A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy
Phase: PHASE2
Conditions: Hypertrophic Cardiomyopathy (HCM)
Sponsor: Cytokinetics

Protocol: CY 6021 
 
Title: A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-ﬁnding Study 
to Evaluate the Safety, and Tolerability and Pharmacodynamics of CK3773274 in Adults 
with Symptomatic Hypertrophic Cardiomyopathy 
 
NCT04219826 
Approval Date: 09NOV2021 
 

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PROTOCOL CY 6021 
A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, DOSE-FINDING STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF CK­3773274 IN ADULTS WITH 
SYMPTOMATIC HYPERTROPHIC CARDIOMYOPATHY 
 
Protocol Version and Date: 
Amendment 04 dated 09 November 2021 
Previous Version(s): 
Amendment 03 dated 17 February 2021 
Amendment 02 dated 13 July 2020 
Amendment GBR-01 dated 24 January 2020 
Amendment 01 dated 09 August 2019 
Original Protocol dated 29 July 2019 
Product: 
CK­3773274 
Regulatory Authority 
Identifier Number(s): 
IND 138814 
EudraCT Number 2019‐002785‐12 
Sponsor: 
Cytokinetics, Inc. 
280 East Grand Avenue 
South San Francisco, CA 94080, USA 
 
 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from Cytokinetics, Inc. 

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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CY 6021 
Protocol Title: 
A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-
finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of CK­3773274 in Adults with Symptomatic 
Hypertrophic Cardiomyopathy  
Protocol Version and Date: 
Amendment 04 dated 09 November 2021 
 
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 Conference on 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 study in accordance with the protocol referenced herein. 
 
Investigator Name: 
 
Date:  
Investigator Signature: 
 
 

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PROTOCOL APPROVAL PAGE 
 
Protocol Number: 
CY 6021 
Protocol Title: 
A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-
finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of CK­3773274 in Adults with Symptomatic 
Hypertrophic Cardiomyopathy  
Protocol Version and Date: 
Amendment 04 dated 09 November 2021  
Sponsor: 
Cytokinetics, Inc. 
280 East Grand Avenue 
South San Francisco, CA 94080 
 
 
, MD, PhD 
Associate Medical Director, Clinical Research, 
Cardiovascular 
 
Date: 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 03 
17 February 2021 
Amendment 02 
13 July 2020 
Amendment GBR-01 
24 January 2020 
Amendment 01 
09 August 2019 
Original Protocol 
29 July 2019 
Amendment 04 (09 November 2021) 
The purpose of this amendment is to describe the design update for Cohort 4. 
No updates to the Benefit/Risk Assessment (Section 2.3) were warranted 
 
 
Table 1: 
Protocol Amendment Summary of Changes 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Update of protocol version date. 
Editorial (formatting, 
typographical, and grammatical) 
corrections throughout the 
protocol. 
Administrative changes. 
Global 
Replaced “oHCM” with “HCM” 
in many places throughout 
To include patients with oHCM 
and nHCM in this study 
Study Title 
Removed “Left Ventricular 
Outflow Tract Obstruction” 
To allow inclusion of patients 
with nHCM in Cohort 4 
Section 1.1 Synopsis 
Clarified objectives and 
endpoints relevant to specific 
cohorts 
Added objectives and endpoints 
for Cohort 4 
Updated to reflect changes made 
to the body of the protocol 
Section 1.2 Schema 
Added Cohort 4 Study Schema 
To differentiate Cohort 4 from 
previous cohorts. 
Section 1.3 Schedule of 
Activities 
Added “(Cohorts 1, 2, and 3)” to 
the title of the section  
To identify that Section 1.3 only 
pertains to Cohorts 1, 2, and 3 
Section 1.4 Schedule of 
Activities 
Added separate schedule of 
activities for patients enrolled in 
Cohort 4 
To clarify the laboratory and 
PRO assessments for patients 
enrolled in Cohort 4. 

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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2 
PROTOCOL APPROVAL PAGE ...................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
1. 
PROTOCOL SUMMARY ..........................................................................................14 
1.1. 
Synopsis ......................................................................................................................14 
1.2. 
Schema ........................................................................................................................24 
1.3. 
Schedule of Activities (Cohort 1, 2, and 3) ................................................................27 
1.4. 
Schedule of Activities (Cohort 4) ...............................................................................29 
1.5. 
Key Contacts ...............................................................................................................31 
2. 
INTRODUCTION ......................................................................................................32 
2.1. 
Study Rationale ...........................................................................................................32 
2.2. 
Background .................................................................................................................32 
2.2.1. 
Hypertrophic Cardiomyopathy ...................................................................................32 
2.2.2. 
CK­3773274 ...............................................................................................................33 
2.2.2.1. 
Overview of Nonclinical Studies of CK­3773274 ......................................................34 
2.2.2.2. 
Overview of Clinical Studies of CK­3773274............................................................36 
2.3. 
Benefit/Risk Assessment ............................................................................................38 
2.3.1. 
Risk Assessment .........................................................................................................38 
2.3.1.1. 
Mitigation Strategy .....................................................................................................39 
2.3.2. 
Benefit Assessment .....................................................................................................39 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................41 
4. 
STUDY DESIGN .......................................................................................................44 
4.1. 
Overall Design ............................................................................................................44 
4.2. 
Scientific Rationale for Study Design ........................................................................44 
4.3. 
Justification for Dose ..................................................................................................45 
4.4. 
End of Study Definition ..............................................................................................45 
5. 
STUDY POPULATION .............................................................................................46 
5.1. 
Inclusion Criteria ........................................................................................................46 

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5.2. 
Exclusion Criteria .......................................................................................................47 
5.3. 
Lifestyle Considerations .............................................................................................49 
5.4. 
Screen Failures ............................................................................................................49 
5.5. 
Retesting .....................................................................................................................49 
6. 
INVESTIGATIONAL PRODUCT ............................................................................50 
6.1. 
Investigational Product(s) Administered ....................................................................50 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................50 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................51 
6.4. 
Investigational Product Compliance and Administration ...........................................51 
6.4.1. 
IP Compliance ............................................................................................................51 
6.4.2. 
IP Administration ........................................................................................................52 
6.5. 
Concomitant Therapy .................................................................................................52 
6.5.1. 
Drug-Drug Interactions ...............................................................................................52 
6.5.2. 
Rescue Medicine .........................................................................................................53 
6.6. 
Dose Modification ......................................................................................................53 
6.6.1. 
Scheduled Dose Modifications ...................................................................................53 
6.6.2. 
Safety Considerations .................................................................................................54 
6.6.3. 
Dose Level Stopping Rules ........................................................................................55 
6.7. 
Access to Investigational Product after the End of the Study ....................................55 
7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................56 
7.1. 
Discontinuation of Investigational Product ................................................................56 
7.1.1. 
Temporary Discontinuation ........................................................................................56 
7.1.2. 
Hepatotoxicity Stopping and Rechallenge Rules .......................................................56 
7.2. 
Patient Discontinuation/Withdrawal from the Study ..................................................56 
7.3. 
Lost to Follow up ........................................................................................................57 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................59 
8.1. 
Efficacy Assessments .................................................................................................59 
8.1.1. 
Echocardiography .......................................................................................................60 
8.1.2. 
New York Heart Association Functional Classification .............................................60 
8.1.3. 
Health Status and Health-related Quality of Life .......................................................61 
8.2. 
Safety Assessments .....................................................................................................61 
8.2.1. 
Physical Examinations ................................................................................................61 

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8.2.2. 
Vital Signs ..................................................................................................................62 
8.2.3. 
Electrocardiograms .....................................................................................................62 
8.2.4. 
Ambulatory Cardiac Monitoring ................................................................................62 
8.2.5. 
Laboratory Assessments .............................................................................................62 
8.3. 
Adverse Events and Serious Adverse Events .............................................................63 
8.3.1. 
Adverse Events ...........................................................................................................63 
8.3.2. 
Serious Adverse Events ..............................................................................................63 
8.3.3. 
Time Period and Frequency for Collecting AE and SAE Information .......................64 
8.3.4. 
Method of Detecting AEs and SAEs ..........................................................................64 
8.3.5. 
Follow-up of AEs and SAEs .......................................................................................64 
8.3.6. 
Regulatory Reporting Requirements for SAEs ...........................................................65 
8.3.7. 
Pregnancy ...................................................................................................................65 
8.3.8. 
Female Patients Who Breastfeed ................................................................................65 
8.4. 
Treatment of Overdose ...............................................................................................66 
8.5. 
Pharmacokinetics ........................................................................................................66 
8.6. 
Pharmacodynamics .....................................................................................................67 
8.7. 
Genetics ......................................................................................................................67 
8.8. 
Biomarkers ..................................................................................................................67 
8.9. 
Immunogenicity Assessments ....................................................................................67 
8.10. 
Medical Resource Utilization and Health Economics ................................................68 
9. 
STATISTICAL CONSIDERATIONS .......................................................................69 
9.1. 
Statistical Hypotheses .................................................................................................69 
9.2. 
Sample Size Determination ........................................................................................69 
9.3. 
Populations for Analyses ............................................................................................69 
9.4. 
Statistical Analyses .....................................................................................................70 
9.4.1. 
General Considerations ...............................................................................................70 
9.4.2. 
Safety Endpoints .........................................................................................................70 
9.4.2.1. 
Primary Safety Endpoints ...........................................................................................70 
9.4.2.2. 
Exploratory Safety Endpoints .....................................................................................71 
9.4.3. 
Pharmacokinetic Endpoints ........................................................................................71 
9.4.4. 
Pharmacodynamic Endpoints .....................................................................................71 
9.4.4.1. 
Exploratory Pharmacodynamic Endpoints .................................................................72 
9.4.5. 
Other Exploratory Endpoints ......................................................................................72 

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9.4.6. 
Patient Disposition ......................................................................................................73 
9.4.7. 
Demographics and Other Baseline Characteristics .....................................................73 
9.4.8. 
Investigational Product Exposure ...............................................................................73 
9.4.9. 
Safety Analysis ...........................................................................................................73 
9.4.9.1. 
Adverse Events ...........................................................................................................73 
9.4.9.2. 
Serious Adverse Events ..............................................................................................73 
9.4.9.3. 
Concomitant Medications ...........................................................................................73 
9.4.9.4. 
Clinical Laboratory Parameters ..................................................................................73 
9.4.9.5. 
Vital Signs ..................................................................................................................74 
9.4.9.6. 
Electrocardiogram .......................................................................................................74 
9.4.10. 
Pharmacokinetic Analysis ..........................................................................................74 
9.4.11. 
Echocardiography Analysis ........................................................................................74 
9.4.12. 
Health Status and Health-related Quality of Life Analysis ........................................75 
9.5. 
Interim Analyses .........................................................................................................75 
9.6. 
Data Monitoring Committee .......................................................................................76 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................77 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................77 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................77 
10.1.2. 
Financial Disclosure ...................................................................................................77 
10.1.3. 
Informed Consent Process ..........................................................................................77 
10.1.4. 
Data Protection ...........................................................................................................78 
10.1.5. 
Committees Structure .................................................................................................78 
10.1.6. 
Data Quality Assurance ..............................................................................................79 
10.1.7. 
Source Documents ......................................................................................................79 
10.1.8. 
Study and Site Start and Closure ................................................................................79 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................81 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................82 
10.3.1. 
Definition of Adverse Event .......................................................................................82 
10.3.2. 
Definition of Serious Adverse Event ..........................................................................83 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................84 
10.3.4. 
Reporting of SAEs ......................................................................................................85 

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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................86 
10.5. 
Appendix 5: Genetics .................................................................................................89 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ..............90 
10.7. 
Appendix 7: Abbreviations .........................................................................................94 
10.8. 
Appendix 8: Protocol Amendment History ................................................................96 
11. 
REFERENCES ...........................................................................................................97 
 

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LIST OF TABLES 
Table 1: 
Protocol Amendment Summary of Changes ................................................................4 
Table 2: 
CY 6021 Dosing Scheme ............................................................................................20 
Table 3: 
Total and Free Concentrations of CK­3773274 in CY 6011 and 13-Week 
Toxicity Studies ..........................................................................................................36 
Table 4: 
CY 6011: Final Steady-State PK Parameters .............................................................38 
Table 5: 
Study Objectives and Endpoints .................................................................................41 
Table 6: 
Investigational Products ..............................................................................................50 
Table 7: 
CY 6021 Dosing Scheme ............................................................................................53 
Table 8: 
CY 6021 Visit Windows .............................................................................................59 
Table 9: 
CY 6021 Echocardiographic Parameters to be Measured ..........................................60 
Table 10: Summary of PK and Echocardiography Time Points .................................................67 
Table 11: Analysis Sets ...............................................................................................................69 
Table 12: Protocol-Required Safety Laboratory Assessments ...................................................81 
Table 13: List of Abbreviations ..................................................................................................94 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................24 
Figure 2: 
CY 6011: Plasma Concentrations of CK­3773274 over Time by Dose Level ...........38 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Investigational Product(s) (IP): CK­3773274 
Name of Active Ingredient(s): CK­3773274 
Protocol Title: A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK­3773274 in Adults 
with Symptomatic Hypertrophic Cardiomyopathy 
Phase of Development: Phase 2 
Rationale: 
This is the first study of CK­3773274 in patients with hypertrophic cardiomyopathy (HCM). 
CK­3773274 is a small molecule cardiac myosin inhibitor being developed as a chronic, oral treatment 
for patients with HCM. CK­3773274 is designed to reduce the hypercontractility that underlies the 
pathophysiology of HCM. 
Objectives and Endpoints: 
Objectives 
Endpoint(s) 
Primary 
To determine the safety and tolerability of 
CK­3773274 in patients with symptomatic HCM 
• Patient incidence of reported adverse events 
(AEs) 
• Patient incidence of reported serious adverse 
events (SAEs) 
• Patient incidence of left ventricular ejection 
fraction (LVEF) <50% 
Secondary 
To describe the concentration-response 
relationship of CK­3773274 on the resting and 
post-Valsalva left ventricular outflow tract 
gradient (LVOTG) on echocardiogram over 
10 weeks of treatment in patients 
with oHCM (Cohorts 1, 2, 3 only) 
• Slope of the relationship of the plasma 
concentration of CK­3773274 to the change 
from baseline in the resting LVOTG 
• Slope of the relationship of the plasma 
concentration of CK­3773274 to the change 
from baseline in the post-Valsalva LVOTG  
To describe the dose response relationship on 
LVOT-G (resting and Valsalva) of CK­3773274 
in patients with symptomatic oHCM (Cohorts 1, 
2, 3 only) 
• Change from baseline in resting and post-
Valsalva LVOTG over time as a function of 
dose 
• Change from baseline in resting and post-
Valsalva LVOTG to Week 10  
To evaluate the concentration-response 
relationship of CK­3773274 on resting left 
ventricular ejection fraction (LVEF) over 
10 weeks of treatment in patients with HCM  
• Slope of the relationship of the plasma 
concentration of CK­3773274 to the change 
from baseline in the resting LVEF  

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Overall Design: 
This is a Phase 2, multi-center, randomized, placebo-controlled, double-blind, dose finding study in 
patients with symptomatic HCM. 
Cohorts 1 and 2: Two sequential cohorts of patients with oHCM will be enrolled in a randomized, 
placebo-controlled, double blind fashion. Within each cohort, patients will be randomized 2:1 to active 
or placebo treatment and receive up to three escalating doses of CK­3773274 or placebo based on 
echocardiographic guidance. Patients receiving disopyramide are excluded from Cohorts 1 and 2. 
Overall, the treatment duration will be 10 weeks with a 4-week follow-up period after the last dose 
Cohort 3: A third cohort will be enrolled consisting of patients with oHCM whose background HCM 
therapy must include disopyramide. Within this cohort, patients will receive up to three escalating 
doses of CK­3773274, titrated based on echocardiographic guidance. Overall, the treatment duration 
will be 10 weeks with a 4-week follow-up period after the last dose. 
Cohort 4: A fourth cohort will be enrolled consisting of patients with nHCM. Background therapy can 
include beta-blockers and/or calcium channel blockers, either as monotherapy or in combination. 
Patients receiving disopyramide are excluded from Cohort 4. Within this cohort, patients will receive 
up to three doses of CK­3773274, titrated based on echocardiographic guidance. Overall, the treatment 
duration will be 10 weeks with a 4-week follow-up period after the last dose. 
Study Center(s): 
This study will take place at approximately 30 sites in North America and Europe.  
Number of Patients: 
Approximately 95 patients will be enrolled in the study. 
In Cohorts 1 and 2, each cohort will comprise approximately 18 patients who will be randomized to 
investigational product (IP): CK­3773274 or placebo. 
In Cohort 3, approximately 8-12 patients will be assigned to CK­3773274. 
In Cohort 4, approximately 30-40 patients will be assigned to CK­3773274. 

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Key Eligibility Criteria: 
A full listing of eligibility criteria can be found in Section 5.1. 
Inclusion Criteria 
Patients who meet all the following criteria at screening may be included in the study: 
• Males and females between 18 and 85 years of age at screening. 
• Body weight is ≥45 kg at screening. 
• Diagnosed with HCM per the following criteria: 
− Has left ventricular (LV) hypertrophy with non-dilated LV chamber in the absence of other cardiac 
disease. 
− Has minimal wall thickness ≥15 mm (minimal wall thickness ≥13 mm is acceptable with a positive 
family history of HCM or with a known disease-causing gene mutation). 
• Adequate acoustic windows for echocardiography. 
• For Cohorts 1, 2, and 3, has LVOT-G during screening as follows: 
− Resting gradient ≥50 mmHg 
OR 
− Resting gradient ≥30 mmHg and <50 mmHg with post-Valsalva LVOT-G ≥50 mmHg 
• LVEF ≥60% at screening. 
• NYHA Class II or III at screening. 
• Patients on beta-blockers, verapamil, diltiazem, or ranolazine should have been on stable doses for 
>4 weeks prior to randomization and anticipate remaining on the same medication regimen during the 
study. 
• For Cohort 3: Patients must be taking disopyramide. Patients should have been on stable 
disopyramide doses for >4 weeks prior to screening and anticipate remaining on the same medication 
regimen during the study. 
• For Cohort 4 has resting and post-Valsalva LVOT-G < 30 mmHg at the time of screening 
• For Cohort 4 has elevated NT-proBNP > 300 pg/mL at the time of screening  

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Exclusion Criteria 
Any of the following criteria will exclude potential patients from the study: 
• Aortic stenosis or fixed subaortic obstruction. 
• Known infiltrative or storage disorder causing cardiac hypertrophy that mimics HCM (eg, Noonan 
syndrome, Fabry disease, amyloidosis). 
• History of LV systolic dysfunction (LVEF <45%) at any time during their clinical course. 
• Documented history of current obstructive coronary artery disease (>70% stenosis in one or more 
epicardial coronary arteries) or documented history of myocardial infarction. 
• Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal 
ablation) or has plans for either treatment during the study period (Cohorts 1, 2, and 3 only). Patients 
having undergone septal reduction therapy > 12 months prior to screening who remain symptomatic 
from nHCM, and who meet all other criteria for inclusion, may be enrolled in Cohort 4. 
• For Cohorts 1, 2 and 4: Has been treated with disopyramide or antiarrhythmic drugs that have 
negative inotropic activity within 4 weeks prior to screening. (For Cohort 3, use of disopyramide is 
required). 
• Paroxysmal atrial fibrillation or flutter documented during the screening period. 
• Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current 
cardioversion, ablation procedure, or antiarrhythmic therapy) ≤6 months prior to screening. (This 
exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately 
rate-controlled for >6 months.) 
• History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to 
screening. 
• Has received prior treatment with CK­3773274 or is currently receiving mavacamten. 
• For Cohort 4: has any documented history of LVOT-G ≥ 30 mmHg at rest, with Valsalva, or with 
exercise (for subjects who have had prior septal reduction therapy, this exclusion criteria only applies 
to gradients detected following septal reduction therapy). 

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IP Dosing Groups and Duration: 
The dose escalation scheme is shown in Table 2. 
Table 2: 
CY 6021 Dosing Scheme 
Cohort 
Dose 1 
Dose 2 
Dose 3 
Cohort 1 
5 mg 
10 mg 
15 mg 
Cohort 2 
10 mg 
20 mg 
30 mg 
Cohort 3  
5 mg 
10 mg 
15 mg 
Cohort 4 
5 mg 
10 mg 
15 mg 
For Cohorts 1, 2, 3 
Each patient will receive Dose 1 for 2 weeks. At Week 2, the patient will have an echocardiogram 
2 hours following administration of their dose of IP. Patients will up-titrate to Dose 2 if either of the 
following conditions are met on echocardiography: 
• Resting LVOT-G ≥30 mmHg and the biplane LVEF ≥50% 
OR 
• Resting LVOT-G <30 mmHg, post-Valsalva LVOT-G ≥50 mmHg, and the biplane LVEF ≥50% 
Otherwise, the patient will remain on Dose 1. 

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After 2 more weeks on the assigned dose (ie, Week 4), 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 
either of the following conditions are met on echocardiography: 
• Resting LVOT-G ≥30 mmHg and the biplane LVEF ≥50% 
OR 
• Resting LVOT-G <30 mmHg, post-Valsalva LVOT-G ≥50 mmHg, and the biplane LVEF ≥50% 
Otherwise, the patient will remain on the same dose. 
If at a scheduled echocardiogram (Week 2, Week 4 or Week 6), the LVEF is <50%, then the patient 
will be returned to a prior dose level or to placebo if the patient is on Dose 1. If a patient’s dose is 
reduced to placebo or IP is discontinued (from Dose 1), then the patient will remain on placebo 
(Cohorts 1 and 2) or off IP (Cohort 3) for the duration of the study. If the scheduled echocardiogram 
shows a LVEF of < 40% at any time, then the study drug will be paused independent of the current 
dose. 
If an unscheduled echocardiogram read by the Echo Cardiologist shows an LVEF < 50%, and the 
patient has symptoms of low cardiac output, the patient will be discontinued from study drug. 
Eligible patients will be followed until they complete the Week 14 assessments. 
 
For Cohort 4 
Each patient will receive Dose 1 for 2 weeks. At Week 2, the patient will have an echocardiogram 
2 hours following administration of their dose of IP. Patients will up-titrate to Dose 2 if LVEF ≥ 55% 
on echocardiogram. Otherwise, the patient will remain on the same dose. 
After 2 more weeks on the assigned dose, 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 LVEF ≥ 55% on 
echocardiogram. Otherwise, the patient will remain on the same dose. 
If at a scheduled echocardiogram (Week 2, Week 4 or Week 6), the LVEF is <50%, then the patient 
will be returned to a prior dose level or IP will be discontinued if the patient was on Dose 1. If 
discontinued, then the patient will remain off drug for the duration of the study. If the scheduled 
echocardiogram shows a LVEF of < 40% at any time, then the study drug will be temporarily 
discontinued independent of the current dose. 
If an unscheduled echocardiogram read by the Echo Cardiologist shows an LVEF < 50%, and the 
patient has symptoms of low cardiac output, the patient will be permanently discontinued from study 
drug. 
 
Eligible patients will be followed until they complete the Week 14 assessments.  
Data Monitoring Committee: 
Representatives of Cytokinetics and the Steering Committee (SC) will conduct interim reviews of the 
available blinded and unblinded safety, echocardiographic, and de-identified PK data (Cohorts 1 and 2) 
to recommend the dose levels of CK­3773274 to be administered in the next cohort. An unblinded Data 
Monitoring Committee (DMC) will review the recommendations along with the available safety, and 
echocardiographic data. The DMC may either endorse the recommendation or suggest a change in 
study conduct, including alteration of planned dosing regimen. 

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Statistical Methods: 
Safety analyses will be performed on the safety analysis set which includes all patients who received at 
least one dose of IP, grouped according to the maximum actual dose received. The pharmacodynamics 
analysis set (PDS) will consist of all patients who received any amount of IP and have a baseline and at 
least one post-baseline echocardiographic assessment during the double-blind treatment period by 
actual treatment group, CK­3773274 or placebo. The pharmacokinetics analysis set (PKS) will consist 
of patients who have at least one measurable plasma concentration of CK­3773274. 
The number and percentage of patients reporting any treatment-emergent AEs will be coded using the 
MedDRA dictionary and tabulated by system organ class and preferred term. 
Descriptive statistics by cohort, treatment, and/or dose will be provided for selected demographics, 
safety, PK, and PD data. 
The slope of the relationship of the plasma concentrations of CK­3773274 on select echocardiographic 
variables measured at baseline and Weeks 2, 4, 6, and 10 (eg, LVEF, resting or post-Valsalva 
LVOT-G) will be evaluated using mixed-effect repeated measures model for all planned measurements 
of LVOT-G, with terms for the baseline value, and time-matched value of the plasma concentrations of 
CK­3773274, with a random intercept assumption. The models will be based on PDS and performed by 
cohort and/or in Cohorts 1 and 2 combined. Similar models may be fitted including time-matched 
CK­3773274 dose level. 
The treatment effect on secondary and exploratory endpoints relating to change from baseline to 
Week 10 will be evaluated in PDS, Cohorts 1 and 2 only, using analysis of covariance for continuous 
variables (with terms for treatment, and baseline value) and logistic regression for categorical or binary 
data. The analyses will test the null hypothesis that there is no treatment difference in change from 
baseline to Week 10 between patients receiving placebo and those receiving CK­3773274 by cohort. 
The analyses may be repeated with data combined across Cohorts 1 and 2, in which case the cohort 
may be used as the stratification factor. 
The effect of the PK of CK­3773274 on select echocardiographic variables will be evaluated using a 
concentration bin analysis of variance in PDS, Cohorts 1 and 2 only, by cohort and/or in Cohorts 1 and 
2 combined. Plasma concentration bin as a categorical variable will be used in the analysis. 
The effect of CK­3773274 dose on echocardiographic variables will also be evaluated including the 
dose as a continuous variable in the analysis. 
Secondary and exploratory endpoints related to change from baseline and responder endpoints in 
patients receiving disopyramide (Cohorts 3 and 4) will be evaluated using descriptive summaries. 
The effect of background disopyramide on PK will be assessed by analysis of variance (ANOVA) 
models including the data from Cohort 1 subjects randomized to CK­3773274 and from Cohort 3 
subjects. The models will be fit for natural log-transformed plasma concentrations: Day 1 (1 hour post-
dose), Ctrough, and Cmax. 
The effect of background disopyramide therapy on pharmacodynamic response over time through 
Week 10 will be assessed by analysis of covariance (ANCOVA) models for change from baseline in 
LVOT-G at rest, LVOT-G post-Valsalva, and LVEF, including the data from Cohort 1 subjects 
randomized to CK­3773274 and from Cohort 3 subjects assigned to CK­3773274. 
The slope of change from baseline to Week 10 in Health Status and Health-related Quality of Life 
endpoints will be evaluated using a mixed-effect repeated measures model in the US subjects 
randomized to Cohort 2. The treatment effect on change from baseline to Week 10 endpoints will be 
evaluated using analysis of covariance. Change from baseline endpoints in the patients assigned to 
receive CK­3773274 in Cohorts 3 or 4 will be evaluated using descriptive summaries. Individual 
responses to the HCM Global Impression of Status and Global Impression of Change questionnaires 
will be summarized categorically. 

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Continuous variables may be log transformed prior to the analysis. Analyses will be further detailed in 
the Statistical Analysis Plan. 
Interim data analyses (Cohorts 1 and 2 only) will be conducted by representatives of Cytokinetics and 
the SC in a blinded manner and by the DMC in an unblinded manner to consider recommendations for 
the dose levels of CK­3773274 to be administered in the next cohort. An interim analysis of cohort data 
will occur after at least 10 randomized patients have completed the Week 6 visit and when the PK and 
echocardiography data from those visits are available.  
 

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1.2. 
Schema 
Figure 1: 
Study Schema 
Cohort 1 & 2 
 

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Cohort 3 
 

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Cohort 4 
 
 

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1.3. 
Schedule of Activities (Cohort 1, 2, and 3) 
Study Procedure 
Screening 
Day 1 
Week 2 Week 4 Week 6 
Week 8 
(Phone 
Visit) 
Week 9 
(Phone 
Visit) 
Week 
10 
Week 
12 
EOS 
(Week 14; 
Phone Visit) 
EDa 
<28 days 
Week -1 
(Phone 
Visit) 
GENERAL PROCEDURES & SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height/weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Vital signs 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE evaluation 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (triplicate) 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
Echocardiography (full protocol)c 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
Echocardiography (truncated protocol)c 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Ambulatory cardiac monitoringd 
 
X 
 
 
 
 
 
X 
 
 
 
 
Cohorts 1 & 2: Randomization  
 
 
X 
 
 
 
 
 
 
 
 
 
Cohort 3: Assigned to CK­3773274  
 
 
X 
 
 
 
 
 
 
 
 
 
CENTRAL LABORATORY 
Genotype sample 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessments 
X 
 
X 
 
 
X 
 
 
X 
X 
 
X 
NT-proBNP 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
Pregnancy test (WOCBP only)e 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
PK samplesf 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 

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Study Procedure 
Screening 
Day 1 
Week 2 Week 4 Week 6 
Week 8 
(Phone 
Visit) 
Week 9 
(Phone 
Visit) 
Week 
10 
Week 
12 
EOS 
(Week 14; 
Phone Visit) 
EDa 
<28 days 
Week -1 
(Phone 
Visit) 
INVESTIGATIONAL PRODUCT 
In-clinic IP dosing 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
IP dose adjustment 
 
 
 
X 
X 
Xg 
 
 
 
 
 
 
PATIENT-REPORTED OUTCOMES AND ASSESSMENTS 
NYHA Functional Classification 
X 
Patient reported outcomesh 
 
 
X 
 
 
X 
 
 
X 
 
 
 
ECG = electrocardiogram; ED = early discontinuation; EOS = end of study; IP = investigational product; WOCBP = women of childbearing potential. 
a Patients who withdraw from the study should complete an early discontinuation (ED) visit as soon as possible. A safety contact (eg, phone call) should occur 
4 weeks following last dose of IP to ascertain vital status and AEs. 
b Only AEs considered related to study procedures and all SAEs are collected during the screening period until initiation of IP (Day 1). Any non-serious medical 
occurrence not related to a study procedure during this period should be collected as medical history. 
c Echocardiography will be done prior to dosing on Day 1 and 2-2.5 hours after dosing in the clinic at Weeks 2, 4, 6 and 10. Patients will fast at least 2 hours 
prior to any scheduled echocardiogram. 
d Ambulatory Cardiac Monitoring will be done for at least 5 days prior to Day 1. 
e Only for WOCBP. Serum pregnancy test at screening; for other visits a urine pregnancy test may be used. 
f Please refer to Table 10 for PK timing. 
g Patients can only be down-titrated at Week 6. 
h Only for US patients. 
 
 

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1.4. 
Schedule of Activities (Cohort 4) 
 
Study Procedure 
Screening 
Day 1 
Week 2 Week 4 Week 6 
Week 8 
(Phone 
Visit) 
Week 9 
(Phone 
Visit) 
Week 
10 
Week 
12 
EOS 
(Week 14; 
Phone Visit) 
EDa 
<28 days 
Week -1 
(Phone 
Visit) 
GENERAL PROCEDURES & SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height/weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Vital signs 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE evaluation 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (triplicate) 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
Echocardiography (full protocol)c 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
Echocardiography (truncated protocol)c 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Ambulatory cardiac monitoringd 
 
X 
 
 
 
 
 
X 
 
 
 
 
Assigned to CK­3773274  
 
 
X 
 
 
 
 
 
 
 
 
 
CENTRAL LABORATORY 
Genotype sample 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessments 
X 
 
X 
 
 
X 
 
 
X 
X 
 
X 
NT-proBNP and hs-cTnI 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
Pregnancy test (WOCBP only)e 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
PK samplesf 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
INVESTIGATIONAL PRODUCT 
In-clinic IP dosing 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 

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Study Procedure 
Screening 
Day 1 
Week 2 Week 4 Week 6 
Week 8 
(Phone 
Visit) 
Week 9 
(Phone 
Visit) 
Week 
10 
Week 
12 
EOS 
(Week 14; 
Phone Visit) 
EDa 
<28 days 
Week -1 
(Phone 
Visit) 
IP dose adjustment 
 
 
 
X 
X 
Xg 
 
 
 
 
 
 
PATIENT-REPORTED OUTCOMES AND ASSESSMENTS 
NYHA Functional Classification 
X 
ECG = electrocardiogram; ED = early discontinuation; EOS = end of study; IP = investigational product; WOCBP = women of childbearing potential. 
a Patients who withdraw from the study should complete an early discontinuation (ED) visit as soon as possible. A safety contact (eg, phone call) should occur 
4 weeks following last dose of IP to ascertain vital status and AEs. 
b Only considered related to study collected during the screening period until initiation of IP (Day 1). Any non-serious medical occurrence not related to a study 
procedure during this period should be collected as medical history. 
c Echocardiography will be done prior to dosing on Day 1 and 2-2.5 hours after dosing in the clinic at Weeks 2, 4, 6 and 10. Patients will fast at least 2 hours 
prior to any scheduled echocardiogram. 
d Ambulatory Cardiac Monitoring will be done for at least 5 days prior to Day 1. 
e Only for WOCBP. Serum pregnancy test at screening; for other visits a urine pregnancy test may be used. 
f Please refer to Table 10 for PK timing. 
g Patients can only be down-titrated at Week 6. 
 
 

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CK­3773274 has been studied in a Phase 1 study of healthy adult participants. This Phase 2 
study will be the first investigation of CK­3773274 in patients with HCM. 
2.2.2.1. 
Overview of Nonclinical Studies of CK­3773274 
Please refer to the Investigator’s Brochure for detailed information on CK­3773274. 
Pharmacology 
CK­3773274 is an allosteric, cardiac myosin inhibitor that binds directly to the motor domain of 
cardiac myosin and prevents it from entering the force-producing state. CK­3773274 directly 
inhibits the adenosine triphosphatase activity in cardiac myofibrils and is selective for cardiac 
myosin compared to smooth and fast skeletal muscle myosin. In isolated cardiomyocytes, 
CK­3773274 reduced contractility without any changes to the intracellular Ca2+ transients. 
CK­3773274 showed acute dose- and concentration-dependent reductions in cardiac contractility 
in both rat and dog that were fully reversible with reductions in plasma concentration and, as 
shown in rat, with co-administration of the β-agonist, dobutamine. Repeat dose administration of 
CK­3773274 in rats induced similar levels of change in contractility (left ventricular fractional 
shortening [LVFS]) over 10 days, further demonstrating a dose and concentration-dependent PD 
effect with no exacerbation or loss of PD response. The concentration-response relationship in 
rat and dog was similar when corrected for free drug concentrations and indicates a similarity in 
response to this mechanism of action across species. 
In a core battery of safety pharmacology studies, test article-related effects of acute oral 
CK­3773274 administration on central nervous and respiratory system function in male rats were 
limited to the 9 mg/kg high-dose level and included transient decreases in alertness, arena rearing 
counts and body temperature accompanied by slightly drooping eyelids and transient increases in 
respiratory rate and/or decreased tidal volume. In telemetry studies of male beagle dogs 
administered 0.5, 1 or 2 mg/kg/day of CK­3773274 for 7 consecutive days, transient 
hemodynamic effects consistent with the known PD properties of CK­3773274 (decreased 
contractility) were noted at all dose levels evaluated on Days 1 and/or 7. There were no test 
article-related effects on quantitative or qualitative electrocardiogram (ECG) parameters at any 
dose level evaluated on either Day 1 or Day 7. The half-maximal inhibitory concentration (IC50) 
of CK­3773274 on human ether-à-go-go related gene potassium current was estimated to be 
greater than 10 µM. All central nervous, respiratory and cardiovascular system effects noted in 
vivo were fully resolved by 24 hours post-dose. 
Drug Metabolism and Pharmacokinetics 
CK­3773274 was classified as a high permeability compound in Caco-2 monolayers and 
exhibited moderate-to-high oral bioavailability in mice, rats, dogs and monkeys. It has a low 
plasma clearance and moderate-to-high volume of distribution. After repeat oral dose 
administration in rats and dogs for up to 28 days, systemic exposures (area under the plasma-
concentration curve [AUC] and maximum plasma concentration [Cmax]) increased with dose in a 
roughly dose-proportional manner. There was no sex-related difference in exposures to 
CK­3773274 in rats or dogs. 
CK­3773274 distributed rapidly into tissues of the rat after oral administration (time to 
maximum observed plasma concentration, tmax ~1 hour). There was low penetration of 

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CK­3773274 into brain tissue in the rat, with exposures in the brain approximately 0.5% of those 
in plasma. Protein binding of CK­3773274 was moderate-to-high in plasma from all species 
tested. Distribution was roughly equal in red blood cells (RBCs) and plasma in human, dog and 
monkey whole blood, and favored the plasma compartment in rat blood. In RBC partitioning 
studies, equal partitioning was observed between RBC and plasma compartments in whole blood 
obtained from human, dog and monkey. In rat whole blood samples, CK­3773274 partitioned 
greater into the plasma compartment. 
Six putative metabolites of CK­3773274 have been identified to date. The most prevalent 
metabolite in all species was M1 (CK-3834282). There were no human-specific metabolites 
detected. Results of cytochrome P450 (CYP) phenotyping implicate CYP2D6 as the primary 
isoform involved in formation of M1 from CK­3773274 with a fraction metabolized of 
approximately 50% from studies in plated human hepatocytes. CYPs 2C9, 2C19 and 3A4 likely 
contribute to the formation of M1 from CK­3773274. However, results from the Phase 1 study 
showed that CYP2D6 does not play a major role in CK­3773274 elimination. 
CK­3773274 did not significantly inhibit CYP isozymes (7 isozyme panel) in a direct or time-
dependent manner. In assays using hepatocytes from 3 human donors, CK­3773274 did not 
induce CYP2B6 or CYP3A4 but may have potential to induce CYP1A2 at a high concentration 
of 50 μM. The results suggest that drug interactions involving CYP metabolism are unlikely for 
CK­3773274. 
CK­3773274 is not a substrate of P-gp, BCRP, OATP1B1 or OATP1B3. CK­3773274 inhibited 
P-gp-, OAT3-, OATP1B1-, MATE1- and MATE2-K-mediated probe substrate transport with 
half-maximal inhibitory concentration (IC50) values of 4.86, 12.1, 71.2, 36.4 and 83.5 µM, 
respectively. CK­3773274 did not significantly inhibit BCRP-, OAT1-, OCT2- or OATP1B3-
mediated transport at a concentration of 50 µM. The results indicate that, depending on the 
necessary clinical exposures required to achieve a meaningful PD effect caution may need to be 
exercised when administering CK­3773274 with known substrates of P-gp and OAT3 (see 
Section 6.5). 
Toxicology 
General toxicology studies conducted with CK­3773274 in dogs include non-Good Laboratory 
Practice (GLP) and GLP repeat-dose studies up to 13 weeks in duration. 
In the GLP 13-week toxicity study conducted in rats using doses of 0, 1.5, 3, and 6 mg/kg/day, 
the no-observed-adverse-effect-level (NOAEL) was determined to be 3 mg/kg/day for males and 
6 mg/kg/day for females. Systemic exposure (Cmax and AUC) to CK­3773274 at the NOAEL on 
Day 91 was 4,700 ng/mL and 73,000 ng∙h/mL, respectively, in males and 10,800 ng/mL and 
99,200 ng∙h/mL, respectively, in females. There were no CK­3773274-related clinical signs, 
changes in body weight, food consumption, ophthalmic findings or changes in any clinical 
pathology parameters including cardiac troponin I. Administration of CK­3773274 was 
associated with early deaths in two toxicology males dosed at 6 mg/kg/day. The principal 
microscopic findings were minimal to moderate dilatation of the atrium/ventricle of the heart in 
males at ≥1.5 mg/kg/day and females at 6 mg/kg/day. 
In the GLP 13-week toxicity study conducted in dogs using doses of 0, 0.5, 1, and 2 mg/kg/day, 
the NOAEL was determined to be 1 mg/kg/day. Systemic exposure (Cmax and AUC) to 

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CK­3773274 at the NOAEL on Day 91 was 387 ng/mL and 3,330 ng∙h/mL, respectively, in 
males and 430 ng/mL and 3,670 ng∙h/mL, respectively, in females. The administration of 
CK­3773274 at 2 mg/kg/day was associated with an early death in one male. There were no 
CK­3773274-related effects on food consumption, ophthalmic findings, coagulation parameters, 
cardiac troponin I biomarker or urinalysis parameters. Cardiac ventricular dilatation was 
observed at 2 mg/kg/day and increased heart weights in males at ≥1 mg/kg/day. 
The adverse cardiac effects noted in these studies are consistent with the anticipated 
physiological response to pharmacological target engagement of CK­3773274. The adaptive 
response of cardiac dilatation is a consequence of an excessive chronic pharmacologic effect, 
namely a large, persistent decrease in cardiac function. The NOAEL values for the 13-week 
toxicity studies are tabulated below in Table 3 with a summary of the exposures and related 
safety margins based on exposures from the first in human experience at steady-state exposures 
for a 10 mg dose (CY 6011, summarized in Section 2.2.2.2). 
Table 3: 
Total and Free Concentrations of CK­3773274 in CY 6011 and 13-Week 
Toxicity Studies 
Species 
NOAEL 
(mg/kg/day) 
Meana Total 
Concentration of 
CK­3773274 
Meana Free 
Concentration of 
CK­3773274 
Marginsb 
Cmax 
(ng/mL) 
AUC24 
(ng∙h/mL) 
Cmax 
(ng/mL) 
AUC24 
(ng∙h/mL) 
Cmax 
AUC24 
Humanc 
- 
144 
2,690 
15.0 
280 
- 
- 
Rat 
3.0 (M) 
4,700 
73,000 
75 
1,168 
5.0 
4.2 
6.0 (F) 
10,800 
99,200 
173 
1,587 
11.5 
5.7 
Dog 
1.0 (M) 
387 
3,330 
96 
829 
6.4 
3.0 
1.0 (F) 
430 
3,670 
107 
914 
7.1 
3.3 
F = female; M = male. 
a Reported as arithmetic mean. 
b Margins are calculated based on free (non-plasma protein bound) concentrations of CK­3773274 in rats and dogs 
compared to humans at plasma protein binding values of 98.4% (rat), 75.1% (dog) and 89.6% (human) from 
NCD18-17. Values are not allometrically scaled. 
c CY 6011 Cohort L (10 mg once daily × 14 days), Day 14 data. 
Source: NCD18-46, NCD18-47 
The results of the genotoxicity testing battery indicate that CK­3773274 is neither mutagenic nor 
clastogenic/aneugenic and does not pose a genotoxic risk to human. 
2.2.2.2. 
Overview of Clinical Studies of CK­3773274 
Prior to the start of CY 6021, one human clinical study, CY 6011, with CK­3773274 has been 
performed in healthy adult participants. 
Study CY 6011 was a Phase 1, randomized, placebo-controlled, double-blind, multi-part study in 
healthy participants. The study evaluated single ascending doses (SAD) and multiple ascending 
doses (MAD), food effect, the impact of a CYP2D6-Poor Metabolizer phenotype on PK, and the 
PK of the tablets used in the current study in comparison with the formulation employed in the 

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SAD/MAD portions. There was no evident effect of food or the CYP2D6-Poor Metabolizer 
phenotype on the PK of CK­3773274. The PK of the tablets was similar to the PK used in the 
SAD/MAD portions, whose conduct is summarized below. 
The SAD and MAD portions of the study were designed to define a pharmacologically active 
dose range that reduces left ventricular ejection fraction (LVEF), as measured by 
echocardiography, by 5 to 15 percentage points. It was not designed to identify a maximum 
tolerated dose. 
During the SAD portion of the study, seven cohorts of healthy participants (57 total participants) 
received a single dose of CK­3773274 (either 1, 3, 10, 25, 40, 50, or 75 mg) or placebo 
administered orally. For the highest dose cohort (75 mg single dose), one participant in the 
sentinel pair received IP and the rest were dosed with 50 mg or placebo. Forty-seven (47) 
adverse events (AEs) and no serious adverse events (SAEs) occurred in the SAD cohorts; all 
AEs were mild to moderate. The most common AEs across all SAD cohorts were gastrointestinal 
symptoms (n=16, including dyspepsia, nausea, bloating and gastroesophageal reflux) and 
headache. There have been no clinically significant laboratory abnormalities, including no 
troponin elevations, nor any clinically significant ECG or vital sign changes. Dose escalation 
stopping criteria (LVEF<45% in one or more participant) were met in the 75 mg cohort. One 
participant developed an LVEF of 35% approximately 2 hours after dosing that recovered to 
normal range (LVEF >50%) within 4 hours after it was noted. The participant remained 
asymptomatic with stable vital signs. More modest (5-15%) decreases in LVEF were noted in 
patients at lower doses and there were no AEs associated with the decrease in LVEF. 
During the MAD portion of the study, data from two cohorts of 8 participants each (16 total 
participants) that received single daily doses of CK­3773274 (either 5 or 10 mg once daily) or 
placebo administered orally over 14 days are available. Nine (9) AEs and no SAEs occurred in 
the MAD cohorts; all AEs were mild. The most common AEs the in the MAD cohorts have been 
gastrointestinal symptoms and headache. There have been no clinically significant laboratory 
abnormalities, including no troponin elevations, nor any clinically significant ECG or vital sign 
changes. Dose escalation stopping criteria (LVEF <50% in two or more patients) were met by 
two patients in the MAD group who received 10 mg once daily (LVEF = 46.6% [62.8% pre-
dose] and 48.5% [61.9% pre-dose]); both patients completed 14 days of dosing and remained 
asymptomatic with stable vital signs. The LVEF returned to the normal range (LVEF >50%) 
within 24 hours of stopping drug. 
The AUC24 and Cmax of CK­3773274 were approximately dose-proportional in the SAD and 
MAD portions of CY 6011. The average apparent plasma terminal elimination half-life (t½) was 
approximately 3.5 days; steady-state plasma concentrations of CK­3773274 were clearly 
obtained within 14 days of dosing (see Figure 2). The pharmacokinetic (PK) parameters obtained 
during the MAD portion of the study are shown in Table 4. 

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Patient contributions to the performance of this study may yield a new therapeutic modality for 
the treatment of their disease. 

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representative of the intended Phase 3 populations while ensuring the safety of the study 
population in this trial. 
For Cohorts 1 and 2, a placebo control and double-blinded approach are being employed in this 
study to avoid bias in data collection, including the safety assessments and PD measures that 
comprise the primary and secondary endpoints. For these cohorts, participants will continue 
taking background medications exclusive of disopyramide. 
Patients enrolled in Cohort 3 will all be assigned to receive CK­3773274 and all patients must be 
taking disopyramide as a background medication. When used in conjunction with other Type 1A 
or 1C anti-arrhythmic drugs, disopyramide may produce negative inotropic effects. Although 
CK­3773274 has a different mechanism of action from anti-arrhythmic drugs, it selectively 
inhibits cardiac contractility and can lower LVEF. This cohort will assess the safety, tolerability 
and PK-PD effects of CK­3773274 in patients taking disopyramide. 
Cohort 4 will include patients with nHCM receiving background standard of care medical 
therapy. All subjects in Cohort 4 will be assigned to receive CK­3773274. This cohort will assess 
the safety, tolerability and PK-PD effects of CK­3773274 in patients with nHCM. 
4.3. 
Justification for Dose 
The doses of CK­3773274 are summarized in Table 7. A dose of 5 mg was chosen for the 
starting dose as this was found to be well-tolerated in healthy participants after achieving steady 
state PK. Within-patient escalation will only occur when the patient’s current dose is well-
tolerated, and the patient meets the escalation criteria described in Section 6.6. 
The dose escalation scheme in Cohort 1 is conservative. Both the initial dose (5 mg × 14 days) 
and the second dose (10 mg × 14 days) were well tolerated by healthy participants in CY 6011. 
The final dose in Cohort 1 will represent a 50% increase in dose (15 mg × 14 days) rather than a 
dose doubling, to mitigate the risk of excessive PD effect. 
In Cohort 3, background HCM medications must include disopyramide, a potential negative 
inotrope. The Cohort 3 starting dose of 5 mg of CK­3773274 was well-tolerated at steady-state 
PK in healthy participants in CY 6011 and in oHCM patients in CY 6021 Cohort 1. The dose 
escalation scheme for Cohort 3 is conservative and will follow the echocardiography-guided 
dose titration criteria described in Section 6.6. 
Cohort 4 will employ a starting dose of 5 mg of CK­3773274. Echocardiography-based dose 
titration will utilize LVEF alone as the metric for dose adjustment. The objective is to escalate 
the dose to a maximum of 15 mg daily if clinically tolerated and the LVEF remains ≥ 55%. The 
dose escalation scheme for Cohort 4 is also conservative and will follow the echocardiography-
guided dose titration criteria described in Section 6.6. 
4.4. 
End of Study Definition 
A patient is considered to have completed the study if he/she has completed all phases of the 
study including the End of Study (EOS) Visit. 
The end of the study is defined as the date of the last visit of the last patient in the study. 

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5. 
STUDY POPULATION 
Before patients begin any study-specific activities/procedures, Cytokinetics requires a copy of 
the site’s written 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. All patients must personally sign and date the ICF before commencement 
of study-specific activities/procedures. The patient may sign and date the ICF electronically if 
the investigator feels that it protects the safety of the patient and prior documented approval of 
the process is given by the Sponsor. 
A patient is considered enrolled when the patient has signed the ICF. The patient is considered 
randomized after meeting all eligibility criteria and is randomized in the IVRS/IWRS. 
Randomization should occur during the Day 1 visit. The investigator is to document the 
enrollment 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 exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria apply: 
101. 
Able to comprehend and willing to sign an ICF and willing to comply with all study 
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 at screening. 
103. 
Body weight is ≥45 kg at screening. 
104. 
Diagnosed with HCM per the following criteria: 
a. Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac 
disease. 
b. Has minimal wall thickness ≥15 mm (minimal wall thickness ≥13 mm is acceptable 
with a positive family history of HCM or with a known disease-causing gene 
mutation). 
105. 
Adequate acoustic windows for echocardiography. 
106. 
For Cohorts 1, 2, and 3 has LVOT-G during screening as follows: 
a. Resting gradient ≥50 mmHg 
OR 
b. Resting gradient ≥30 mmHg and <50 mmHg with post-Valsalva LVOT-G 
≥50 mmHg 
107. 
LVEF ≥60% at screening. 
108. 
New York Heart Association (NYHA) Class II or III at screening. 
109. 
Patients on beta-blockers, verapamil, diltiazem, or ranolazine should have been on 
stable doses for >4 weeks prior to randomization and anticipate remaining on the same 
medication regimen during the study. 

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110. 
Male patients are eligible to participate if they agree to the following during the study 
and for at least 10 weeks after the last dose of investigational product (IP): 
a. Refrain from donating sperm 
Plus either: 
b. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR 
Must agree to use a male condom and, when his female partner is a woman of 
childbearing potential, have his female partner use a highly effective method of 
contraception (as described in Appendix 4 [Section 10.4]) 
111. 
A female patient is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
a. Is not a woman of childbearing potential (WOCBP; as described in Appendix 4 
[Section 10.4]) 
OR 
Is a WOCBP and using a highly effective method of contraceptive (as described in 
Appendix 4 [Section 10.4]) during the study 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) within 3 days before the first dose of study intervention. 
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 4 (Section 10.4) and local regulations regarding the methods of 
contraception for those participating in clinical studies. 
112. 
Able to complete all screening procedures. 
113. 
Taking stable doses of disopyramide for >4 weeks prior to screening (Cohort 3 only). 
114. 
For Cohort 4 has resting and post-Valsalva LVOT-G < 30 mmHg at the time of 
screening. 
115. 
For Cohort 4 has elevated NT-proBNP > 300 pg/mL at the time of screening. 
5.2. 
Exclusion Criteria 
Patients will be excluded from the study if any of the following criteria apply: 
201. Aortic stenosis or fixed subaortic obstruction. 
202. Known infiltrative or storage disorder causing cardiac hypertrophy that mimics HCM 
(eg, Noonan syndrome, Fabry disease, amyloidosis). 
203. History of LV systolic dysfunction (LVEF <45%) at any time during their clinical 
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204. Documented history of current obstructive coronary artery disease (>70% stenosis in 
one or more epicardial coronary arteries) or documented history of myocardial 
infarction. 
205. Has been treated with septal reduction therapy (surgical myectomy or percutaneous 
alcohol septal ablation) or has plans for either treatment during the study period 
(Cohorts 1, 2, and 3 only). Patients having undergone septal reduction therapy 
> 12 months prior to screening who remain symptomatic from nHCM, and who meet 
all other criteria for inclusion, may be enrolled in Cohort 4. 
206. Prior treatment with cardiotoxic agents such as doxorubicin or similar. 
207. For Cohorts 1, 2, and 4: Has been treated with disopyramide or antiarrhythmic drugs 
that have negative inotropic activity within 4 weeks prior to screening. 
For Cohort 3: Has been treated with an antiarrhythmic drug other than disopyramide 
that has negative inotropic activity within 4 weeks prior to screening. 
208. Has any ECG abnormality considered by the investigator to pose a risk to patient 
safety (eg, second degree atrioventricular block type II). 
209. Paroxysmal atrial fibrillation or flutter documented during the screening period. 
210. Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment 
(eg, direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) 
≤6 months prior to screening. (This exclusion does not apply if atrial fibrillation has 
been treated with anticoagulation and adequately rate-controlled for >6 months.) 
211. History of syncope or sustained ventricular tachyarrhythmia with exercise within 
6 months prior to screening. 
212. ICD placement within 3 months prior to screening or planned ICD placement during 
the study. 
213. History of appropriate ICD shock for life-threatening ventricular arrhythmia within 
six months prior to screening. 
214. Recipient of a major organ transplant (eg, heart, lung, liver, bone marrow, renal) or 
anticipated transplantation within 12 months from randomization). 
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 disease, 
are permitted. 
216. 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 study 
evaluation, procedures, or completion. 
217. Hemoglobin <10.0 g/dL at screening. 
218. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (by the modified 
Modification of Diet in Renal Disease equation) at screening. 

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221. Currently participating in another investigational device or drug study 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 study are 
not permitted. 
222. Has received prior treatment with CK­3773274 or mavacamten. 
223. Has a known hypersensitivity to any excipients in CK­3773274 Tablets, Film-Coated. 
224. For Cohort 4: has any documented history of LVOT-G ≥ 30 mmHg at rest, with Valsalva, 
or with exercise (for subjects who have had prior septal reduction therapy, this exclusion 
criteria only applies to gradients detected following septal reduction therapy). 
5.3. 
Lifestyle Considerations 
Patients will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. 
5.4. 
Screen Failures 
For Cohorts 1 and 2, screen failures are defined as patients who consent to participate in the 
clinical study but are not subsequently randomized to IP. For Cohorts 3 and 4, screen failures are 
defined as patients who consent to participate in the clinical trial but are not assigned to 
CK­3773274. 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 study-related procedures. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 
5.5. 
Retesting 
Vital signs, hemoglobin, and liver function assessments may be repeated once during the 
screening period. The new results used to determine eligibility if all the following criteria are 
met: 
• The first screening value is inconsistent with the patient’s immediate prior medical 
history 
• In the investigator’s judgment, the results of the assessments in question are likely to 
be transient 
• Results of retesting can be evaluated for eligibility and the patient randomized within 
the allowed screening period 
If the patient meets LVEF and LVOT-G-based eligibility criteria per site evaluation of a 
screening echocardiogram, but the core laboratory deems acoustic windows inadequate, an 
echocardiogram may be repeated once during the screening period to ensure adequate acoustic 
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Further guidance and information for the final disposition of unused IP 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 patients in Cohorts 1 and 2 will be centrally assigned to randomized IP using an Interactive 
Voice/Web Response System (IVRS/IWRS). Patients in Cohort 3 will be assigned to receive 
only CK­3773274 by the IVRS/IWRS. Before the study is initiated, the log in information & 
directions for the IWRS will be provided to each site. 
An unblinded sonographer at the study site will perform the echocardiograms. An unblinded 
cardiologist, who is not the study investigator and is called the Echo Cardiologist, will read the 
echocardiograms, measure the LVOT-G and LVEF and enter the echocardiogram results in the 
IVRS/IWRS for dose titration adjustments. The investigator and study staff will be blinded to the 
echocardiograms and the results. Patients on placebo will also have dose titrations (both up and 
down) to maintain the blind. 
IP will be dispensed at the study visits summarized in the SoA (Section 1.3). Returned IP should 
not be re-dispensed to the patients. 
The IVRS/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 highly 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. 
6.4. 
Investigational Product Compliance and Administration 
6.4.1. 
IP 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 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. 
A record of the number of CK­3773274 tablets dispensed to and taken by each patient must be 
maintained and reconciled with IP and compliance records. IP dosing start and stop dates, 
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After 2 more weeks on the assigned dose (ie, Week 4), each patient will have an echocardiogram 
2 hours following administration of their dose of IP. Patients will escalate to the next higher dose 
if either of the following conditions are met on echocardiography: 
• Resting LVOT-G ≥30 mmHg and the biplane LVEF ≥50% 
OR 
• Resting LVOT-G <30 mmHg, post-Valsalva LVOT-G ≥50 mmHg, and the biplane 
LVEF ≥50% 
Otherwise, the patient will remain on the same dose. If LVEF is <50% at Week 4, the patient 
will be returned to a prior dose level or to placebo if the patient was on Dose 1. 
After 2 more weeks on the assigned dose (ie, Week 6), each patient will have an echocardiogram 
2 hours following administration of their dose of IP. If LVEF is <50% at Week 6, the patient will 
be down-titrated to a prior dose level or to placebo if the patient was on Dose 1. 
If at any time, a patient’s dose is down-titrated to placebo, then they will remain on placebo for 
the duration of the study. 
For Cohort 4 
Each patient will receive Dose 1 for 2 weeks. At Week 2, the patient will have an 
echocardiogram 2 hours following administration of their dose of IP. Patients will up-titrate to 
Dose 2 if LVEF ≥ 55% on the echocardiogram. If the LVEF is ≥ 50% but < 55% at Week 2, the 
patient will remain on Dose 1. If LVEF is <50% at Week 2, then IP will be discontinued. 
At Week 4, 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 LVEF ≥ 55% or remain on the 
same dose if the LVEF is ≥ 50% but < 55%. If LVEF is <50% at Week 4, the patient will be 
down-titrated to a prior dose level or IP will be discontinued if the patient was on Dose 1. 
At Week 6, each patient will have an echocardiogram 2 hours following administration of their 
dose of IP. Patients will remain on the same dose if the LVEF ≥ 50%. If LVEF is <50% at 
Week 6, the patient will be down-titrated to a prior dose level or IP will be discontinued if the 
patient was on Dose 1. 
6.6.2. 
Safety Considerations 
If the Echo Cardiologist notes echocardiographic findings that cross the defined safety threshold 
of LVEF <40% or feels the patient requires urgent medical attention, the Echo Cardiologist will 
discuss the results with the investigator or qualified designee. The Medical Monitor will be 
informed in these cases. 
If a patient’s LVEF is <40% at a scheduled echocardiogram visit (Week 2, Week 4, or Week 6), 
a repeat echocardiogram may be performed at the discretion of the investigator to confirm the 
initial finding (preferably within 24 hours of the original echocardiogram). If the 
echocardiography findings are confirmed, then the IP dose will be reduced to a prior tolerated 
dose level after at least a 2-day drug holiday and a local echocardiogram documenting an LVEF 
>50% and after approval from the Medical Monitor. Dosing may be discontinued at any time at 
the discretion of the investigator. 

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7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Investigational Product 
In rare instances, it may be necessary for a patient to permanently discontinue (definitively 
discontinue) IP. If IP is definitively discontinued, the patient should be encouraged to remain in 
the study and continue all safety assessments including AE collection, vital signs and laboratory 
assessments. See the SoA (Section 1.3) for data to be collected at the time of discontinuation of 
IP and follow-up and for any further evaluations that need to be completed. 
Reasons for removal from protocol-required IP or procedural assessments include any of the 
following: 
• withdrawal by patient 
• safety concern (eg, due to an AE, pregnancy) 
• death 
• lost to follow-up 
• decision by Cytokinetics (other than patient request, safety concern, lost to follow-up) 
If a clinically significant finding is identified after randomization, the investigator or qualified 
designee will determine if the patient can continue in the study and if any change in patient 
management is needed. Any new clinically relevant finding should be reported as an AE. 
7.1.1. 
Temporary Discontinuation 
Please see Section 6.6 for further information on temporary drug discontinuation. The 
investigator must consult with the Medical Monitor prior to restarting IP. If dosing is interrupted 
for more than 3 consecutive days in the first 6 weeks and more than 7 consecutive days 
thereafter, the patient may be discontinued from the study. That patient may be replaced after 
discussion with the Medical Monitor. 
7.1.2. 
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 (as 
described below) 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 6 (Section 10.6) for 
guidance on the assessment and management of abnormal hepatic laboratory values. 
7.2. 
Patient Discontinuation/Withdrawal from the Study 
Patients have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution. 
Patients can decline to continue receiving IP and/or other protocol-required therapies or 
procedures at any time during the study but continue participation in the study. If this occurs, the 

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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 study. Whenever safe and feasible it is imperative that patients 
remain on-study 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). 
Withdrawal of consent for follow-up should be accompanied by documentation of the reason for 
withdrawal. Withdrawal of consent for treatment should be distinguished from withdrawal of 
consent for follow-up visits and from withdrawal of consent for non-patient contact follow-up 
(eg, medical records checks). Patients requesting withdrawal should be informed that withdrawal 
of consent for follow-up will jeopardize the public health value of the study. 
Patients who withdraw 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 unavailable, the site should document and sign the reason 
for the patient’s failure to withdraw consent in writing. The ICF for the study should note that 
although a patient is free to leave the study 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 will review public 
records as permitted by applicable law to determine vital status of the patient at the end of the 
study or before. 
Reasons for removal of a patient from the study include: 
• decision by Cytokinetics 
• withdrawal of consent from study 
• death 
• lost to follow-up 
See Section 7.1 for additional reasons for removal of patient from the study. 
7.3. 
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 study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 

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schedule and ascertain whether the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient (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 
withdrawn from the study and are lost to follow-up. 
Discontinuation of specific sites or of the study are handled as part of Appendix 1 (Section 10.1). 

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8.2.2. 
Vital Signs 
Temperature, 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 after the 
patient has rested for at least 5 minutes in a quiet setting without distractions (eg, television, cell 
phones). 
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. 
8.2.3. 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained as outlined in the SoA (see 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 required, three individual ECG tracings should 
be obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes. 
Patients should be sitting or supine prior to the ECG for at least 5 minutes. The investigator may 
perform additional ECG recordings as needed for the care of the patient. 
A patient will be withdrawn from the study by the PI or designee if, in their medical judgment, 
ECG findings are present which make continued study 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 or echocardiogram results as determined by the investigator or the Medical 
Monitor. 
All ECG tracings will be kept as part of the patient’s permanent study file at the study site. 
Digital recordings will be analyzed and stored at a central ECG laboratory. 
8.2.4. 
Ambulatory Cardiac Monitoring 
During the week prior to the first dose and the week prior to the last dose of IP, patients will 
wear an ambulatory cardiac monitoring device. Patients will be provided the device at screening 
and will wear it for at least five but no more than 7 days prior to first dose and at least 5 days 
prior to the last dose. Patients will return the device at the visit after completion of wear period. 
Data from the monitoring device will be read by a central reader and will be made available to 
Cytokinetics on a regular basis. 
8.2.5. 
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. 

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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. Clinically 
significant abnormal laboratory findings are those which are not associated with the underlying 
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). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
significant by the investigator (eg, SAE or AE or result in a dose modification), then the results 
must be recorded in the CRF. 
8.3. 
Adverse Events and Serious Adverse Events 
8.3.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical trial patient. The event does 
not necessarily have a causal relationship with study treatment. The investigator is responsible 
for ensuring that any AE observed by the investigator or reported by the patient are recorded in 
the patient’s medical record. 
The definition of an AE includes worsening of a pre-existing medical condition. Worsening 
indicates that the pre-existing medical condition or underlying disease (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration more than would be 
expected, and/or has an association with a significantly worse outcome than expected. A pre-
existing condition that has not worsened more than anticipated (i.e., more than usual fluctuation 
of disease) during the study or involves an intervention such as elective cosmetic surgery or a 
medical procedure while on study, is not considered an AE. 
If the severity of an AE changes from the date of onset to the date of resolution, record as a 
single event with the worst severity on the AE CRF. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative). 
In addition, the investigator and any qualified designees are responsible for detecting, 
documenting, and recording events that meet the definition of an AE or SAE and remain 
responsible for following up all SAEs to resolution or determined to be clinically stable. 
8.3.2. 
Serious Adverse Events 
An SAE is defined as an AE that meets at least one of the following regulatory criteria: 
• fatal 
• immediately life-threatening (places the patient at immediate risk of death) 
• requires hospitalization or prolongation of existing hospitalization 
• results in persistent disability/incapacity 

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• congenital anomaly/birth defect 
• other medically important serious event 
An AE would meet the criterion of “requires hospitalization” if the event necessitated an 
admission to a health care facility (eg, overnight stay). 
If an investigator considers an event to be clinically important, but it does not meet any of the 
serious criteria, the event could be classified as an SAE under the criterion of “other medically 
important serious event”. Examples of such events could include allergic bronchospasm, 
convulsions, blood dyscrasias, drug-induced liver injury (DILI) or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention. 
8.3.3. 
Time Period and Frequency for Collecting AE and SAE Information 
The investigator is responsible for ensuring that all AEs observed by the investigator or reported 
by the patient that occur after initiation of IP through 4 weeks following the last dose of IP. AEs 
must be recorded in the AE CRF. SAEs are reported to Cytokinetics from the time of signing of 
the ICF through 4 weeks following the last dose of IP, as noted in Section 8.3.6. 
All AEs considered related to study procedures and all SAEs that occur during the screening 
period (after signing of the ICF until initiation of IP) are also reported in the CRF. 
Medical occurrences that are not associated with study 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. 
All SAEs must both be reported to Cytokinetics and recorded in the AE CRF, as indicated in 
Appendix 3 (Section 10.3). The investigator will submit any SAE or updated SAE information to 
Cytokinetics within 24 hours of awareness. 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of the study 
participation (ie, more than 4 weeks following the last dose of IP). However, if the investigator 
learns of any SAE, including a death, at any time after a patient has been discharged from the 
study, and he/she considers the event to be reasonably related to the IP or study participation, the 
investigator must promptly notify Cytokinetics. 
8.3.4. 
Method of Detecting AEs and SAEs 
The method of recording and assessing AEs and SAEs and the procedures for completing and 
transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.5. 
Follow-up of AEs and SAEs 
The investigator is required to proactively ensure each AE is followed to resolution, stabilization, 
or the EOS, whichever comes first. SAEs are followed to resolution or stabilization and reporting 
may continue after the EOS and database lock. Further information on follow-up procedures is 
provided in Appendix 3 (Section 10.3). 

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8.3.6. 
Regulatory Reporting Requirements 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 signing of the ICF through 4 weeks following the last 
dose of IP are reported to Cytokinetics immediately and no later than 24 hours following the 
investigator’s knowledge of the event. 
To report an SAE: 
Email: 
DrugSafety@cytokinetics.com 
Facsimile: +1 (650) 243-4199 
Cytokinetics has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IP under clinical investigation. Cytokinetics will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
The reference safety document to assess expectedness of a suspect serious adverse reaction and 
reported by the sponsor to Health Authorities, IRBs/IECs, and investigators is the reference safety 
information section of the Investigator’s Brochure [CK­3773274 IB]. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Cytokinetics policy and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from Cytokinetics will review and will 
notify the IRB/IEC, if appropriate according to local requirements. 
8.3.7. 
Pregnancy 
If a woman becomes pregnant while on IP, the IP must be discontinued. The Principal 
Investigator or designee must counsel the patient and discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus. 
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. 
If a pregnancy is reported, the investigator should inform Cytokinetics within 24 hours of 
learning of the pregnancy on the Pregnancy Report Form to DrugSafety@cytokinetics.com, as 
per the procedures outlined in Appendix 4 (Section 10.4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.8. 
Female Patients Who Breastfeed 
If a female patient breastfeeds while on study drug, study drug will be discontinued. 

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The Principal Investigator or designee will collect breastfeeding information on any female 
patient who breastfeeds while taking the study drug 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 
Principal Investigator’s or designee’s knowledge of event. 
8.4. 
Treatment of Overdose 
For this study, 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. The use of rescue medications to treat a low 
cardiac output state is recommended if necessary. 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: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the patient for any AEs/SAEs and laboratory abnormalities. 
3. Obtain a plasma sample for PK analysis as soon as practical and note the date of the last 
dose of IP. 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
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. 
8.5. 
Pharmacokinetics 
Blood samples of approximately 4 mL will be collected for measurement of plasma 
concentrations of CK­3773274 as specified in the SoA (Section 1.3). Samples will be used to 
evaluate the PK of CK­3773274 and its metabolites. Instructions for the collection and handling 
of biological samples will be provided in the study 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 10 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 
study will not be reported to investigative sites or blinded personnel until the study has been 
unblinded. 

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Table 10: 
Summary of PK and Echocardiography Time Points 
Visit 
PK Time Pointa 
Echocardiography 
Time Point 
Type of 
Echocardiogram 
Screening 
NA 
No specific time requirement 
Full protocol 
Day 1 
Pre-dose and 1 hour 
Pre-dose 
Full protocol 
Week 2 
Pre-dose, 0.5, 1 and 
2 hours post-dose 
2-2.5 hours post dose 
Truncated protocol 
Week 4 
Pre-dose, 0.5, 1 and 
2 hours post-dose 
2-2.5 hours post dose 
Truncated protocol 
Week 6 
Pre-dose, 0.5, 1 and 
2 hours post-dose 
2-2.5 hours post dose 
Truncated protocol 
Week 10 
Pre-dose, 0.5, 1 and 
2 hours post-dose 
2-2.5 hours post dose 
Full protocol 
Week 12 (EOS) 
Untimed PK at visit 
No specific time requirement 
Full protocol 
Early Discontinuation 
Untimed PK at visit 
No specific time requirement 
Full protocol 
NA = not applicable 
a When PK collection and an echocardiogram are scheduled for the same time point, PK collection should be 
completed prior to the echocardiogram. 
8.6. 
Pharmacodynamics 
Echocardiography is the main assessment modality of the PD of CK­3773274. Please see 
Section 8.1.1 for description of the echocardiographic procedures. 
8.7. 
Genetics 
As HCM is a genetic disease, a blood sample will be collected for analysis through the use of 
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, drug metabolism, susceptibility to developing AEs, or to increase 
the knowledge and understanding of cardiovascular, muscle and disease biology. 
See Appendix 5 (Section 10.5) 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. 
Biomarkers 
No long-term banking of blood for biomarkers will be done in this study. 
8.9. 
Immunogenicity Assessments 
No immunogenicity assessments will be done for this study. 

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8.10. 
Medical Resource Utilization and Health Economics 
No medical resource utilization or health economic assessments will be done for this study. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
This is the first study of CK­3773274 in patients with HCM and the analyses of dose, PK, and 
PD, and their relationships are descriptive and hypothesis-generating in nature. The analyses 
evaluating treatment effect on secondary and exploratory endpoints relating to change from 
baseline to Week 10 will test the null hypothesis that there is no treatment difference in change 
from baseline between patients receiving placebo and those receiving CK­3773274. The analyses 
may be repeated by cohort or in data combined across cohorts. There will be no adjustments for 
multiplicity. 
9.2. 
Sample Size Determination 
Approximately 18 eligible patients per cohort will be randomly assigned to once daily 
CK­3773274 or placebo in a 2:1 ratio in Cohorts 1 and 2; approximately 8-12 patients will be 
assigned to receive CK­3773274 in Cohort 3. Approximately 15 evaluable patients per cohort in 
Cohorts 1 and 2 will yield approximately 30 evaluable patients in the CK­3773274 group and 
15 evaluable patients in the placebo group. Approximately 8-12 patients assigned to 
CK­3773274 in Cohort 3 will yield at least 6 evaluable patients receiving CK­3773274. 
Approximately 30-40 patients will be assigned to CK­3773274 in Cohort 4. Evaluable patients in 
this study are those who received at least one dose of IP, CK­3773274 or placebo, and have at 
least one post-dose evaluation as further described in Section 9.3. 
The sample size was not chosen based on statistical considerations. Randomizing approximately 
18 patients per cohort is considered adequate for the initial evaluation of safety and tolerability 
of CK­3773274 in this population. Enrolling at least 8 patients in Cohort 3 is considered 
adequate for the initial evaluation of safety and tolerability of CK­3773274 in patients receiving 
disopyramide. Enrolling 30-40 in Cohort 4 is considered adequate for the initial evaluation of 
safety and tolerability of CK­3773274 in patients with nHCM. 
9.3. 
Populations for Analyses 
The analysis populations are defined in Table 11. 
Table 11: 
Analysis Sets 
Analysis Set 
Description 
Enrolled  
All patients who signed the ICF. 
All Randomized or 
Assigned CK­3773274 
Set 
Patients randomly assigned to once daily CK­3773274 or placebo in 2:1 ratio 
in Cohorts 1 and 2 and all patients assigned to receive CK­3773274 in 
Cohort 3 
Safety Analysis Set 
All patients who received at least one dose of IP, CK­3773274 or placebo. 
Patients will be grouped according to the maximum actual dose of IP 
received. 
Pharmacokinetics 
Analysis Set (PKS) 
All patients who have at least one measurable plasma concentration of 
CK­3773274, provided they have no major protocol violations deviations that 
could affect the PK of CK­3773274. 

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Table 11: 
Analysis Sets (Continued) 
Analysis Set 
Description 
Pharmacodynamics 
Analysis Set (PDS) 
All patients who received any amount of IP and have a baseline and at least 
one post-baseline echocardiography assessment during the double-blind 
treatment period. Patients will be grouped according to their actual treatment, 
CK­3773274 or placebo. 
9.4. 
Statistical Analyses 
The Statistical Analysis Plan 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 
Data will be analyzed by study part separately within each cohort. Select analyses and 
summaries will combine the data across the cohorts. Summary statistics for continuous variables 
will include numbers of patients, means, medians, standard deviations, minima, and maxima. For 
categorical variables, frequencies and percentages will be reported. 
Assumptions for statistical models will be evaluated. If assumptions are substantially violated, 
alternative analysis methods will be considered. Missing data will not be imputed unless 
specified. 
Baseline will be defined as the last available measurement taken before the first dose of IP unless 
otherwise specified. Patients will be grouped according to the initial treatment received, 
CK­3773274 or placebo, and, in general, any patients who receive any amount of CK­3773274 
or placebo will be included in the analyses. 
Statistical hypotheses will be tested at the nominal 10% two-sided significance level. When 
applicable, 90% confidence intervals will be presented, unless otherwise specified. 
9.4.2. 
Safety Endpoints 
9.4.2.1. 
Primary Safety Endpoints 
The primary endpoints of the study are: 
• Patient incidence of reported AEs from first dose of IP up to safety follow-up 
• Patient incidence of reported SAEs from first dose of IP up to safety follow-up 
• Patient incidence of LVEF <50% from first dose of IP up to safety follow-up. 
The safety follow-up is defined as 4 weeks following the last dose of IP. 

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9.4.6. 
Patient Disposition 
The number of patients who are randomized (Cohorts 1 and 2) or assigned to CK­3773274 
(Cohorts 3 and 4), 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 within 
each cohort. Reasons for premature discontinuation as recorded on the termination page of the 
CRF will be summarized. 
9.4.7. 
Demographics and Other Baseline Characteristics 
Patient demographics and other baseline characteristics will be summarized descriptively by 
cohort, treatment and/or dose. 
9.4.8. 
Investigational Product Exposure 
IP exposure will be summarized, including the number of doses administered at each dose level, 
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. 
9.4.9. 
Safety Analysis 
Safety analyses will be performed on safety analysis set. Patients will be grouped according to 
the maximum actual dose of IP received. Select safety summaries may be produced by the 
titration sequence within the subset of patients randomized or assigned to CK­3773274. 
9.4.9.1. 
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 preferred terms and grouped by 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 the follow up visit will be 
summarized. All AEs will be included in patient listings. 
9.4.9.2. 
Serious Adverse Events 
Summaries of SAEs (by preferred term and system organ class) and SAE severity will be 
presented. 
9.4.9.3. 
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. 
9.4.9.4. 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values and changes from baseline at each protocol 
specified assessment time point will be presented. 

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9.4.9.5. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline at each protocol specified 
assessment time point will be presented. 
9.4.9.6. 
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. 
9.4.10. 
Pharmacokinetic Analysis 
Descriptive statistics including mean, standard deviation, geometric mean, coefficient of 
variation, median, and range will be provided for the plasma concentrations. Individual or 
geometric mean concentrations over time will be graphically displayed. 
The effect of background disopyramide on PK plasma concentrations will be assessed by 
ANOVA models including the data from Cohorts 1and 2 subjects randomized to CK­3773274 
and from Cohort 3 subjects assigned to CK­3773274. The models will be fit for natural log 
transformed plasma concentrations: Day 1 (1 hour post-dose), Ctrough, and Cmax. 
9.4.11. 
Echocardiography Analysis 
The slope of the relationship of the plasma concentrations of CK­3773274 on select 
echocardiographic variables, including resting or post-Valsalva LVOT-G, will be evaluated 
using a mixed-effect repeated measures model for all planned measurements. The model will 
include terms for the baseline value and time-matched value of the plasma concentration of 
CK­3773274. A random intercept will be assumed in the model. The plasma concentrations may 
be logarithmically transformed prior to the analysis. The analyses may be performed by Cohort 
and/or in Cohorts 1 and 2 combined. 
The effect of CK­3773274 dose on echocardiographic variables will be similarly evaluated 
including the dose as a continuous variable rather than plasma concentration in the analysis. This 
analysis will include all PDS patients treated with CK­3773274. 
The treatment effect on secondary and exploratory endpoints relating to change from baseline to 
Week 10 will be evaluated in PDS, Cohorts 1 and 2 only, using analysis of covariance for 
continuous variables (with terms for treatment and baseline value) and logistic regression for 
categorical or binary data by cohort. The analyses will test the null hypothesis that there is no 
treatment difference in change from baseline to Week 10 between patients receiving placebo and 
those receiving CK­3773274 by cohort. The analyses may be repeated with data combined across 
Cohorts 1 and 2, in which case the cohort may be used as the stratification factor. 
The effect of the PK of CK­3773274 on select echocardiographic variables will be evaluated 
using a concentration bin analysis of variance in PDS, Cohorts 1 and 2 only. Plasma 
concentration bin as a categorical variable will be used in the analysis. The analyses may be 
performed by Cohort and/or in Cohorts 1 and 2 combined. 

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The effect of CK­3773274 dose on echocardiographic variables will also be evaluated including 
the dose as a continuous variable in the analysis. 
Secondary and exploratory endpoints related to change from baseline in patients receiving 
disopyramide (Cohort 3) and patients in Cohort 4 will be evaluated using descriptive summaries. 
The effect of background disopyramide therapy on pharmacodynamic response over time 
through Week 10 will be assessed by ANCOVA models for change from baseline in LVOT-G at 
rest, LVOT-G post-Valsalva, and LVEF, including the data from Cohort 1 subjects randomized 
to CK­3773274 and from Cohort 3 subjects assigned to CK­3773274. The models will include 
terms for baseline and Cohort. 
For the PD parameters with statistical distributions likely to depart from normal, the values may 
be log transformed prior to the analysis. The analysis results will be back-transformed and 
reported in terms of proportional change from baseline. 
Both exploratory graphical and model-based PK-PD analyses may be conducted with select PD 
endpoints. A detailed description of these analyses will be presented in the Statistical Analysis 
Plan. 
9.4.12. 
Health Status and Health-related Quality of Life Analysis 
The slope of change from baseline to Week 10 in Health Status and Health-related Quality of 
Life endpoints will be evaluated using a mixed-effect repeated measures model in the US 
subjects randomized to Cohort 2. The treatment effect on change from baseline to Week 10 will 
be evaluated using analysis of covariance. 
Change from baseline in patients assigned to CK­3773274 in Cohort 3 and Cohort 4 will be 
evaluated using descriptive summaries. 
Individual responses to the HCM Global Impression of Status and Global Impression of Change 
questionnaires will be summarized categorically. 
Further details of the analyses will be provided in the Statistical Analysis Plan. 
9.5. 
Interim Analyses 
Both blinded and unblinded interim analyses of the available safety, echocardiography, and PK 
data will be performed at the discretion of the Sponsor, with the PK data de-identified for the 
blinded analysis. Due to the exploratory nature of the study, there are no formal efficacy or 
futility stopping rules and the analyses will be descriptive in nature. The analyses will be 
described in the Interim Analysis Plan. 
Representatives of Cytokinetics and the SC will review the blinded analysis results and 
recommend the dose levels of CK­3773274 to be administered in the next cohort. The DMC will 
review the unblinded analysis results, as described in Section 9.6. The timing of the interim 
review or the criteria for dose selection are not driven by statistical considerations. An interim 
analysis of Cohort 1 data will occur after at least 10 randomized patients have completed Week 6 
visit and when the PK and echocardiography data from those visits are available. Including 
10 randomized patients ensures that at least 6 patients randomized to CK­3773274 have been up-
titrated to their maximum individual dose level and provided safety, PK, and PD data after two 
weeks a that dose level (ie, once steady-state PK has been reached). 

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Additional interim data analyses may also be conducted to facilitate planning future 
development. 
9.6. 
Data Monitoring Committee 
An unblinded DMC will review the dose level recommendations along with the unblinded 
analysis results, prior to initiating Cohort 2. The DMC may either endorse the recommendation 
or suggest a change in study conduct, including alteration of planned dosing regimen. 
For details on the DMC, refer to Appendix 1 (Section 10.1). 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (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 study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study 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 study 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 study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 

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Patients must be informed that their participation is voluntary. Patients will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
Patients who are rescreened are required to sign a new ICF. 
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 study-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 study organization will include an SC and DMC. 
The SC will contribute to study design, implementation, data analysis, and communication of 
study results and will consist of experts external to Cytokinetics who are qualified by their 
medical and scientific expertise and experience, one of the study investigators, and a 
Cytokinetics representative. The responsibilities of the SC will be described in a SC charter. 
The DMC will be established in order to review the SC recommendations regarding the cohort 
dose levels. The DMC will also be responsible for periodic review of study data to ensure the 
safety of study patients, and for review of SAEs on an ongoing basis. 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) study team involved in study conduct. The DMC members will 
have access to treatment assignments and patient level data from the clinical trial database. DMC 
membership, responsibilities, relationship with Cytokinetics and the CRO, and the purpose and 
timing of the meetings will be further described in the DMC charter. 

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10.1.6. 
Data Quality Assurance 
All patient data relating to the study 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 study-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 study including quality 
checking of the data. 
Cytokinetics assumes accountability for actions delegated to other individuals (eg, CROs). 
Study 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 study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator until at least 2 years after the last approval of a marketing application 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the IP. The study site should plan on retaining such documents for 
approximately 25 years after study completion unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention period 
without the written approval of Cytokinetics. No records may be transferred to another location 
or party without written 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 study. Also, 
current medical records must be available. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 

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The first act of recruitment is the first site open. 
Cytokinetics or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of Cytokinetics. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-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 study 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 study is prematurely terminated or suspended, Cytokinetics shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study 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 12 will be performed by the central laboratory. 
Local laboratory results are not required for dosing decisions and/or response evaluation; they 
are only expected for urgent evaluation where same-day results are required for patient 
management. If a local sample is required, it is important that the sample for central analysis is 
obtained at the same time. Information regarding use of local laboratories (date/time of draw and 
results) should be kept with the patient source documentation. 
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 study as determined necessary by the 
investigator or required by local regulations. 
Table 12: 
Protocol-Required Safety Laboratory Assessments 
Chemistry 
Urinalysis 
Hematology 
Other Assessments 
Sodium 
Total bilirubin 
Specific gravity 
Hemoglobin 
CK­3773274 plasma 
concentration (PK) 
Potassium 
Direct bilirubin 
pH 
Hematocrit 
Chloride 
CK 
Blood 
RBC 
Pregnancy testa 
Calcium 
ALP 
Protein 
RDW 
FSHa 
Magnesium 
LDH 
Glucose 
MCV 
NT-proBNP 
Phosphorus 
AST (SGOT) 
Bilirubin 
MCH 
hs-cTnI  
Urea 
ALT (SGPT) 
 
MCHC 
 
Creatinine 
 
 
WBC 
 
 
 
 
Platelets 
 
 
 
 
INR 
 
ALP = alkaline phosphatase; CK = creatine kinase; FSH = follicle-stimulating hormone; hs-cTnI = high sensitivity 
cardiac troponin I; INR = international normalized ratio; 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; RBC = red blood cell; RDW = red cell distributions width; 
SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; WBC = white 
blood cell 
a A pregnancy test is required for WOCBP; FSH only at screening if needed. 
Investigators must document their review of each laboratory report. 
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 

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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of Adverse Event 
AE Definition 
An AE is defined as any untoward medical occurrence in a clinical study patient. The event does 
not necessarily have a causal relationship with IP. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after IP administration even though it may 
have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 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. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE. 
• SAEs occurring before initiation of IP and assessed as related to study procedures 
must be recorded on the AE CRF. 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 

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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
10.3.2. 
Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
• The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
patient was at immediate risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
4. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should 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 

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convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording/Reporting 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF and 
report SAEs within 24 hours of awareness to Cytokinetics. 
• It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to Cytokinetics in lieu of completion of the AE/SAE CRF. 
• There may be instances when copies of medical records for certain cases are 
requested by Cytokinetics. In this case, all patient identifiers, except the patient 
number, will be redacted on the copies of the medical records before submission to 
Cytokinetics. 
The investigator will 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. 
Assessment of Intensity 
• The investigator will assess the intensity for each AE and SAE reported during the 
study and assign it to one of the following categories: 
− Mild: An event that is easily tolerated by the patient, causing minimal discomfort 
and not interfering with everyday activities. 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities 
− Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least one of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between IP and each 
occurrence of each AE/SAE. 
• 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. 

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• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to 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. 
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 study or during a recognized follow-up 
period, the investigator will provide Cytokinetics with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to Cytokinetics within 24 hours of 
receipt of the information. 
10.3.4. 
Reporting of SAEs 
SAE Reporting to Cytokinetics via Paper Form 
• Facsimile or email transmission of the SAE paper CRF is the preferred method to 
transmit this information to Cytokinetics. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
To report an SAE: 
Email: 
DrugSafety@cytokinetics.com 
Facsimile: +1 (650) 243-4199 

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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
 
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 study 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 study. Otherwise, they must discontinue hormone replacement therapy to 
allow confirmation of postmenopausal status before study 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 study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study 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 hormonal 
contraception is used as a highly effective method of birth control, 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 study 
patient. 
Collection of Pregnancy Information: 
Pregnancies must be recorded in the eCRF and reported on the Cytokinetics Pregnancy Report 
Form, which is to be emailed or faxed to Cytokinetics Drug Safety (contact details are provided 
on the Pregnancy Report Form): 

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Email: 
DrugSafety@cytokinetics.com 
Facsimile: +1 (650) 243-4199 
Note: Sites are not required to provide any information on the Pregnancy Report Form that 
violates the country or region’s local privacy laws. 
While pregnancy itself is not considered to be an AE or SAE, it is reportable within 24 hours of 
investigator awareness. Any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an AE or SAE. 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
Any post-study pregnancy-related SAE considered reasonably related to the IP by the 
investigator will be reported to Cytokinetics as described in Section 8.3.6. While the investigator 
is not obligated to actively seek this information in former study patients, he or she may learn of 
an SAE through spontaneous reporting. 
Pregnancies will be followed until their conclusion. 
Male Patients with Partners Who Become Pregnant 
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 study. This applies only to male 
patients who receive IP. 
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. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Patients Who Become Pregnant 
The investigator will collect pregnancy information on any female patient who becomes pregnant 
while participating in this study. The initial information will be recorded on the Pregnancy 
Report Form and submitted to Cytokinetics as per Section 8.3.6 within 24 hours of learning of a 
patient’s pregnancy. 
The patient will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on the patient and the neonate and forward to Cytokinetics on a 
Pregnancy Report Form. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. The follow-up of an infant (if applicable) will be conducted 
up to 12 months after the birth of the child. 
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Any female patient who becomes pregnant while participating in the study will discontinue IP or 
be withdrawn from the study. 

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10.5. 
Appendix 5: 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 be part of this study. 
DNA samples will be used for research related to this study 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 study 
summary. 
Cytokinetics will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 

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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Drug-induced Liver Injury Reporting & Additional Assessments 
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases of 
concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and total 
bilirubin (TBL) and/or international normalized ratio (INR) elevation according to the criteria 
specified in Section 7.1.2 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 Appendix 3 (Section 10.3). 
Criteria for Permanent Discontinuation of Investigational Product and Other Protocol-
required Therapies due to Potential Hepatotoxicity 
CK­3773274 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 

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− heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− alpha-one antitrypsin deficiency 
− alcoholic hepatitis 
− autoimmune hepatitis 
− Wilson’s disease and hemochromatosis 
− nonalcoholic fatty liver disease including steatohepatitis 
− nonhepatic causes (eg, rhabdomyolysis, hemolysis) 
Criteria for Conditional Withholding 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 withholding 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. 

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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. 
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 return to normal or 
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 is to 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 

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• Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
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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10.7. 
Appendix 7: Abbreviations 
Table 13: 
List of Abbreviations 
Abbreviation/Term 
Explanation 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
Cmax 
Maximum plasma concentration observed 
Ctrough 
Trough plasma concentration observed 
CRF 
Case report form 
CRO 
Contract research organization 
CYP 
Cytochrome P450 
DILI 
Drug induced liver injury 
DMC 
Data monitoring committee 
ECG 
Electrocardiogra(m/phy) 
EOS 
End of study 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HCM 
Hypertrophic cardiomyopathy 
ICD 
Implantable cardioverter defibrillators 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
IVRS/IWRS 
Interactive voice/web response system 
LV 
Left ventricle(ular) 
LVEF 
Left ventricular ejection fraction 
LVFS 
Left ventricular fractional shortening 
LVOT 
Left ventricular outflow tract 
LVOT-G 
Left ventricular outflow tract gradient 

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Abbreviation/Term 
Explanation 
HCM 
Hypertrophic cardiomyopathy 
MAD 
Multiple ascending dose 
nHCM 
Non-obstructive hypertrophic cardiomyopathy 
NOAEL 
No-observed-adverse-effect-level 
NYHA 
New York Heart Association 
oHCM 
Obstructive hypertrophic cardiomyopathy 
PD 
Pharmacodynamics 
PDS 
Pharmacodynamics analysis set 
PK 
Pharmacokinetics 
RBC 
Red blood cell 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SC 
Steering Committee 
SoA 
Schedule of activities 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
WOCBP 
Women of childbearing potential 

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10.8. 
Appendix 8: 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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11.
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