVEF 
assessment <50%  
• Incidence of treatment emergent adverse events 

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Table 2: 
Trial Objectives and Endpoints (Continued) 
Objectives 
Endpoint(s) 
Exploratory 
To evaluate the effect of CK-3773274 
on exercise capacity and functional 
class 
• Compared with baseline, proportion of patients at Week 24 
achieving either: 
− Change from baseline of ≥1.5 mL/kg/min in pVO2 
AND ≥1 class improvement in NYHA Functional 
Class 
OR 
− Change from baseline of ≥3.0 mL/kg/min in pVO2 
AND no worsening of NYHA Functional Class  
To evaluate the effect of CK-3773274 
on patient response over time 
• Proportion of patients with improvement in KCCQ-CSS 
≥5 points at Weeks 12 and 24 
• Proportion of patients with resting LVOT-G <30 mmHg, 
post-Valsalva LVOT-G <50 mmHg, and NYHA Functional 
Class I at Weeks 12 and 24 
• Proportion of patients with resting LVOT-G <30 mmHg, 
post-Valsalva LVOT-G <50 mmHg, and ≥1 class 
improvement in NYHA Functional Class at Weeks 12 and 
24 
To evaluate the effect of CK-3773274 
on septal reduction therapy eligibility 
• Proportion of patients who are eligible for septal reduction 
therapy at Week 24 among patients who were eligible for 
septal reduction therapy at baseline 
To evaluate the effect of CK-3773274 
on other CPET parameters 
Change from baseline to Week 24 in: 
• Ventilatory efficiency (VE/VCO2 slope) 
• Circulatory power (VO2 × systolic BP) 
• Ventilatory anaerobic threshold (VAT) 
To evaluate the effect of CK-3773274 
on health status and health-related 
quality of life as measured by PRO 
questionnaire 
• Change from baseline to Week 24 in individual responses 
to the EuroQol 5-dimension 5-level instrument (EQ-5D-5L) 
To evaluate the effect of CK-3773274 
on health status and quality of life 
related to chest pain-like angina 
Change from baseline to Week 24 in summary and domain 
scores for the Seattle Angina Questionnaire-7 (SAQ-7) 
To evaluate the effect of CK-3773274 
on cardiac function and structure  
• Change from baseline to Week 24 in echocardiographic 
measurements of cardiac structure and of systolic function 
including: 
− LVEF 
− Left ventricular end-systolic and end-diastolic volumes 
(LVESV and LVEDV, respectively) 
− Left atrial volume 

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Table 2: 
Trial Objectives and Endpoints (Continued) 
Objectives 
Endpoint(s) 
To evaluate the effect of CK-3773274 
on biomarker levels  
• Change from baseline values in NT-pro-BNP, hs-cardiac-
TnI and other biomarkers through Week 24 
To evaluate the effect of CK-3773274 
on left ventricular mass, function, and 
structure by cardiac magnetic 
resonance (CMR) imaging  
• Change from baseline to Week 24 in CMR measurements 
of: 
− Left ventricular (LV) mass index 
− LVEF 
− Septal, free wall, and maximal wall thickness 
− Left atrial volume index 
− LVESV 
− LVEDV 
To assess the pharmacokinetics of 
CK-3773274 and its metabolites 
• Pharmacokinetic parameters through Week 24 

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4. 
TRIAL DESIGN  
4.1. 
Overall Design 
This is a Phase 3, randomized, placebo-controlled, double-blind, multi-center trial in patients 
with symptomatic oHCM. Approximately 270 eligible patients will be randomized in a 1:1 ratio 
to receive CK-3773274 or placebo. Randomization will be stratified by use of beta-blockers (yes 
or no) and CPET exercise modality (treadmill or bicycle) and implemented in the Interactive 
Web Response System (IWRS). A cap on the number of patients taking beta-blockers and will 
not exceed approximately 70% of total enrollment. The number of patients taking disopyramide 
will be capped at approximately 10% of total enrollment. The number of patients with persistent 
atrial fibrillation at screening will also be capped at approximately 15%, and the number of 
patients using the bicycle CPET exercise modality will be capped at approximately 50% as well. 
IP will be administered orally once daily with or without food. During the initial six weeks of the 
treatment period, IP doses will be individually titrated at Weeks 2, 4, and 6 using 
echocardiography. Dose escalation at Weeks 2, 4, and 6 will occur only if a patient has a 
post-Valsalva LVOT-G ≥30 mmHg and a biplane LVEF ≥55%. Echocardiograms will be 
performed at each subsequent visit during the trial and the dose down titrated if necessary. The 
primary endpoint of pVO2 will be measured by CPET at screening and at end of treatment 
(Week 24). Patients’ background HCM therapy should be individually optimized according to 
the local practice. 
All patients will be followed according to the Schedule of Activities (SoA) from randomization 
through the date of their final visit irrespective of whether the patient is continuing to receive IP, 
unless the patient has discontinued prematurely from the trial or withdrawn consent. An early 
discontinuation visit will be performed for patients who discontinue prematurely from the trial. 
The overall study design is described by a trial schema in Figure 2. 
The trial endpoints and objectives are defined in Table 2. 
4.1.1. 
Number of Sites 
Approximately 120 investigative sites worldwide will participate in this trial. 
4.1.2. 
Number of Patients 
Approximately 270 patients will be randomized in the trial. 
4.1.3. 
Replacement of Patients 
Patients who are withdrawn or removed from treatment or the trial will not be replaced. 
4.1.4. 
Trial Duration 
The trial will comprise three periods. After signing the informed consent form, patients will 
complete assessments to determine trial eligibility during a screening period of up to 6 weeks in 
duration. The double-blind placebo-controlled treatment period will last 24 weeks. Following the 
final dose of IP, there will be a 4-week safety follow-up period. 

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4.1.5. 
CMR Imaging Sub-Study 
A CMR imaging sub-study will be open to approximately 100 patients who consent to 
participate. 
4.2. 
Scientific Rationale for Trial Design 
This trial is designed to provide data supporting the clinical efficacy and safety of CK-3773274 
in patients with symptomatic oHCM and an LVOT-G >50 mmHg post-Valsalva. Reduction of 
the LVOT-G is expected to correlate with improvement in the patients’ symptoms, health status 
and exercise capacity. 
Since patient characteristics vary substantially in this disease, individualized dose titration to a 
PD response (reduction of the post-Valsalva LVOT-G to <30 mmHg with preservation of LVEF 
≥55%) is being employed to maximize efficacy and safety. The eligibility criteria are designed to 
enable enrollment of a patient population representative of the general population of patients 
with oHCM while ensuring the safety of the patients in this trial. 
A placebo control and double-blinded approach are being employed in this trial to avoid bias in 
data collection, including the safety assessments and PD measures that comprise the primary and 
secondary endpoints. 
4.3. 
Justification for Dose 
The doses of CK-3773274 are summarized in Table 3. A starting dose of 5 mg and a maximum 
dose of 20 mg were chosen as these were found to be well-tolerated in the Phase 2 study of 
patients with oHCM and effective at reducing the LVOT-G without adversely impacting overall 
LVEF. Within-patient dose escalation will only occur when the patient’s current dose is well-
tolerated, and the patient meets the criteria described in Section 6.6. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last patient in the trial. 

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5. 
STUDY POPULATION 
Before patients begin any trial-specific activities/procedures, Cytokinetics requires a copy of the 
site’s institutional review board/independent ethics committee (IRB/IEC) approval of the 
protocol, informed consent form (ICF), and all other patient information and/or recruitment 
material, if applicable. A signed ICF must be obtained from each patient before commencement 
of any trial-specific activities/procedures. 
A patient’s participation in the trial begins after signing the informed consent. After confirming 
the patient has met all eligibility criteria, randomization should then occur before the first dose 
on Day 1 is administered. The site is to document the informed consent signature and 
randomization dates in the patient’s medical record and in/on the case report form (CRF). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exceptions, is not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the trial only if all the following criteria apply: 
101. Able to comprehend and willing to sign an ICF and willing to comply with all trial 
procedures and restrictions for the duration specified in the Schedule of Activities 
(SoA; Section 1.3). 
102. Males and females between 18 and 85 years of age, inclusive, at screening. 
103. Body mass index <35 kg/m2. 
104. Diagnosed with HCM per the following criteria: 
a. Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac 
disease and 
b. Has an end-diastolic LV wall thickness as measured by the echocardiography core 
laboratory of: 
•  ≥15 mm in one or more myocardial segments OR 
• ≥13 mm in one or more wall segments and a known-disease-causing gene 
mutation or positive family history of HCM 
105. Has resting LVOT-G ≥30 mmHg and post-Valsalva LVOT-G ≥50 mmHg during 
screening as determined by the echocardiography core laboratory  
106. LVEF ≥60% at screening as determined by the echocardiography core laboratory. 
107. New York Heart Association (NYHA) Functional Class II or III at screening 
108. Hemoglobin ≥10 g/dL at screening. 
109. Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the screening 
CPET per the core laboratory. 
110. Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on a 
stable regimen for >6 weeks prior to randomization and anticipate remaining on the 
same medication regimen during the trial. Patients treated with disopyramide must also 
be concomitantly treated with a beta blocker and/or calcium channel blocker. 

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111. Male patients are eligible to participate if they agree to the following: 
a) Refrain from donating sperm during the trial plus at least 10 weeks after the last dose 
of IP 
AND  
b) During the trial plus 4 weeks after the last dose of IP either:  
1. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent in 
writing  
OR 
2. Must agree to use a male condom when his female partner is a woman of 
childbearing potential, and have his female partner use a highly effective method of 
contraception (as described in Appendix 3 [Section 10.3]) 
112. A female patient is eligible to participate if she is not pregnant, breastfeeding or 
planning to donate eggs, and at least one of the following conditions applies: 
a. Is not a woman of childbearing potential (WOCBP; as described in Appendix 3 
[Section 10.3]) 
OR 
Is a WOCBP and using a highly effective method of contraception (as described in 
Appendix 3 [Section 10.3]) and male partner agrees to use a condom, during the trial 
and for at least 4 weeks after the last dose of IP. 
b. A WOCBP must have a negative pregnancy test (urine or serum as required by local 
regulations) at Day 1, prior to the first dose of study IP. 
Note: The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Contraceptive use by men or WOCBPs should be consistent with the guidance in 
Appendix 3 (Section 10.3) and local regulations regarding the methods of contraception 
for those participating in clinical studies. 
113. Willing and able to complete all screening procedures. 
5.2. 
Exclusion Criteria 
Patients will be excluded from the trial if any of the following criteria apply: 
201. 
Significant valvular heart disease (per investigator judgment). 
a. Moderate-severe valvular aortic stenosis and/or regurgitation. 
b. Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral 
valve  

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202. Documented history of current obstructive coronary artery disease (>70% stenosis in 
one or more epicardial coronary arteries) or documented history of myocardial 
infarction. 
203. Known or suspected infiltrative, genetic or storage disorder causing cardiac 
hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis). 
204. Prior treatment with cardiotoxic agents such as doxorubicin or similar. 
205. History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time 
during their clinical course. 
206. Has any ECG abnormality considered by the investigator to pose a risk to patient safety 
(eg, second degree atrioventricular block type II). 
207. Documented paroxysmal atrial fibrillation during the screening period. 
208. Paroxysmal or permanent atrial fibrillation is only excluded IF: 
- 
rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation 
procedure, or antiarrhythmic therapy) has been required ≤6 months prior to screening 
- 
rate control and anticoagulation have not been achieved for at least 6 months prior to 
screening 
209. History of syncope or sustained ventricular tachyarrhythmia with exercise within 
6 months prior to screening. 
210. ICD placement within 3 months prior to screening or planned ICD placement during 
the trial. 
211. History of appropriate ICD discharge for life-threatening ventricular arrhythmia within 
6 months prior to screening. 
212. Has been treated with septal reduction therapy (surgical myectomy or percutaneous 
alcohol septal ablation) or cannot postpone plans for septal reduction therapy until after 
the trial period. 
213. Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations). 
214. Documented room air oxygen saturation reading <90% at screening. 
215. Hepatic impairment defined by a total bilirubin (TBL) ≥1.5 × the upper limit of normal 
(ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≥3 × ULN at screening. Patients with documented Gilbert syndrome and TBL 
≥1.5 × ULN due to unconjugated hyperbilirubinemia, without other hepatic 
impairment, are permitted. 
216. Recipient of a major organ transplant (eg, heart, lung, liver, bone marrow, renal) or 
anticipated transplantation within 12 months from randomization. 
217. History or evidence of any other clinically significant disorder, malignancy, active 
infection, other condition, or disease that, in the opinion of the investigator or the 
Medical Monitor, would pose a risk to patient safety or interfere with the trial 
evaluation, procedures, or completion. 

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218. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (by the modified 
Modification of Diet in Renal Disease equation) at screening. 
219. Currently participating in another investigational device or drug trial or received an 
investigational device or drug <1 month (or 5 half-lives for drugs, whichever is longer) 
prior to screening. Other investigational procedures while participating in this trial are 
not permitted. 
Note: At the EOS visit for CY 6031, screening assessments for entry into an 
open-label extension study of aficamten are permitted. 
220. Has received prior treatment with CK-3773274 or mavacamten. 
221. Any known hypersensitivity to excipients in study drug tablets 
Exclusion Criteria for CMR sub-study 
222. Inability to tolerate CMR. 
223. Has an ICD. 
224. Has a cardiac pacemaker. 
225. Does not consent to participate in CMR sub-study 
5.3. 
Lifestyle Considerations 
Patients will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests and before CPET. Patients should not exercise at all for 12 hours prior to 
CPET. Patients should also fast for at least 4 hours prior to CPET. Any medications that may 
cause drowsiness should be avoided for 8 hours prior CPET. 
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently randomized to IP. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demographics, reason for screen failure, eligibility criteria, and any SAEs 
related to trial-related procedures. 
The screening eligibility period is 42 days as defined in Section 4.1. An individual who does not 
meet the criteria for participation in this trial is referred to as a screen failure. Patients may be 
rescreened one time after initial screening when the reason for screen failure is resolved or 
expected to be resolved. 
Patients must re-sign an informed consent before they are rescreened. At rescreening, they must 
meet all inclusion/exclusion criteria at the time of rescreening and have all elements of the 
screening visit performed again to be eligible. Patients who screen fail and rescreen do not need 
a repeat CMR. 
If an element of the screening visit could not be performed for logistical or technical reasons (eg, 
trained evaluator was out sick, equipment malfunction) the patient can return within the 

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screening eligibility period to complete the visit. Echocardiograms and CPETs failed due to 
technical insufficiencies can be repeated. 
Retesting for abnormal laboratory results within the original screening period may also be 
performed if there is reason to believe the repeat laboratory results may improve and not be 
clinically significant and the patient is otherwise eligible to participate. Patients cannot be 
retested for abnormal bilirubin laboratory results. Patients who are retested during the original 
screening eligibility period do not need to re-sign an informed consent. The screening window is 
established by the date of the original screening visit and not by the date that laboratory retesting 
takes place. Patients who repeat echocardiograms and CPETs due to technical insufficiencies do 
not need to re-sign an informed consent. 
No waivers will be granted regarding inclusion/exclusion criteria. 

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6. 
INVESTIGATIONAL PRODUCT  
This section describes any IP, marketed product(s), or placebo intended to be administered to a 
trial patient according to the study protocol. 
6.1. 
Investigational Product(s) Administered 
Table 3: 
Investigational Products 
Arm Name 
Active 
Placebo 
IP/Product Name 
CK-3773274 
Placebo 
Type  
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strength(s) 
5mg  
Matching placebo 
Dosage Level(s) 
5mg, 10mg, 15mg, 20mg 
 
Route of 
Administration 
Oral 
Oral 
Use 
Experimental 
Placebo 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Patheon Inc. 
Toronto Regional Operations (TRO) 
2100 Syntex Court 
Mississauga, Ontario L5N 7K9 
Canada 
Patheon Inc. 
Toronto Regional Operations (TRO) 
2100 Syntex Court 
Mississauga, Ontario L5N 7K9 
Canada 
Excipients 
Microcrystalline Cellulose 
Mannitol 
Croscarmellose Sodium 
Hydroxypropyl Cellulose 
Sodium Lauryl Sulfate 
Magnesium Stearate 
Opadry QX White 
Microcrystalline Cellulose 
Lactose Monohydrate 
Croscarmellose Sodium 
Magnesium Stearate 
Opadry QX White 
Packaging and 
Labeling 
IP will be provided in blister packs 
which will be labeled as required 
per country requirement 
IP will be provided in blister packs 
which will be labeled as required 
per country requirement 
IMP = investigational medicinal product; NIMP = non-investigational medicinal product 
6.2. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and resolved 
before use of the IP. 
Only patients randomized in the trial may receive IP and only authorized site staff may supply or 
administer IP. All IP must be stored in a secure, environmentally controlled, and monitored 

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(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, chain of custody, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Patients should be instructed to take four tablets each day from one row on the blister pack. 
Further guidance and information regarding IP storage condition, dispensation, packaging, 
labeling, and accounting procedures are provided in the Pharmacy Manual. 
IP should be stored at or below 25°C. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All eligible patients will be centrally assigned to randomized IP using the IWRS. Before the trial 
is initiated, the login information & directions for the IWRS will be provided to each site. 
Because viewing echocardiogram results could potentially compromise the blinded investigator 
and blinded study coordinator, specified unmasked study staff will perform and read the 
echocardiograms. 
An unmasked sonographer at the site will perform the echocardiograms. An unmasked 
cardiologist, who is not the investigator and is called the unmasked echocardiologist, will read 
the echocardiograms, measure the LVOT-G and LVEF and enter the echocardiogram results in 
the IWRS for dose titrations and adjustments. An unmasked designee, who is also not involved 
in other aspects of the study visits, may be delegated to enter data into IWRS on the unmasked 
echocardiologist’s behalf. All site staff, including the unmasked echocardiologist and the 
unmasked designee, will be blinded to randomized treatment assignments. Neither the unmasked 
echocardiologist nor the unmasked data entry designee will reveal echocardiogram results to the 
rest of the study team, except in the event of a critical safety issue (eg, LVEF < 40%). Therefore, 
the investigator and site staff will remain blinded to the echocardiogram images and results. 
IP will be dispensed at the trial visits summarized in the SoA (Section 1.3). Returned IP should 
not be re-dispensed to the patients. 
Patients randomized to placebo will receive placebo throughout the study and will perform all 
protocol procedures in order to maintain the blind for the treatment group allocation and IP dose. 
Patients should continue to take IP through the morning of the Week 24 Visit. 
The IWRS will be programmed with blind-breaking instructions and the unblinding procedure is 
documented in the study manual. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a patient’s intervention assignment is warranted. 
Patient safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator is encouraged to contact 
Cytokinetics prior to unblinding a patient’s intervention assignment unless this could delay 
emergency treatment of the patient. If a patient’s intervention assignment is unblinded, 
Cytokinetics 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. 

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6.4. 
Investigational Product Compliance 
When patients are dosed at the site, the date and time of the dose administered in the clinic will 
be recorded in the source documents and recorded in the CRF. 
When patients self-administer IP at home, compliance with IP will be assessed at each site visit. 
Compliance will be assessed by counting returned tablets during the site visits and documented 
in the source documents and CRF. Deviation(s) from the prescribed dosage regimen should be 
recorded in the CRF. 
For IP accountability, a record of the following should be documented in the CRF at every visit 
and reconciled with IP and compliance records: 
• the date and kits dispensed  
• date and tablets returned 
IP dosing first and last dates, including dates for dosing interruptions will also be recorded in the 
CRF. 
6.5. 
Concomitant Therapy 
Any medication, including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements, that the patient is receiving at the time of enrollment or receives during the trial 
must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on stable 
doses for >6 weeks prior to randomization and anticipate remaining on the same medication 
regimen during the trial. Patients treated with disopyramide must also be concomitantly treated 
with a beta blocker and/or calcium channel blocker. Patients’ background HCM therapy should 
be individually optimized according to the local practice. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Patients may continue to take prescription medications, which in the opinion of the investigator 
and the Medical Monitor, will not interfere with the trial. 
While medications and doses should remain stable whenever appropriate during the trial, 
investigators may prescribe or adjust any concomitant medication or treatment deemed necessary 
to provide adequate supportive care. 
6.5.1. 
Drug-Drug Interactions 
In vitro studies showed that CK-3773274 was metabolized by CYP2D6 and CYP3A with 
potential contributions from CYPs 2C9 and 2C19. Since CYP2D6 was identified in vitro as a 
metabolizing enzyme of CK-3773274, the degree of dependence of its metabolism on CYP2D6 
was explored in the first-in-human study, CY 6011, in participants with a poor metabolizing 

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CYP2D6 genotype. Compared to participants with an extensive metabolizing CYP2D6 genotype, 
the pharmacokinetics of CK-3773274 in participants with a poor metabolizing genotype were not 
different, suggesting that CYP2D6-mediated interactions are unlikely. In the absence of clinical 
data, the use of strong CYP3A inhibitors or inducers should be used with caution and careful 
monitoring. 
Caution may be needed when administering CK-3773274 with known substrates of P-gp until 
drug-drug interaction studies are completed. Contact the Medical Monitor to determine if a 
potentially meaningful drug-drug interaction may exist. 
6.5.2. 
Rescue Medicine 
The use of rescue medications in the event of a low cardiac output state (eg, dobutamine) is 
allowable at any time during the trial (Section 8.5). The date and time of rescue medication 
administration as well as the name and dosage regimen of the rescue medication must be 
recorded. 
6.6. 
Dose Modifications 
6.6.1. 
Scheduled Dose Titrations 
Patients randomized to CK-3773274 may receive up to four escalating doses of IP over the initial 
6 weeks of the trial as outlined below in Table 4. Patients receiving CK-3773274 start at a dose 
of 5 mg once daily (Dose 1) and may escalate through doses of 10, 15, and 20 mg once daily if 
they continue to meet the escalation criteria or will stop at their current dose when escalation 
criteria are not met. 
6.6.1.1. 
Week 2 Visit 
After randomization each patient will receive Dose 1 once daily for two weeks. At the Week 2 
visit, the patient will have an echocardiogram 2 hours following administration of their dose of 
IP. Patients will up-titrate to Dose 2 if the following conditions are met on echocardiography: 
• Post-Valsalva LVOT-G ≥30 mmHg, and the biplane LVEF ≥55% 
Otherwise, the patient will remain on Dose 1. 
If LVEF is <50% at Week 2, the IWRS will assign the patient to placebo. 
6.6.1.2. 
Week 4 Visit 
After two more weeks on the assigned dose, at the Week 4 visit each patient will have an 
echocardiogram 2 hours following administration of their dose of IP. Patients will up-titrate to 
the next higher dose if the following conditions are met on echocardiography: 
• Post-Valsalva LVOT-G ≥30 mmHg, and the biplane LVEF ≥55% 
Otherwise, the patient will remain on the same dose. 
If LVEF is <50% at Week 4, the IWRS will assign the patient to the prior dose level or to 
placebo if the patient was on Dose 1. 

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echocardiologist will enter the LVEF value in the IWRS and discuss the results with the blinded 
investigator or qualified designee. The Medical Monitor will be informed in these cases. 
If a patient’s LVEF is <40% at any time, the following steps should occur after consultation with 
the Medical Monitor:  
• IP should be stopped and held for at least 7 days. 
• Repeat echocardiograms should be performed per investigator judgment until a 
normal LVEF (≥55%) has been documented at which point the patient can be 
re-started on IP after being down-titrated. 
• Document dose interruption in the eCRF and include the reason for interruption, the 
date of the last dose, and the restart date (Section 7.1). 
6.6.4. 
Hepatotoxicity Stopping and Rechallenge Rules 
Patients with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, ALT, 
TBL) and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis may meet 
the criteria for withholding or permanent discontinuation of IP or other protocol-required 
therapies as specified in the FDA Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation, July 2009. See Appendix 5 (Section 10.5) for guidance on the 
assessment and management of abnormal hepatic laboratory values. 
6.7. 
Access to Investigational Product after the End of the Study 
Patients who complete CY 6031 and meet eligibility criteria will be offered participation in an 
open-label extension study of aficamten. Participation in the open-label extension study is at the 
discretion of the patient and not a condition of participation in CY 6031. The commitment to the 
conduct of an open-label extension trial will be at Cytokinetics’s discretion. 

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7. 
TEMPORARY INTERRUPTION OF INVESTIGATIONAL 
PRODUCT, DISCONTINUATION OF INVESTIGATIONAL 
PRODUCT, AND PATIENT CONSENT WITHDRAWAL 
Emergent safety concerns should be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the patient should continue, interrupt or permanently 
discontinue IP. 
Unless a safety concern arises, the investigator should make every effort to keep a patient on the 
IP for as long as possible during the trial. The degree to which a patient withdraws from the trial 
varies. There are three types of discontinuation: temporary IP interruption, permanent IP 
discontinuation and patient withdrawal of consent. 
7.1. 
Temporary IP Interruption 
Initially, any IP interruption should be considered temporary unless permanent IP 
discontinuation is mandated by the protocol. 
A temporary IP interruption: 
• Will be implemented when a predefined safety threshold has been met (Section 6.6) 
• May be considered by the investigator in the case of an AE/SAE or for another reason 
If a temporary IP interruption occurred because a safety threshold was met, blinded treatment 
will be resumed at least 7 days later, either at a lower dose or with a permanent switch to placebo 
if the patient was at 5mg, as determined by the IWRS (Section 6.6.3). 
If the IP was temporarily interrupted because of an AE/SAE, the investigator should make the 
best effort to resume IP as soon as practically possible, assuming there are no remaining safety 
concerns. 
If dosing is interrupted for more than 3 consecutive days in the first 6 weeks and more than 
7 consecutive days thereafter, the investigator should contact the Medical Monitor to discuss the 
patient. 
All temporary IP interruptions of greater than 3 days should be recorded in the eCRF (stop and 
start dates and reason for interruption) and the Medical Monitor should be notified. 
7.2. 
Permanent Discontinuation of IP 
In all cases, patients should be encouraged to discuss stopping IP with the investigator or the 
investigator’s designee. Best efforts should be made to address the patient’s questions, adjust 
concomitant medical therapies if needed and arrange follow-up safety assessments. Refer to 
Section 7.2.1. for management of patients who permanently discontinue IP. 
Any permanent discontinuation of IP should be recorded in the eCRF including the reason for 
permanent discontinuation. 
Reasons for permanent IP discontinuation may include any of the following: 
• Patient request  
• Pregnancy 

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• All criteria for possible drug-induced liver injury (DILI) are met (Appendix 5 
[Section 10.5]) 
• The investigator judges that continued administration of IP would be detrimental to 
the patient’s safety or well-being. 
• Protocol violation 
• Lost to follow-up 
• Any breaking of the trial blind requested by the investigator 
• Death 
• The Sponsor requests that the patient permanently discontinue IP 
7.2.1. 
Management of Patients after Permanent Discontinuation of IP 
If IP is permanently discontinued, the patient should be encouraged to remain in the trial to 
continue to obtain outcome measures and safety data (see Section 7.2). 
There are several options for a patient after permanently discontinuing IP:  
• Patient agrees to continue to return to clinic for all remaining trial visits. 
• Patient agrees to complete the early discontinuation (ED) visit as soon as possible 
after the decision is made and complete an EOS visit. 
• Patient only agrees to complete the ED visit. 
• Patient agrees to be contacted by phone to obtain patient trial data. 
• Patient withdraws consent (see Section 7.4) and does not agree to any further trial 
procedures or visits. 
• For those patients who have not withdrawn consent and have difficulty returning for 
all remaining trial visits, they can be contacted by phone to obtain patient trial data. 
7.3. 
Discontinuation from Trial Procedures 
Patients can decline to continue receiving IP and/or other protocol-required therapies or 
procedures at any time during the trial but continue participation in the trial. If this occurs, the 
investigator is to discuss with the patient the appropriate processes for discontinuation from IP or 
other protocol-required therapies and must discuss with the patient the options for continuation 
of the SoA (Section 1.3) including different options of follow-up (eg, in person, by phone/mail, 
through family/friends, in correspondence/communication with other treatment physicians, from 
the review of medical records) and collection of data, including endpoints and AEs. Patients who 
have discontinued IP and/or protocol required therapies or procedures should not be 
automatically removed from the trial. Whenever safe and feasible it is imperative that patients 
remain on-trial to ensure safety surveillance and/or collection of outcome data. The investigator 
must document the change to the SoA (Section 1.3) and the level of follow-up that is agreed to 
by the patient (eg, in person, by telephone/mail, through family/friends, in 
correspondence/communication with other physicians, from review of the medical records). 

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7.4. 
Patient Consent Withdrawal 
Patients have the right to withdraw consent and no longer participate in the trial at any time and 
for any reason without prejudice to their future medical care by the physician or at the institution. 
Consent withdrawal means the patient no longer wishes to undergo any follow-up visits, trial 
procedures, investigator contact, and non-patient contact follow-up (eg, medical records check). 
• Discontinuing IP should be distinguished from consent withdrawal for follow-up 
since the patient may agree to undergo trial procedures or still be contacted even 
though they have stopped taking IP (see Section 7.3). 
• Consent withdrawal should be accompanied by documentation of the reason for 
withdrawal. Patients requesting consent withdrawal for any follow-up should be 
informed that it may limit the public health value of the trial. 
Patients who withdraw consent should be asked explicitly about the contribution of possible AEs 
to their decision to withdraw consent, and any AE information elicited should be documented. 
Preferably, the patient should withdraw consent in writing and, if the patient or the patient’s 
representative refuses or is physically unable, the site should document and sign the reason for 
the patient’s failure to withdraw consent in writing. The ICF for the trial may note that although 
a patient is completely free to leave the trial and stop taking IP, the investigators hope the patient 
will remain for follow-up status evaluations. 
For patients who have withdrawn consent for further follow-up, investigators may review public 
records as permitted by applicable law to determine vital status of the patient before or at the end 
of the trial. 
7.5. 
Lost to Follow up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a patient fails to return to the clinic for a required trial 
visit: 
• The site must attempt to contact the patient or the patient’s family and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether the patient wishes to 
and/or should continue in the trial. 
• Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient or the patient’s family (where possible, 
3 telephone calls and, if necessary, a certified letter to the patient’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
discontinued from the trial and is lost to follow-up. 
Closing of specific sites or discontinuation of the trial are handled as part of Appendix 1 
(Section 10.1.8). 

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8. 
TRIAL ASSESSMENTS AND PROCEDURES 
Trial assessments and procedures and their timing are summarized in the SoA (Section 1.3). 
Protocol waivers or exceptions are not allowed. Adherence to the trial design requirements, 
including those specified in the SoA, is essential and required for trial conduct. 
There will be a total of 11 in-person trial visits per patient, with windows to aid in scheduling as 
shown in Table 5. If a patient visit must be scheduled outside the visit window, the Medical 
Monitor should be contacted. 
Table 5: 
CY 6031 Visit Windows 
Visit 
Visit Window 
Screening 
Up to 42 days prior to Day 1 visit 
Day 1 (First Dosing Day) 
N/A 
Week 2 
+3 days 
Week 4 
+3 days 
Week 6 
+3 days 
Week 8 
+3 days 
Week 12 
±3 days 
Week 16 
±7 days 
Week 20 
±7 days 
Week 24 (EOT) 
±7 days 
Week 28 (EOS) 
+7 days 
All visits should be scheduled based on Day 1 
8.1. 
Visit Schedule 
Activities will be completed during clinic visits as described in this section. General guidance for 
the preferred order of assessments and procedures are outlined below: 
• On visit days, patients should wait to take their daily IP dose at the clinic. 
• Patient-reported outcomes questionnaires should be completed by patients prior to 
any other activities. (ie, KCCQ (administered first), EQ-5D-5L, SAQ-7, Patient 
Global Impression of Change [PGI-C]) 
• IP should be administered after completion of vital signs, ECG, and blood draws. 
• ECGs and vital signs must be performed prior to blood draws or other invasive 
procedures. 
• Echocardiograms should be done prior to IP dosing on Day 1 and 2 hours after IP 
dosing in the clinic at other time points. 
• CPET should be performed after other visit activities including IP administration. 
CMR should occur after CPET if the assessments are performed on the same day. 

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Please refer to the study manuals for additional details. 
8.1.1. 
Screening Visit 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Laboratory values obtained at screening and reported through the central laboratory will be used 
to determine patient eligibility. 
The screening period will be up to 6 weeks in duration to allow greater flexibility for visit 
scheduling and the potential for retesting. 
The CPET should not be completed until the patient is otherwise deemed eligible. The CPET 
used for eligibility should be completed within four weeks but not less than one week prior to 
randomization. 
8.1.2. 
Day 1 
Patients who meet all eligibility criteria including confirmation from the CPET core laboratory at 
the end of the screening period will return to the site for randomization and Day 1 activities as 
defined in the SoA. 
8.1.3. 
Weeks 2 through 20 
Please refer to the SoA (Section 1.3) for Weeks 2-20. 
8.1.4. 
Week 24: End of Treatment Visit 
Week 24 is defined as the EOT visit and includes assessments and procedures critical for 
analysis of the trial’s endpoints. These assessments are outlined in the Schedule of Activities. 
Additionally, the following should be considered in advance of Week 24: 
• Contact patients shortly before the Week 24 EOT visit to confirm their ability to 
perform the CPET, and schedule the procedure to ensure it is completed within the 
protocol-defined window 
• For patients temporarily unable to exercise on the treadmill or bicycle (whichever 
modality was used at baseline) due to an adverse event (eg, ankle sprain, upper 
respiratory infection, migraine), but not due to HCM symptoms, or if the site is 
unable to perform the CPET (eg, equipment malfunction), then the Week 24 visit may 
be postponed by up to 4 weeks and those patients should continue to receive IP until 
the visit 
• Schedule CMR imaging for sub-study (if applicable) 
− For patients who provided consent and completed baseline imaging at screening, 
schedule the CMR imaging to ensure it is completed within the protocol-defined 
window. The baseline CMR should be performed within the 6-week screening 
period prior to randomization. 

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− The EOT CMR should be performed after the Week 20 visit, but prior to the last 
dose of IP at Week 24. 
• If necessary, the Week 24 visit may be split across two consecutive days within the 
visit window. If the visit is split, all assessments, except the CPET, should occur on 
the first day of the split visit. The CPET should occur on the second day of the split 
visit. Dosing will occur on site on both split visit days. 
8.1.5. 
Week 28: End of Study Visit 
All patients should complete an end of study (EOS) visit: 
• For subjects who complete all study visits, the EOS visit will occur at Week 28 (or 
4 weeks after a delayed Week 24 visit). 
• For subjects who early-terminate IP more than 4 weeks before Week 24 and continue to 
stay on-study for all follow-up assessments, the Week 24 visit can be considered the EOS 
visit (and the EOS visit does not need to be performed). 
• For subjects who withdraw consent and do not wish to continue the participation in 
follow-up assessments, an EOS visit should be performed 4 weeks after their final IP 
dose if possible. 
To ensure a 4-week safety follow-up (to assess any Adverse Events), the EOS Exit Date must 
correspond to either 4 weeks after last dose, or at their last study visit (ie, Week 24), whichever 
is later. 
Screening assessments for entry into an open-label extension study of aficamten are permitted at 
the EOS visit. CY 6031 EOS visit assessments must occur before the open-label screening 
assessments. Assessments for each visit must be done in the order defined by the protocol. 
8.1.6. 
Early Discontinuation Visit 
For patients who discontinue the trial prematurely, the activities outlined in the SoA will be 
completed during an Early Discontinuation visit as soon as possible. 
8.1.7. 
Unscheduled Visit 
Assessments may be completed at the investigator’s discretion during an Unscheduled visit. In 
addition, assessments performed at a scheduled visit that are not defined in the SOA will be 
considered unscheduled assessments. 
8.2. 
Efficacy Assessments 
8.2.1. 
Cardiopulmonary Exercise Testing 
All patients will undergo CPET with gas-exchange analysis and the methodology will be 
standardized across all participating sites, as described in the CPET manual. Testing will include 
continuous ECG monitoring by trained personnel and be performed in an area that is equipped 
for cardiopulmonary resuscitation. Treadmill is the preferred modality for exercise testing. For 
CPET laboratories that do not perform treadmill testing, cycle ergometry is an acceptable 
alternative. Exercise protocols for both modalities will be provided in the CPET manual. Patients 

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must use the same testing modality for all exercise tests during the trial. Whenever possible, 
CPET should be administered by the same trial personnel using the same equipment and 
performed after the other trial procedures on that visit day (including echocardiogram, KCCQ, 
EQ-5D-5L, CGI, PGI-C, NYHA class, SAQ-7, vital signs, ECG, blood sampling, IP 
administration). Patients naïve to exercise protocols will be familiarized with the technique 
during screening. 
All CPET testing will be symptom-limited and patients will be strongly encouraged to achieve 
maximal exertion and an RER ≥1.05. The reason(s) for termination of sub-maximal exercise 
tests will be documented. A test will be identified as being maximal effort if the RER is ≥1.05. 
Patients should not engage in strenuous exercise for 24 hours prior to the CPET, and patients 
should not exercise at all within 12 hours prior to the test. Patients should fast for at least 4 hours 
prior to CPET. All regularly scheduled medications should be taken as normal. Patients should 
avoid taking medications that cause drowsiness within 8 hours prior to the test. Weight should be 
collected immediately prior to each CPET. 
The Week 24 CPET should be performed at approximately the same time of day (eg, morning, 
mid-day, afternoon) as the baseline CPET at screening, at a consistent time after the last dose of 
beta-blocker and IP. Whenever possible, patients should perform exercise testing between three 
and ten hours after taking beta blocking agents. 
If a life-threatening arrhythmia, early ischemia, severe hypotension or other serious finding is 
identified by the investigator during CPET, the patient will be asked to stop the exercise test, and 
his/her physicians will be notified of the results. If the patient is performing the screening test, 
s/he will not be randomized to the trial. Enrolled patients who have a non-life-threatening event 
or finding that stops the test can resume testing when it is safe to do so and after appropriate 
treatment, per the investigator. 
All sites must be qualified by the CPET core laboratory prior to the initiation of screening. To 
qualify, sites will perform an exercise test on two healthy adults and submit them for core 
laboratory review. Sites may be required to submit additional normal exercise tests during the 
conduct of the trial for review by the CPET core laboratory in order to confirm proper function 
of testing equipment. Sites may be qualified based on exercise tests recently reviewed by the 
CPET core laboratory during the conduct of other trials. 
8.2.2. 
Echocardiography 
Echocardiography will be done during screening and prior to dosing on Day 1. 
Echocardiography will be performed 2 hours (±30 min) after dosing in the clinic on Weeks 2, 4, 
6, 8, 12, 16, 20, and 24. Echocardiography will also be performed at Week 28. 
Certified sonographers will perform echocardiography using standard high-quality, high-fidelity 
machines approved by Cytokinetics. Whenever possible, the same sonographer will perform all 
studies for a single patient. Echocardiograms will be performed after the patient has been resting 
in a supine position for at least 10 minutes and in accordance with the echocardiography manual. 
Instructions for the performance of the Valsalva maneuver and imaging the LVOT-G will also be 
included in the echocardiography manual. 

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When echocardiograms are scheduled at the same time as blood draws, vital signs, and/or ECGs, 
the order of evaluation will be vital signs, ECGs, blood draw and echocardiogram. The blood 
draw should be obtained at the scheduled time point and the echocardiograms will follow. 
Echocardiographic parameters to be measured will at least include the left ventricular parameters 
in Table 6 in addition to right heart function metrics detailed in the echocardiography protocol. 
Table 6: 
CY 6031 Echocardiographic LV Parameters to be Measured 
Resting LVOT-G 
LVEDV 
IVST 
Post-Valsalva LVOT-G 
LVESD 
IVCT 
LVEF 
LVESV 
IVRT 
LVFS 
LVCO 
E/E’ ratio (septal and lateral) 
GLS 
LV Stroke Volume 
LAV 
LVEDD 
LVOT VTI 
 
GLS = global longitudinal strain; IVCT = isovolumic contraction time; IVRT = isovolumic relaxation time; 
IVST = interventricular septum thickness; LAV = left atrial volume; LVCO = left ventricular cardiac output; 
LVEDD = left ventricular end diastolic diameter; LVEDV = left ventricular end diastolic volume; LVESD = left 
ventricular end systolic diameter; LVESV = left ventricular end systolic volume; VTI = velocity time integral. 
Unscheduled echocardiograms may be obtained when clinically indicated, for example to assess 
an AE or follow-up a clinically significant change in a prior echocardiogram, as determined by 
the investigator. Results will be interpreted by the unmasked echocardiologist at the 
investigational site. 
All echocardiograms (including unscheduled) will be sent to the core laboratory for 
interpretation. On-site interpretation of LVEF and LVOT-G will be used for dose escalation and 
reduction decisions via IWRS. The core laboratory quantification of the echocardiograms will be 
used for all statistical analyses. 
8.2.3. 
Cardiac Magnetic Resonance 
A CMR imaging sub-study will assess the effects of administration of CK-3773274 dosing on 
cardiac morphology, function, and fibrosis in approximately 100 oHCM patients who are eligible 
and consent to participate. CMR will be performed during screening period and Week 24. CMR 
should occur after CPET if the assessments are performed on the same day. 
Patients with eGFR <30 mL/min/1.73 m2 or an allergy to gadolinium may have a non-contrast 
CMR. 
Patients who screen fail and rescreen do not need a repeat CMR. 
8.2.4. 
New York Heart Association Functional Classification 
After interviewing the patient, the investigator (or qualified designee) will record the NYHA 
Functional Classification in the CRF (Criteria Committee of the New York Heart 1994). The 
NYHA classification is as follows: 
• Class I - No symptoms and no limitation in ordinary physical activity (eg, shortness 
of breath when walking, climbing stairs) 

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• Class II - Mild symptoms (eg, mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
• Class III - Marked limitation in activity due to symptoms, even during less-
than-ordinary activity (eg, walking short distances [20-100 m]). Comfortable only at 
rest. 
• Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
8.2.5. 
Clinical Global Impression Scale 
The investigator (or qualified designee) will record the CGI scale assessment of the patient’s 
global functioning in the CRF at the time points outlined in the SoA. 
8.2.6. 
Patient-Reported Outcomes 
The following questionnaires will be completed at trial visits specified in the SoA (Section 1.3): 
• KCCQ 
• EQ-5D-5L 
• PGI-C 
• SAQ-7 
Patients will be asked to complete the KCCQ, EQ-5D-5L, SAQ-7 and PGI-C questionnaires in a 
quiet place prior to the medical consultation and prior to undergoing any tests and procedures to 
avoid biasing their responses. 
Site staff will verify the questionnaires for completeness before the patients leave the clinic or 
hospital. 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, and neurological systems. Breast, genital, and rectal examinations are not required 
unless specific evaluation is warranted. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Physical examinations may be conducted at any time during the treatment period if clinically 
indicated. 
8.3.2. 
Height and Weight 
Height and weight will be measured while patient is fully clothed with shoes removed. Height 
will be measured at screening only. 

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8.3.3. 
Vital Signs 
At the Screening visit, a room air oxygen saturation will be assessed. 
At all visits, heart rate, respiratory rate, and blood pressure will be assessed. 
Blood pressure and heart rate measurements will be assessed with the patient in a supine or 
sitting position. Blood pressure and heart rate measurements should be performed with an 
automated oscillometer after the patient has rested for at least 5 minutes in a quiet setting without 
distractions (eg, television, cell phones). The position selected for a patient should be the same 
that is used throughout the trial. 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 heart rate 
reading and 3 consecutive blood pressure readings recorded at intervals of at least 1 minute. The 
average of the 3 blood pressure readings will be recorded in the CRF. 
8.3.4. 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained as outlined in the SoA (Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. 
At each time point at which triplicate ECGs are performed, three individual ECG tracings should 
be obtained as closely as possible in succession, but no more than 2 minutes apart. 
Patients should be sitting or supine in a rested and calm state for at least 5 minutes prior to the 
ECG. The investigator may perform additional ECG recordings as needed for the care of the 
patient. 
A patient will be withdrawn from the trial by the investigator or designee if, in their medical 
judgment, ECG findings are present which make continued trial participation not in the patient’s 
best interest. 
For safety monitoring purposes, the investigator or designee must review, sign, and date all ECG 
tracings. 
Unscheduled ECGs may be collected at additional time points, for example in case of an AE or 
based on vital signs, PK results or PD results, as determined by the investigator or the Medical 
Monitor. 
All ECG tracings will be kept as part of the patient’s permanent trial file at the site. Digital 
recordings will be analyzed and stored at a central ECG laboratory. 
8.3.5. 
Laboratory Assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and see the 
SoA (Section 1.3) for the timing and frequency. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the trial in the AE section of the CRF. Clinically 
significant abnormal laboratory findings are those which are not associated with the underlying 

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disease, unless judged by the investigator to be more severe than expected for the patient’s 
condition. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
8.4. 
Adverse Events and Serious Adverse Events 
8.4.1. 
Adverse Events 
8.4.1.1. 
Definition of Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of IP, whether or not related to the IP. 
Adverse events include: 
• 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 IP administration even though it may 
have been present before the start of the trial. 
• Abnormal assessments, eg, change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at trial start or worsened 
during the course of the trial. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at trial start or worsened during the course 
of the trial, require treatment or led to dose reduction, interruption or permanent 
discontinuation of IP. In general, abnormal laboratory findings without clinical 
significance (based on the investigator's judgment) are not to be recorded as adverse 
events. Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either IP or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it 
is an intentional overdose taken with possible suicidal/self-harming intent. Such 
overdoses should be reported regardless of sequelae. 
8.4.1.2. 
Definition of Serious Adverse Event 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose:  
• results in death, 
• Is life threatening, NOTE: The term "life-threatening" in the definition of "serious" 
refers to an event in which the patient was at risk of death at the time of the event; it 

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does not refer to an event which hypothetically might have caused death if it were 
more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Important medical event 
Medical and scientific judgement should be exercised in deciding whether expedited 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 patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually 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. 
An adverse event would meet the criterion of “requires hospitalization,” if the event necessitated 
an admission to a health care facility (eg, overnight stay). 
The following reasons for hospitalization are exempted from being reported: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (ie, planned prior to signing informed consent) 
surgery or standard monitoring of a pre-existing disease or medical condition that did 
not worsen, eg, hospitalization for coronary angiography in a patient with stable 
angina pectoris. 
However, complications that occur during an exempted hospitalization are AEs or SAEs (for 
example if a complication prolongs a pre-planned hospitalization). 
8.4.1.3. 
Intensity of Adverse Events 
The investigator must assess the intensity for each AE and SAE reported during the trial 
according to a three-point scale: mild, moderate, severe. 
If the intensity of an AE worsens during IP administration, only the worst intensity should be 
reported on the AE page. If the AE lessens in intensity, no change in the severity is required. 
The three categories of intensity are defined as follows: 
Mild 
The event is noticeable to the patient. It does not influence daily activities and 
does not require intervention. 
Moderate 
The event makes the patient uncomfortable. Performance of daily activities 
are influenced, and intervention is needed. 

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Severe 
The event causes noticeable discomfort and interferes with daily activities. 
The patient may not be able to continue in the trial, and treatment or 
intervention is needed. 
A mild, moderate, or severe AE may or may not be serious. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than severity assessment, determines the regulatory reporting obligations. 
8.4.1.4. 
Relationship to Investigational Product 
Each AE must be assessed by the investigator, based on clinical judgment, as to whether or not 
there is a reasonable possibility of causal relationship to the IP and reported as either related or 
unrelated. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to IP administration will be 
considered and investigated. 
• 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 to Cytokinetics. However, it is 
very important that the investigator always assesses causality for every event before 
the initial transmission of the SAE data to Cytokinetics. 
• The investigator may change his/her opinion of causality considering follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
8.4.1.5. 
Relationship to Trial Procedures 
An AE is defined as related to trial procedures if it appears to have a reasonable possibility of a 
causal relationship to protocol-required procedures. 
8.4.1.6. 
Reporting of AEs 
The investigator is responsible for ensuring that all SAEs and non-serious AEs observed by the 
investigator or reported by the patient that occur after starting the IP through study exit are 
recorded in the AE eCRF. 
Only SAEs and non-serious AEs considered related to trial procedures are reported after signing 
of the informed consent until IP administration. 
Medical occurrences that are not associated with trial procedures and that begin before the start 
of IP but after signing of the ICF will be recorded on the Medical History/Current Medical 
Conditions CRF, not the AE CRF. 

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8.4.1.7. 
Reporting Procedures for SAEs 
Prompt notification by the investigator to Cytokinetics of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of an IP 
under clinical investigation are met. 
The investigator is responsible for ensuring that all SAEs observed by the investigator or 
reported by the patient that occur after starting the IP through end of study, or 4 weeks after the 
last administration of IP, whichever is later, are reported to Cytokinetics on an SAE Report Form 
within 24 hours following the investigator’s knowledge of the event and recorded in the AE 
eCRF. These events must be reported regardless of the investigator-attributed causal relationship 
with IP. 
The SAE Report forms must be emailed or faxed to Cytokinetics Drug Safety (contact details are 
provided on the SAE Report form): 
Email: 
CY6031DrugSafety@cytokinetics.com 
Facsimile: +1 (650) 243-4199 
The investigator must attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
The investigator must complete the SAE Report form in English and must assess the causal 
relationship of the event to IP. 
If the patient is hospitalized in a hospital other than the trial site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and documentation. 
New information relating to a previously reported SAE must be reported to Cytokinetics within 
24 hours following knowledge of the new information. Cytokinetics Drug Safety may contact the 
investigator to obtain further information. 
8.4.1.8. 
Follow-up of AEs and SAEs 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Cytokinetics 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 patient dies during participation in the trial or during a protocol-defined follow-up period, the 
investigator will provide Cytokinetics with a copy of any post-mortem findings including 
histopathology if it has been performed. 
Non-serious AEs must be followed until they resolve or until the patient completes the trial, 
whichever comes first. 
Serious AEs still ongoing at the end of study must be followed up until resolution or 
stabilization, or until the event outcome is provided, eg, death. Reporting after study exit to Drug 
Safety may continue after the EOS visit. 

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New SAEs occurring after the 4-week follow-up period must be reported to the Cytokinetics 
drug safety department within 24 hours of the investigator’s knowledge of the event, only if 
considered by the investigator to be causally related to previous exposure to the IP. 
8.4.1.9. 
Regulatory Reporting 
The reference safety document used for the assessment of expectedness of a suspected serious 
adverse reaction for the purpose of expedited reporting to Health Authorities, IRBs/IECs, and 
investigators is the reference safety information section of the Investigator’s Brochure 
[CK-3773274 IB]. 
Cytokinetics will report SAEs and/or suspected unexpected serious adverse reactions as required 
to regulatory authorities, investigators/institutions, and IRBs/IECs in compliance with all 
reporting requirements according to local regulations and good clinical practice. 
The investigator is to notify the appropriate IRB/IEC of SAEs occurring at the site and other AE 
reports received from Cytokinetics, in accordance with local procedures and statutes. 
8.4.1.10. Pregnancy and Breastfeeding 
If a woman becomes pregnant while on IP, IP must be discontinued. The investigator must 
counsel the patient and discuss the risks of continuing with the pregnancy and the possible 
effects on the fetus. 
Please refer to Appendix 3 (Section 10.3) regarding contraceptive guidance. 
Irrespective of the treatment received by the patient, any pregnancy occurring in a female patient, 
or female partner of a male patient, after starting the IP up to 4 weeks following IP 
discontinuation must be reported to Cytokinetics within 24 hours of the investigator’s knowledge 
of the event. 
Pregnancies must be recorded in the eCRF and reported on the Cytokinetics Pregnancy form, 
which is emailed or faxed to Cytokinetics Drug Safety (contact details are provided on the 
Pregnancy Report form): 
Email: 
CY6031DrugSafety@cytokinetics.com 
Facsimile: +1 (650) 243-4199  
Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of IP and until the conclusion of the pregnancy. The follow-up of an infant 
(if applicable) will be conducted up to 12 months after the birth of the child. 
Any pregnancy complication or elective termination of a pregnancy for medical reasons must be 
reported as an AE or SAE. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Any post-trial pregnancy-related SAE considered reasonably related to the IP by the investigator 
will be reported to Cytokinetics as described in Section 8. While the investigator is not obligated 
to actively seek this information in former trial patients, he or she may learn of an SAE through 
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Male Patients with Partners Who Become Pregnant 
If the partner of a male subject becomes pregnant while on study drug, he may continue 
receiving treatment; however, he must use barrier method (ie, condom) during sexual intercourse 
to avoid further fetal exposure. 
The investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this trial. 
After obtaining the necessary signed ICF from the pregnant female partner directly, the 
investigator must complete the Pregnancy Report Form and submit it to Cytokinetics within 
24 hours of receipt of the partner’s consent. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to Cytokinetics. 
Female Patients Who Breastfeed  
If a female patient breastfeeds while on study drug, study drug will be discontinued. 
The investigator will collect breastfeeding information on any female patient who breastfeeds 
while taking the IP through one month after the end of study drug treatment. The mother and 
infant health information will be recorded on the Pregnancy Report Form and submitted to 
Cytokinetics immediately and no later than 24 hours following the investigator’s knowledge of 
event. 
8.5. 
Treatment of Overdose 
For this trial, any dose of IP that exceeds the protocol-specified dose or dosing frequency will be 
considered an overdose. 
There is no established treatment for an overdose. In the event of overdose, monitor for signs and 
symptoms including but not limited to hypotension, cardiac dysrhythmia, tachycardia, tachypnea, 
peripheral and pulmonary edema, decrease renal function, dizziness, dyspnea, palpitation, 
fatigue. The use of rescue medications (eg, dobutamine) to treat a low cardiac output state is 
recommended if necessary. 
If a patient experiences low cardiac output due to systolic dysfunction, the investigator should 
follow appropriate regional heart failure treatment guidelines. 
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication must be recorded. 
In the event of an overdose, the investigator should: 
• Contact the Medical Monitor immediately who may recommend: 
a. Close monitoring of the patient for any AEs/SAEs and laboratory abnormalities. 
b. Obtaining a plasma sample for PK analysis as soon as practical and note the date 
of the last dose of IP. 
• Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 

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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.6. 
Pharmacokinetics 
Eighteen blood samples of approximately 4 mL will be collected for measurement of plasma 
concentrations of CK-3773274 as specified in the SoA (Section 1.3) and Table 7 below. Samples 
will be used to evaluate the PK of CK-3773274 and potentially its metabolites. Instructions for 
the collection and handling of biological samples will be provided in the laboratory manual. 
The actual date and time (24-hour clock time) of each sample will be recorded. The time of 
administration of IP on the day of PK sampling will be recorded in the CRF. It is important to 
provide instructions to patients that they should not take their dose on the day of their clinic visit 
until in the clinic. 
See Table 7 for a summary of PK sampling time points. All samples should be drawn within 
±10 minutes of the scheduled time point. Drug concentration information that would unblind the 
trial will not be reported to investigative sites or blinded personnel until the trial has been 
unblinded. 
Table 7: 
Summary of PK Time Points 
Visit 
PK Time Point 
Day 1 
Pre-dose and 2 hours post-dose 
Week 2 
Pre-dose and 2 hours post-dose 
Week 4 
Pre-dose and 2 hours post-dose 
Week 6 
Pre-dose and 2 hours post-dose 
Week 8 
Pre-dose and 2 hours post-dose 
Week 12 
Pre-dose and 2 hours post-dose 
Week 16 
Pre-dose and 2 hours post-dose 
Week 20 
Pre-dose and 2 hours post-dose 
Week 24 (EOT) 
Pre-dose and 2 hours post-dose 
Early Discontinuation 
untimed 
8.7. 
Genetics 
As HCM is a genetic disease, blood and/or DNA from patients who consent may be analyzed 
through the use of both clinically reportable testing (Clinical Laboratory Improvement 
Amendments (CLIA) certified laboratory), and non-clinically reportable (non-CLIA certified 
laboratory) whole genome sequencing, whole exome sequencing, next-generation sequencing, 
and/or other method to identify genetic variants and mutations that are predictive of patient 
phenotype, response to IP, resistance to IP, metabolism of IP, susceptibility to developing AEs, 
or to increase the knowledge and understanding of cardiovascular, muscle and disease biology. 
If a participant consents, and where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from participants consenting to provide the sample. In the event of 

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DNA extraction failure, a replacement genetic blood sample may be requested from the patient. 
CLIA certified genetic test results may be made available to the investigator. 
See Appendix 4 (Section 10.4) for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in the laboratory 
manual. 
8.8. 
Serum for Biomarker Analysis 
Blood will be collected for analysis of serum biomarkers. See Section 10.2 for list of biomarkers. 
8.9. 
Serum and Plasma Collection for Future Analyses 
For participants who provide consent, serum, plasma, and DNA samples (as described in 
Section 8.7) will be collected and banked in this trial for future research on biomarkers and 
genetics. Serum, plasma, and DNA samples will be stored in a long-term storage facility 
designated by Cytokinetics for up to 20 years. 
8.10. 
Immunogenicity Assessments 
No immunogenicity assessments will be done for this trial. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The analyses evaluating treatment effect on the primary and secondary efficacy endpoints will 
test the null hypothesis that there is no treatment difference between patients receiving placebo 
and those receiving CK-3773274 in the full analysis set (FAS). Adjustments for multiplicity will 
be specified in Section 9.4.1.1. 
9.2. 
Sample Size Determination 
Assuming a difference in change from baseline in pVO2 of 1.5 mL/kg/min for CK-3773274 
compared to placebo, a standard deviation (SD) of 3.5 mL/kg/min, accounting for limiting 
beta-blocker use (less than ~70%), limiting exercise modality of bicycle (less than ~50%) and 
10% of patients missing change from baseline data of the primary endpoint, a sample size of 
270 patients at randomization ratio of 1:1 (approximately 135 randomized to CK-3773274 and 
135 randomized to placebo) provides more than 90% power to detect the difference in pVO2 
change from baseline to Week 24 with a 2-sided type I error of 0.05. 
During the study, the aggregate pooled missing data rate and overall pooled SD for the change 
from baseline in pVO2 at Week 24 will be monitored periodically in a blinded fashion. If the 
pooled SD is larger than expected, Cytokinetics may consider increasing the sample size once in 
order to maintain the intended power. 
9.3. 
Populations for Analyses 
The analysis populations are defined in Table 8. 
Table 8: 
Analysis Sets 
Analysis Set 
Description 
All Randomized Set 
All randomized patients. 
Full Analysis Set 
All randomized patients. Patients will be analyzed according to 
their randomized treatment group assignment. Efficacy endpoints 
will be analyzed based on the FAS. 
Safety Analysis Set 
All randomized patients who received at least one dose of IP, 
CK-3773274 or placebo. Patients will be analyzed by their 
randomized treatment group assignment. If a patient receives 
treatment throughout the study that is different than the 
randomized treatment group assignment, then this patient will be 
grouped by the actual treatment group 
Pharmacokinetics 
Analysis Set (PKS) 
All randomized patients who have at least one evaluable plasma 
concentration of CK-3773274, provided they have no major 
protocol violations deviations that could affect the PK of 
CK-3773274. 

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9.4. 
Statistical Analyses 
The Statistical Analysis Plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.4.1. 
General Considerations 
Summary tables will present descriptive statistics such as number of patients, mean, median, 
standard deviation, minimum and maximum for continuous variables, and number of patients 
and the percentage for categorical variables, overall and by treatment in the planned analysis 
sets. For model-based analysis, least squares means (LSMs), difference of LSMs between 
treatments, their standard errors and 95% confidence intervals (CI), and two-sided p-values for 
the relative statistical inferences will be presented. Baseline is defined as the last available 
measurement taken before the first dose of randomized IP unless otherwise specified. Listings 
will include patient ID, demographics, treatment assigned and other relevant items, and sorted by 
treatment assignment, patient ID and date of assessment. Unless specified otherwise, efficacy, 
safety and pharmacokinetics analyses will be performed on the full analysis set, safety analysis 
set and pharmacokinetics analysis set, respectively. Statistical analysis methods will be detailed 
in the SAP. 
9.4.1.1. 
Multiplicity Adjustment 
The null hypothesis for the primary and secondary efficacy variables in the FAS will be tested in 
the pre-specified order using a closed testing procedure. 
For preservation of the overall type I error rate at two-sided 0.05 for the primary and secondary 
endpoints will be tested in the following specified order using a closed testing procedure . If the 
primary endpoint achieves statistical significance at two-sided p<0.05, then secondary endpoints 
will be tested with two-sided 0.05, with their testing being in the sequential order of KCCQ-CSS 
change from baseline, proportion of patients with >1 NYHA functional class improvement, 
post-Valsalva LVOT-G change from baseline, proportion of patients with post-Valsalva 
LVOT-G < 30 mm Hg, and duration of SRT eligibility for participants who are SRT eligible at 
baseline, for each after 24 weeks of treatment; then KCCQ-CSS change from baseline, 
proportion of patients with ≥1 NYHA functional class improvement, post-Valsalva LVOT-G 
change from baseline, and proportion of patients with post-Valsalva LVOT-G < 30 mmHg, for 
each after 12 weeks of treatment; and lastly change from baseline to Week 24 in total workload. 
SRT eligibility is defined as resting or post-Valsalva LVOT-G ≥ 50 mmHg AND NYHA 
Functional Class ≥ 3. The multiple testing procedure is illustrated in Figure 1. The description of 
testing sequence will be detailed in the SAP. 
9.4.2. 
Primary Endpoint(s) 
The primary endpoint of the study is change in pVO2 by CPET from baseline to Week 24. 
The primary estimand is the difference in means of the change from baseline to Week 24 in 
pVO2 between CK-3773274 and placebo for the target population of potentially treatable 
CK-3773274 patients despite intercurrent events after a first dose. Missing data will be imputed 
using multiple imputation method under the missing at random (MAR) assumption. The 

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distribution of missing CPET data at Week 24 and the reasons for the missing data will be 
tabulated in the FAS. The primary analysis of the primary endpoint will use an ANCOVA model 
with treatment group, randomization stratification factors, baseline pVO2 and baseline weight as 
covariates in the FAS. Sensitivity analyses will be performed by repeating the primary analysis 
examining assumptions that data are not missing at random: missing pVO2 from patients who 
discontinued CK-3773274 treatment or missing pVO2 from patients from the placebo arm will be 
imputed based on the model that is constructed using observed pVO2 data from the placebo arm. 
Missing pVO2 from patients who remained on CK-3773274 treatment will be imputed based on 
the model that is constructed using observed pVO2 data from the CK-3773274 arm. The LSMs, 
LSM treatment difference, and the standard error from each imputed dataset will be combined 
using Rubin’s rules to produce an overall LSM estimate of the treatment difference, its 95% 
confidence interval, and p-value. 
Other sensitivity analyses and the details will be included in the SAP. 
9.4.3. 
Secondary Endpoint(s) 
The secondary endpoint(s) of the study are: 
• Change in KCCQ-CSS from baseline to Week 12 and Week 24 
• Proportion of patients with ≥1 class improvement in NYHA Functional Class from 
baseline to Week 12 and Week 24 
• Change in post-Valsalva LVOT‑G from baseline to Week 12 and Week 24  
• Proportion of patients with post-Valsalva LVOT-G <30 mmHg at Week 12 and Week 24 
• 
Duration of eligibility for septal reduction therapy (SRT) during the 24-week treatment 
period in patients who were eligible for SRT at baseline. Participants are classified as being 
SRT eligible if they have NYHA Class ≥3 AND resting or Valsalva LVOT-G ≥50 mmHg. 
• Change in total workload during CPET from baseline to Week 24 
Change in KCCQ-CSS and change in post-Valsalva LVOT-G from baseline to Week 12 and 
Week 24 will be analyzed using a mixed model repeated measures (MMRM) model with 
baseline as covariate, randomization stratification factors, visit, treatment group, and interaction 
terms of treatment by visit and baseline by visit. An unstructured covariance matrix will be 
specified. 
Proportion of patients with ≥1 class improvement in NYHA Functional Class from baseline to 
Week 12 and Week 24 or proportion of patients with post-Valsalva LVOT-G <30 mmHg at 
Week 12 and Week 24 will be analyzed using Cochran– Mantel–Haenszel (CMH) test stratified 
by randomization factors. Patient’s Week 20 NYHA Functional Class will be used when 
Week 24 NYHA Functional Class is not available. Total duration of SRT eligibility (NYHA 
Class ≥3 AND resting or Valsalva LVOT-G ≥50 mmHg) during the 24-week treatment period 
will be analyzed using an ANCOVA model with treatment group and randomization 
stratification factor beta blocker use/no use as fixed effects adjusting for significant baseline 
characteristics. The p-value and 95% CI will be obtained using exact method. Adjustment of 
multiplicity of the primary and secondary endpoints is specified in Section 9.4.1.1. 

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9.4.4. 
Exploratory Endpoint(s) 
The exploratory endpoints of the study are: 
• Compared with baseline, proportion of patients at Week 24 achieving either: 
− Change from baseline of ≥1.5 mL/kg/min in pVO2 AND ≥1 class improvement in 
NYHA Functional Class 
OR  
− Change of ≥3.0 mL/kg/min from baseline in pVO2 AND no worsening of NYHA 
Functional Class 
• Proportion of patients with improvement in KCCQ-CSS ≥5 points at Week 12 and 
Week 24 
• Proportion of patients with resting LVOTG <30 mmHg, post-Valsalva LVOTG 
<50 mmHg, and NYHA Functional Class I at Week 12 and Week 24 
• Proportion of patients with resting LVOTG <30 mmHg, post-Valsalva LVOTG 
<50 mmHg, and ≥1 class improvement in NYHA Functional Class at Week 12 and 
Week 24 
• Proportion of patients who are eligible for SRT at Week 24 among patients who were 
eligible for SRT at baseline 
• Change from baseline to Week 24 in: 
− VE/VCO2 slope 
− VO2 × systolic BP 
− VAT 
• Change from baseline to Week 24 in individual responses to the EQ-5D-5L 
• Change from baseline to Week 24 in summary and individual domain scores for the 
SAQ-7 
• Change from baseline to Week 24 in echocardiographic measurements of cardiac 
structure and of systolic function including: 
− LVEF 
− LVESV and LVEDV 
− Left atrial volume 
• Change from baseline values in NT-pro-BNP, hs-cardiac-TnI and other biomarkers 
through Week 24 
• Change from baseline to Week 24 in CMR measurements of: 
− LV mass index 
− LVEF 

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− Septal and free wall thickness 
− Left atrial volume index 
− LVESV 
− LVEDV 
• Pharmacokinetic parameters through Week 24 
Proportion of responders will be analyzed using CMH test stratified by randomization factors. 
Change from baseline in continuous echocardiography parameters will be analyzed using 
MMRM model with baseline as covariate, randomization stratification factors, visit, treatment 
group and treatment group by visit as interaction. An unstructured covariance matrix will be 
specified. Change from baseline in other CPET parameters will be analyzed using the same 
primary model for the primary endpoint. Change from baseline in parameters of CMR 
measurements and 5Q-5D-5L will be analyzed using an ANCOVA model with baseline as 
covariate, randomization stratification factors and treatment group as fixed effects. Median and 
median difference of NT-pro-BNP between treatment group and 95% confidence of the median 
difference will be presented. Log transformed NT-pro-BNP may be performed and analyzed 
using MMRM model with log baseline as covariate, visit, randomization stratification factors, 
treatment group as fixed effects and treatment group by visit interaction. The same model for 
KCCQ-CSS will be used to analyze the change from baseline in SAQ-7. 
9.4.5. 
Safety Analysis 
Safety analyses will be performed on the safety analysis set. 
9.4.5.1. 
Adverse Events 
A treatment-emergent AE is an AE with an onset after initiation of IP, or an AE present at 
initiation of IP dosing that worsens in severity during the treatment. AEs will be coded using 
MedDRA dictionary and summarized by preferred terms and system organ class. The version of 
the MedDRA dictionary will be specified in the clinical study report. AEs will be classified 
according to severity. The number and percentage of patients reporting AEs will be tabulated. 
Only treatment-emergent AEs with an onset from the first dose until 4 weeks after last dose of IP 
will be summarized. All AEs will be included in patient listings. 
Patient incidence of reported major adverse cardiac events (CV death, cardiac arrest, non-fatal 
stroke, non-fatal myocardial infarction, CV hospitalization) will be summarized by treatment 
group and event type. Patient incidence of new onset persistent atrial fibrillation, patient 
incidence of appropriate ICD discharges and aborted sudden cardiac death, patient incidence of 
LVEF <50% will be summarized by treatment group. 
9.4.5.2. 
Serious Adverse Events 
Summaries of SAEs (by preferred term and system organ class) and SAE severity will be 
presented. 
The safety follow-up is defined as 4 weeks following the last dose of IP. 

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9.4.6. 
Pharmacokinetic Endpoints 
Plasma concentrations of CK-3773274 and PK parameter Cmax and Ctrough will be summarized 
using descriptive statistics including mean, standard deviation, geometric mean, coefficient of 
variation, median, and range. Geometric mean concentrations over time will be graphically 
displayed. 
9.4.7. 
Patient Disposition 
The number of patients who are randomized, who complete the planned treatment, and who 
prematurely discontinue from the planned treatment and/or the study will be presented by 
treatment group and overall. Reasons for premature discontinuation as recorded on the End of 
Study page of the CRF will also be summarized. 
9.4.8. 
Demographics and Other Baseline Characteristics 
Patient demographics and other baseline characteristics will be summarized descriptively by 
treatment group. 
9.4.9. 
Investigational Product Exposure 
IP exposure will be summarized, including the total number of doses administered, total amount 
of drug administered, and the total duration of IP administration, defined as the date of the last 
dose minus the date of first dose + 1. 
9.4.10. 
Concomitant Medications 
Concomitant medications will be summarized and classified by drug class and preferred term 
using the World Health Organization (WHO) Drug Dictionary. The version of the WHO Drug 
Dictionary will be specified in the clinical study report. 
9.4.11. 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values and changes from baseline at each protocol 
specified assessment time point will be presented. 
9.4.12. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline at each protocol specified 
assessment time point will be presented. 
9.4.13. 
Electrocardiogram 
Descriptive statistics for ECG parameters (eg, heart rate, PR interval, QRS interval, QT interval, 
and QTc interval [both Bazett’s and Fridericia’s corrections]) and changes from baseline at each 
protocol specified assessment time point will be presented. Select ECG parameters will be 
analyzed using a repeated measures analyses with dose and time points as factors and baseline 
ECG parameter as a covariate. Dose-response trend will be estimated. 

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9.5. 
Data Monitoring Committee 
An unblinded DMC will regularly review the emerging data for safety monitoring purpose. The 
DMC or Cytokinetics can require an ad hoc DMC meeting at any time. No study activities will 
be suspended during the safety review. For details on the DMC, refer to Appendix 1 
(Section 10.1.5). 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This trial 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 (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate hazard 
to trial patients. 
The investigator will be responsible for the following: 
• Providing summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide Cytokinetics with sufficient, accurate financial 
information as requested to allow Cytokinetics to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and for 
1 year after completion of the trial. 
10.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the trial to the patient or 
his/her legally authorized representative and answer all questions regarding the trial. 
Patients must be informed that their participation is voluntary. Patients must be able to 
comprehend and be willing to sign a statement of informed consent that meets the requirements 

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of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable, and the IRB/IEC or trial center. 
The medical record must include a statement that informed consent was obtained before any 
trial-specific activities/procedures were performed and the date the consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the trial. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
Patients are not required to sign a new ICF if they are retested during the initial screening 
window. 
10.1.4. 
Data Protection 
Patients will be assigned a unique identifier by Cytokinetics. Any patient records or datasets that 
are transferred to Cytokinetics will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal trial-related data will be used by Cytokinetics 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the ICF. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by Cytokinetics, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
The trial organization will include an Executive Committee (EC), Steering Committee (SC) and 
DMC. 
The EC will contribute to trial design, implementation, data analysis, and communication of trial 
results and will consist of experts external to Cytokinetics who are qualified by their medical and 
scientific expertise and experience, one of the trial investigators, and a Cytokinetics 
representative. The responsibilities of the EC will be described in an EC charter. 
The SC will contribute to implementation of the trial, data analysis, and communication of trial 
results. They will be HCM experts external to Cytokinetics and represent the different 
geographies the trial will be conducted in. The responsibilities of the SC will be described in a 
SC charter. 
An independent DMC will be established for this trial to formally review the accumulating data 
periodically in order to assess risk to patients during the conduct of the trial. The DMC will 
include an external cardiologist with relevant expertise and other designated members with 
relevant expertise, eg, representing clinical science, clinical pharmacology, and biostatistics. The 
independent DMC membership will exclude the individuals from Cytokinetics or the contract 
research organization (CRO) trial team involved in trial conduct. The DMC members will have 
access to treatment assignments and patient level data from the clinical trial database. DMC 

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membership, responsibilities, relationship with Cytokinetics and the CRO, and the purpose and 
timing of the meetings will be further described in the DMC charter. 
10.1.6. 
Data Quality Assurance 
All patient data relating to the trial will be recorded on printed or electronic CRF unless 
transmitted to Cytokinetics or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
authority inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
Cytokinetics or designee is responsible for the data management of this trial including quality 
checking of the data. 
Cytokinetics assumes accountability for actions delegated to other individuals (eg, CROs). 
Trial monitors will perform ongoing source data verification to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of patients are being protected; and that the trial is being conducted in 
accordance with the currently approved protocol and any other trial agreements, ICH GCP, and 
all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial, must be 
retained by the investigator in accordance with the strictest regulation applicable to this study 
and as obligated by the clinical trial agreement. No records may be destroyed during the 
retention period without the approval of Cytokinetics. No records may be transferred to another 
location or party without notification to Cytokinetics. 
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data reported in the CRF or entered in the CRF that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the trial. Also, 
current medical records must be available. 
10.1.8. 
Trial and Site Start and Closure 
The trial start date is the date on which the clinical trial will be open for recruitment of patients. 
The first act of recruitment is the first site activated. 

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Cytokinetics or designee reserves the right to close the trial site or terminate the trial at any time 
for any reason at the sole discretion of Cytokinetics. Trial sites will be closed upon trial 
completion. A trial site is considered closed when all required documents and trial supplies have 
been collected and a site closure visit has been performed. 
The investigator may initiate trial-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by Cytokinetics or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local regulatory authorities, Cytokinetics’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the investigator 
• Discontinuation of further IP development 
If the trial is prematurely terminated or suspended, Cytokinetics shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the trial of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the patient and should assure appropriate patient therapy 
and/or follow-up. 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 9 will be performed by the central laboratory. If an issue arises with 
the central laboratory, a local laboratory can be used for eligibility after approval from the 
sponsor. If the results used for eligibility cannot be obtained from the central laboratory, a local 
laboratory may be used with the approval of the sponsor. If a local laboratory is used, duplicate 
samples must be drawn at the same time and sent to the central laboratory. Pregnancy testing for 
WOCBP at time points after screening may be performed locally. 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Section 5 of 
the protocol. 
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. 
Table 9: 
Protocol-Required Safety Laboratory Assessments 
Chemistry 
Urinalysis 
Hematology 
Other Assessments 
Sodium 
Total bilirubin 
Specific gravity 
Hemoglobin 
CK-3773274 plasma 
concentration  
Potassium 
Direct bilirubin 
pH 
Hematocrit 
Chloride 
CK 
Blood 
RBC 
Pregnancy testa 
Calcium 
ALP 
Protein 
RDW 
FSHa 
Magnesium 
LDH 
Glucose 
MCV 
NT-proBNPb 
Phosphorus 
AST (SGOT) 
Bilirubin 
MCH 
hs-cTnI  
Urea 
ALT (SGPT) 
 
MCHC 
Other biomarkers 
including: Galectin-3, 
PINP, TIMP-1, CITP 
and Soluble ST2 
Creatinine 
GGT 
 
WBC 
Iron 
TIBC 
 
Platelets 
Glucose 
Ferritin 
 
 
PT-INR 
Total protein 
Bicarbonate 
 
 
 
ALP = alkaline phosphatase; ALT (SGPT) = alanine aminotransferase (serum glutamic-pyruvic transaminase); AST 
(SGOT) = aspartate aminotransferase (serum glutamic-oxaloacetic transaminase); CITP = collagen type 1; CK = 
creatine kinase; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; hs-cTnI = high-
sensitivity cardiac troponin I; LDH = lactic acid dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = 
mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; NT-proBNP = N-terminal pro-B-
type natriuretic peptide; PINP = procollagen type 1 N-terminal propeptide; PT-INR = prothrombin 
time/international normalized ratio; RBC = red blood cell; RDW = red cell distributions width; SGOT = serum 
glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; Soluble ST2 = soluble 
suppression of tumorigenicity 2; TIBC= total iron binding protein; TIMP-1 = tissue inhibitor matrix 
metalloproteinase 1; WBC = white blood cell 
a A pregnancy test is required for WOCBP; FSH only at screening if needed. If a urine pregnancy test is positive, a 
serum pregnancy test should be performed. 
b NT-proBNP results will be masked throughout the study. 
Investigators must document their review of each laboratory report. 
Laboratory results that could unblind the trial will not be reported to investigative sites or other 
blinded personnel until the trial has been unblinded. 

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10.3. 
Appendix 3: Contraceptive Guidance 
Definitions: 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of IP, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining trial entry. 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy. However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement 
(>40 IU/L or mIU/mL) is required. 
• Females on hormone replacement therapy and whose menopausal status is in doubt 
will be required to use one of the non-estrogen hormonal highly effective 
contraception methods if they wish to continue their hormone replacement therapy 
during the trial. Otherwise, they must discontinue hormone replacement therapy to 
allow confirmation of postmenopausal status before trial enrollment. 
Highly Effective Method of Contraception 
A highly effective method of contraception is one that has a failure rate of <1% per year when 
used consistently and correctly. 

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Examples of highly effective contraception that have low user dependency are: 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner, only when the absence of sperm has been confirmed and 
vasectomized partner is the sole sexual partner of the female patient 
Examples of highly effective contraception that are user-dependent are: 
• Combined hormonal methods of birth control include oral, intravaginal, transdermal, 
injectable, or implantable 
• Oral or injectable progestogen-only hormone contraception associated with the 
inhibition of ovulation 
• Sexual abstinence 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the trial intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the trial and the preferred and usual lifestyle of the 
patient. Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception. 
Contraception Guidance: 
Women of Childbearing Potential 
WOCBP must use at least one highly effective method of birth control. If any of the above 
highly effective methods of birth control are used, a male condom must also be used. Male 
condom and female condom should not be used together (due to risk of failure with friction). 
If additional medications are given during treatment, the investigator is to review the prescribing 
information/summary of product characteristics for all concomitant therapy, as they may alter the 
contraceptive requirements. These additional medications may require an increase in the number 
of contraceptive methods and/or length of time that contraception is to be utilized after the last 
dose of protocol-required therapies. The investigator is to discuss these changes with the trial 
patient. 

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10.4. 
Appendix 4: Genetics 
Use/Analysis of DNA 
Genetic variation may impact a patient’s response to IP, susceptibility to, and severity and 
progression of disease. Variable response to IP may be due to genetic determinants that impact 
drug absorption, distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. Therefore, where local 
regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis from patients 
consenting to provide the sample. 
DNA samples will be used for research related to this trial may consist of the analysis of one or 
more candidate genes or the analysis of genetic markers throughout the genome (as appropriate). 
The results of genetic analyses may be reported in the clinical study report or in a separate trial 
summary. 
Cytokinetics will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 

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10.5. 
Appendix 5: Liver Safety: Actions and Follow-up Assessments 
Drug-induced Liver Injury Reporting & Additional Assessments 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) and total bilirubin (TBL) and/or 
international normalized ratio (INR) elevation require the following: 
• The event is to be reported to Cytokinetics as an SAE within 24 hours of discovery or 
notification of the event (ie, before additional etiologic investigations have been 
concluded) 
• The AE CRF that captures information necessary to facilitate the evaluation of 
treatment-emergent liver abnormalities is to be completed and sent to Cytokinetics. 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Section 8.4.1.2. 
Criteria for Permanent Discontinuation of Investigational Product and Other 
Protocol-required Therapies due to Potential Hepatotoxicity 
CK-3773274 must be discontinued permanently and the patient should be followed according to 
the following recommendations for possible DILI, if ALL of the criteria below are met: 
• TBL >2 × ULN or INR >1.5 
AND 
• increased AST or ALT from the relevant baseline value as specified below: 
Baseline AST or ALT Value 
AST or ALT Elevation 
<ULN 
>3 × ULN 
 
AND 
• no other cause for the combination of the above laboratory abnormalities is apparent; 
important alternative causes for elevated AST/ALT and 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) 

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− alpha-one antitrypsin deficiency 
− alcoholic hepatitis 
− autoimmune hepatitis 
− Wilson’s disease and hemochromatosis 
− nonalcoholic fatty liver disease including steatohepatitis 
− nonhepatic causes (eg, rhabdomyolysis, hemolysis) 
Criteria for Conditional Interruption of Investigational Product and Other 
Protocol-required Therapies due to Potential Hepatotoxicity 
For patients who do not meet the criteria for permanent discontinuation of IP outlined above and 
have no underlying liver disease, the following rules are recommended for interruption of IP and 
other protocol required therapies: 
• Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT Value 
AST or ALT Elevation 
Any 
>8 × ULN at any time 
Any 
>5 × ULN but <8 × ULN for ≥2 weeks 
Any 
>5 × ULN but <8 × ULN and unable to adhere to 
enhanced monitoring schedule 
Any 
>3 × ULN with clinical signs or symptoms that 
are consistent with hepatitis (such as right upper 
quadrant pain/tenderness, fever, nausea, 
vomiting, jaundice) 
OR 
• TBL >3 × ULN at any time 
IP and other protocol-required therapies, as appropriate must be withheld pending investigation 
into alternative causes of DILI. If IP is withheld, the patient is to be followed according to 
recommendations in this section for possible DILI. Rechallenge may be considered if an 
alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered 
and the laboratory abnormalities resolve to normal or baseline. 
Rechallenge of Investigational Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity 
The decision to rechallenge the patient must be discussed and agreed upon unanimously by the 
patient, investigator, and Medical Monitor. Patients reinitiating IP after withholding for potential 
hepatotoxicity will restart IP, according to initial randomized allocation, on the same IP dose as 
established before the event and will not further titrate the dose. 
If signs or symptoms recur with rechallenge, then IP must be permanently discontinued. Patients 
who clearly meet the criteria for permanent discontinuation must never be rechallenged. 

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Additional Clinical Assessments and Observation 
All patients in whom IP(s) or protocol-required therapies is/are withheld (either permanently or 
conditionally) due to potential DILI or who experience AST or ALT elevations >3 × ULN are to 
undergo a repeat test and a period of “close observation” until abnormalities have stabilized, 
returned to normal, or returned to the patient’s baseline levels. Recommended assessments and 
testing frequency that are to be performed during this period include: 
• Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 48 hours of 
receiving results with repeat testing until stabilized 
• In cases of TBL >2 × ULN or INR >1.5, retesting of liver tests, bilirubin (total and 
direct), and INR should be performed within 48 hours of receiving results with repeat 
testing 2-3 times per week until stabilized 
Testing frequency of the above laboratory tests may decrease if the abnormalities stabilize or the 
IP(s) or protocol-required therapies has/have been discontinued AND the patient is 
asymptomatic. 
• Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
− Obtain complete blood count (CBC) with differential to assess for eosinophilia 
− Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
− Obtain serum acetaminophen (paracetamol) levels 
− Obtain a more detailed history of: 
• Prior and/or concurrent diseases or illness 
• Exposure to environmental and/or industrial chemical agents 
• Symptoms (if applicable) including right upper quadrant pain, hypersensitivity 
type reactions, fatigue, nausea, vomiting and fever 
• Prior and/or concurrent use of alcohol, recreational drugs and special diets 
• Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− Obtain viral serologies 
− Obtain creatine phosphokinase, haptoglobin, lactate dehydrogenase, and 
peripheral blood smear 
− Perform appropriate liver imaging if clinically indicated 
• Obtain appropriate blood sampling for PK analysis if this has not already been 
collected 
• Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 

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Follow the patient and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal. The “close observation period” is to continue for a 
minimum of 4 weeks after discontinuation of all IP(s) and protocol required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications, and laboratory results must be captured in corresponding CRFs. 

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10.6. 
Appendix 6: Abbreviations 
Table 10: 
List of Abbreviations 
Abbreviation/Term 
Explanation 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANA 
Anti-nuclear antibody 
AST 
Aspartate aminotransferase 
CBC 
Complete blood count 
CGI 
Clinical Global Impression scale 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax  
Maximum plasma concentration observed 
Ctrough  
Trough plasma concentration observed 
CMH 
Cochran–Mantel–Haenszel 
CMR 
Cardiac magnetic resonance 
CPET 
Cardiopulmonary exercise testing 
CRF 
Case report form 
CRO 
Contract research organization 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
DILI 
Drug induced liver injury 
DMC 
Data monitoring committee 
EC 
Executive Committee 
ECG 
Electrocardiogra(m/phy) 
ED 
Early discontinuation 
EOS 
End of study 
EOT 
End of treatment 
EQ-5D-5L 
EuroQol 5-dimension 5-level instrument 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
FU 
Follow up 
GCP 
Good Clinical Practice 

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Abbreviation/Term 
Explanation 
GLP 
Good Laboratory Practice 
HCM 
Hypertrophic cardiomyopathy 
HIPAA 
Health Insurance Portability and Accountability Act 
hs-cTnI 
High sensitivity cardiac troponin I 
IB 
Investigator’s Brochure 
ICD 
Implantable cardioverter defibrillators 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IWRS 
Interactive web response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LAM 
Lactational amenorrhoea method 
LKM1 
Liver Kidney Microsomal antibody 1 
LSM 
Least squares mean 
LV 
Left ventricle(ular) 
LVEDV 
Left ventricular end-diastolic volume 
LVEF 
Left ventricular ejection fraction 
LVESV 
Left ventricular end-systolic volume 
LVFS 
Left ventricular fractional shortening 
LVOT 
Left ventricular outflow tract 
LVOT-G 
Left ventricular outflow tract gradient 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIMP 
Non-investigational medicinal product 
NT-proBNP 
n-terminal prohormone brain natriuretic peptide 
NYHA 
New York Heart Association 

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Abbreviation/Term 
Explanation 
oHCM 
Obstructive hypertrophic cardiomyopathy 
PD 
Pharmacodynamics 
PDS 
Pharmacodynamics analysis set 
PGI-C 
Patient Global Impression of Change scale 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetics analysis set 
PRO 
Patient-reported outcomes 
pVO2 
Peak oxygen uptake 
RBC 
Red blood cell 
RER 
Respiratory exchange ratio 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SAQ-7 
Seattle Angina Questionnaire -7 
SC 
Steering Committee 
SD 
Standard deviation 
SoA 
Schedule of activities 
SoC 
Standard of care 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
VAT 
Ventilatory anaerobic threshold 
WOCBP 
Women of childbearing potential 
 
 
 

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10.7. 
Appendix 7: Protocol Amendment History 
The Protocol Amendment Summary of Changes (Table 1) for the current amendment is located 
directly before the Table of Contents (TOC). 
 
 

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