Conditions: Obstructive Hypertrophic Cardiomyopathy
Keywords: Symptomatic, left ventricular outflow tract gradient
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 251
Healthy volunteers: no

Brief summary:
This is a multicenter, international, double-blind study of the administration of mavacamten in participants with symptomatic obstructive HCM (oHCM). Approximately 220 participants will be randomized to receive placebo or mavacamten.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: mavacamten intervention 2: Placebo
Intervention descriptions: intervention 1: mavacamten capsules intervention 2: placebo oral capsule

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor Name 
MyoKardia, A Bristol Myers Squibb Company 
NCT Number 
NCT03470545 
Sponsor Trial ID 
MYK-461-005 
Official Study Title 
A Randomized, Double-blind, Placebo-controlled 
Clinical Study to Evaluate Mavacamten (MYK-
461) in Adults With Symptomatic Obstructive 
Hypertrophic Cardiomyopathy 
Document Date 
04 October 2019 
 


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CLINICAL STUDY PROTOCOL 
Protocol Number: 
MYK-461-005 (EXPLORER-HCM) 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled Clinical Study to 
Evaluate Mavacamten (MYK-461) in Adults with Symptomatic 
Obstructive Hypertrophic Cardiomyopathy 
Indication: 
Hypertrophic Cardiomyopathy 
Phase: 
3 
Investigational 
Medicinal Product: 
Mavacamten (MYK-461) or matching placebo 
Sponsor: 
MyoKardia, Inc. 
 
 
IND Number: 
121904 
EudraCT Number: 
2017-002530-23 
US Coordinating 
Investigator: 
Stephen Heitner, MD 
Oregon Health & Science University 
Portland, Oregon, USA 
EU Coordinating 
Investigator: 
Iacopo Olivotto, MD 
Careggi University Hospital 
Florence, Italy 
Key Sponsor Contacts: 
Hilary Nelson 
Director, Clinical Operations 
 
 
Amy Sehnert, MD 
Medical Monitor 
 
 
Original Protocol Date: 
14 July 2017 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Amendment 5: 
09 August 2017 
25 January 2018 
21 March 2018 
13 November 2018 
04 October 2019 
Confidentiality Statement 
This document contains trade secrets or otherwise confidential and/or proprietary information of 
MyoKardia, Inc. Access to and use of this information is strictly limited and controlled by 
MyoKardia, Inc. Acceptance of this document constitutes agreement by the recipient that the contents 
will be not be copied, distributed, or otherwise disclosed to third parties, and will not be used in any 
way, except as expressly authorized by MyoKardia, Inc. 


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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES TABLE 
Protocol Amendment 5: 04 October 2019 
This amendment is considered nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
 
 
 
 
 
 
  
Section(s) 
Summary of Change 
Reason(s) for Change 
Title Page 
 Hilary Nelson 
 Director, Clinical 
Operations 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Synopsis 
Secondary Efficacy 
Endpoints 
 
and 
 
Section 12.2.2 
Secondary Efficacy 
Endpoints 
• 
Change from baseline to Week 
30 in post-exercise LVOT peak 
gradient 
• 
 Proportion of 
participants with at least 
1 class improvement in NYHA 
functional class from baseline 
to Week 30 
 
 
• 
Change from baseline to Week 
30 in (pVO2) as determined by 
CPET 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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Section(s) 
Summary of Change 
Reason(s) for Change 
 
 
 
 
 
 
 
 
 
• 
Change from baseline to 
Week 30 in participant-
reported health-related 
quality of life as assessed by 
the KCCQ score 
• 
Change from baseline to Week 
30 in patient-reported severity 
of HCM symptoms as assessed 
by the HCM Symptom 
Questionnaire score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 


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Section(s) 
Summary of Change 
Reason(s) for Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Synopsis 
Sample Size and Statistical 
Analysis 
and 
 
 
 
 
Analyses for echocardiographic 
indices of cardiac structure as 
well as systolic and diastolic 
ventricular function, and 
accelerometer parameters, 
 and HCM risk 
prediction model will be 
specified in the SAP. 
 
 
 
Section 4 
Description of Other 
Procedures and Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section(s) 
Summary of Change 
Reason(s) for Change 
Section 9.1.4.6 
HCM Risk Prediction Model 
Text was added to describe the 
HCM Risk Prediction Model that 
was included as an exploratory 
endpoint 
 
Section 9.2.4 
Hs-Cardiac Troponin-I 
Text was added to describe 
assessment for hs-cardiac 
troponin-I 
 
 
 
Section 11.1.1.1 
Events Not Meeting the 
Definition of Adverse Event 
Text was added to clarify what 
does not meet the definition of 
an adverse event 
  
 
 


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PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-blind, Placebo-controlled Clinical Study to 
Evaluate Mavacamten (MYK-461) in Adults with Symptomatic 
Obstructive Hypertrophic Cardiomyopathy 
Study Number 
MYK-461-005 (EXPLORER-HCM) 
Study Phase 
3 
Number of Centers 
~90 sites worldwide 
Primary Objective 
• 
To compare the effect of a 30-week course of mavacamten with 
placebo on clinical response comprising of exercise capacity and 
clinical symptoms in participants with symptomatic obstructive 
hypertrophic cardiomyopathy (oHCM) 
Secondary Objectives 
• 
To compare the effect of a 30-week course of mavacamten with 
placebo on symptoms and left ventricular outflow tract (LVOT) 
obstruction as determined by Doppler echocardiography 
• 
To compare the effect of a 30-week course of mavacamten with 
placebo on exercise capacity, clinical symptoms and Patient 
Reported Outcomes individually 
• 
To assess the safety and tolerability of mavacamten 
• 
To assess the pharmacokinetic (PK) characteristics of mavacamten 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design 
This is a Phase 3, double-blind, randomized, placebo-controlled, 
multicenter, international, parallel-group study to evaluate the safety, 
tolerability, and efficacy of mavacamten compared with placebo (1:1) 
in participants with symptomatic oHCM. Approximately 
220 participants will be enrolled. This includes ~80 participants 
(~40 per treatment group) who consent to participate in a CMR 
substudy at selected sites. Randomization will be stratified according 
to New York Heart Association (NYHA) functional classification 
(II or III), current treatment with β-blocker (yes or no), planned type of 
ergometer used during the study (treadmill or exercise bicycle), and 
consent for the CMR substudy (yes or no). The study will comprise 
3 periods as follows: 
Screening period (Day -35 to Day -1): Participants will undergo a 
variety of general, cardiopulmonary, laboratory, symptom, and PRO 
assessments over 1 to 2 days in order to assess eligibility (see Table 1 


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and Table 2). Key Screening tests include electrocardiogram (ECG); 
transthoracic echocardiography (TTE) conducted at rest, with Valsalva 
maneuver, and post-exercise; as well as cardiopulmonary exercise 
testing (CPET). The following screening assessments may be repeated, 
as long as within the 35-days screening window: blood tests, ECG, 
and/or TTE. Repeat assessments are allowed if central core labs 
require a repeat submission due to quality and in order to better assess 
inclusion/exclusion values. Participants who screen fail may be 
considered for rescreening based on the investigator’s discretion, 
taking into consideration the reason(s) for screen fail. One attempt at 
rescreening will be allowed, and all procedures must be repeated. 
Double-blind treatment period (Day 1 [randomization] to 
Week 30/end of treatment [EOT]): The double-blind treatment 
period will include a two-step dose titration scheme designed to 
achieve safe and effective dosing for each participant based on their 
own response parameters. Participants who meet all eligibility criteria 
at Screening will first be randomized via an interactive response 
system in a 1:1 ratio to receive treatment with mavacamten 5 mg 
starting dose or matching placebo once daily (QD). Subsequently, 
assessments including ECG, PK (trough plasma concentrations), and 
TTE will be performed at each of 7 study visits, beginning at Week 4, 
and read by core laboratories (see also Safety Monitoring and Study 
Treatment sections in this synopsis and Table 1). At Week 8 and 
Week 14, the dose may be increased, decreased, or remain unchanged 
based upon results of Week 6 and Week 12 assessments, respectively. 
At Week 8, the dose may be increased to a maximum daily dose of 
10 mg (ie, increase from 5 mg QD to 10 mg QD), and at Week 14 to a 
maximum daily dose of 15 mg (ie, increase from 10 mg QD to 15 mg 
QD). Dose increases are designed to be step-wise and are not allowed 
to skip doses (eg, from 5 mg to 15 mg). 
At Week 30/EOT, participants will complete CPET and post-exercise 
TTE. For any participants permanently discontinuing treatment prior to 
Week 30, an early termination (ET) visit should be conducted as soon 
as possible, including CPET and post-exercise TTE. Participants with 
ET will also be encouraged to complete all remaining study visits and 
assessments, including the Week 30 visit. 
Posttreatment follow-up period (Week 30/EOT to Week 38/end of 
study [EOS]): When double-blind treatment ends at Week 30, 
participants will be contacted by phone at Week 34 and return to the 
site at Week 38 for an EOS visit. At the EOS visit, specified 
assessments will be repeated. This posttreatment follow-up period 
applies only to participants who are receiving study drug after 
Week 22. 
Safety Monitoring 
To maintain safety throughout the double-blind treatment period, a 
clinic visit will occur every 2 to 4 weeks, beginning at Week 4 for an 
initial evaluation of clinical tolerability and safety (Table 1). Clinic 
visits will include but are not limited to clinical evaluation (symptoms, 
PRO evaluations, adverse event [AE]/serious adverse event [SAE] 
assessment), ECGs, PK sample, TTEs, and laboratory assessments. 
Results of TTE performed by study site sonographers at each 


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scheduled visit following randomization should be kept blinded to the 
investigator and other study site personnel. An exception may occur if 
left ventricular ejection fraction (LVEF) ≤30% is measured at the site, 
then the investigator will be immediately notified and study drug will 
be permanently discontinued as described within the protocol. 
Assessments at Weeks 4, 6, 8, 12, 18, 22, and 26 will be used to guide 
dose reduction or temporary discontinuation if indicated, based on 
predefined criteria detailed within the protocol. If at any time during 
the double-blind treatment period the mavacamten dose is decreased 
from the previous dose, the participant will continue on the reduced 
dose to the EOT (Week 30) unless further safety concerns or 
intolerability arise. 
 
 
 
 
 
 
 
 
 
 
Number of Participants 
Approximately 220, with 110 participants in each of 2 treatment 
groups. 
Study Treatment 
Participants will receive mavacamten immediate-release capsules 5 mg 
or matching placebo QD for the first 8 weeks of the dosing period with 
trough PK samples drawn at Week 4, Week 6, and Week 8. If at Week 
4 the trough PK is between 700 ng/mL and 1000 ng/mL, the dose will 
be decreased to 2.5 mg at Week 6. 
Otherwise, the dose will be adjusted (increase, decrease, or remain 
unchanged) at Week 8 based on Week 6 assessments and Week 14 
based on Week 12 assessments. The permissible doses after dose 
adjustment at Week 8 will be 2.5 mg, 5 mg, 10 mg, or placebo. The 
permissible doses after dose adjustment at Week 14 will be 2.5 mg, 
5 mg, 10 mg, 15 mg, or placebo. 
For added safety, if 700 ng/mL < Week 8 PK < 1000 ng/mL then an 
unscheduled visit will be arranged 2 weeks later (Week 10) to reduce 
dose. After Week 14, assessments will continue every 4 weeks to 
Week 30/EOT for safety monitoring. 
At any time if PK plasma concentration ≥ 1000 ng/mL, then study 
drug will be temporarily discontinued. 
Study Duration 
Each participant will be in the study for up to 43 weeks: for Screening, 
up to 5 weeks; for study conduct, 38 weeks (±7 days). 
Inclusion Criteria 
Each participant must meet the following criteria to be included in this 
study: 
1. Able to understand and comply with the study procedures, 
understand the risks involved in the study, and provide written 
informed consent according to federal, local, and institutional 
guidelines before the first study-specific procedure 
2. Is at least 18 years old at Screening 
3. Body weight is greater than 45 kg at Screening 


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4. Has adequate acoustic windows to enable accurate TTEs (refer to 
Echocardiography Site Instruction Manual) 
5. Diagnosed with oHCM consistent with current American College 
of Cardiology Foundation/American Heart Association and 
European Society of Cardiology guidelines, ie, satisfy both criteria 
below (criteria to be documented by the echocardiography core 
laboratory): 
A. Has unexplained left ventricular (LV) hypertrophy with 
nondilated ventricular chambers in the absence of other 
cardiac (eg, hypertension, aortic stenosis) or systemic disease 
and with maximal LV wall thickness ≥15 mm (or ≥13 mm 
with positive family history of hypertrophic cardiomyopathy 
[HCM]) as determined by core laboratory interpretation, and 
B. Has LVOT peak gradient ≥50 mmHg during Screening as 
assessed by echocardiography at rest, after Valsalva 
maneuver, or post-exercise (confirmed by echocardiography 
core laboratory interpretation) 
6. Has documented LVEF ≥55% by echocardiography core 
laboratory read of Screening TTE at rest 
7. Has LVOT gradient with Valsalva maneuver at Screening TTE of 
>30 mmHg, determined by echocardiography core laboratory 
8. Has NYHA Functional Class II or III symptoms at Screening 
9. Has documented oxygen saturation at rest ≥90% at Screening 
10. Is able to perform an upright CPET and has a respiratory exchange 
ratio (RER) ≥1.0 at Screening per central reading; if the RER is 
between 0.91 and 1.0, the participant may be enrolled only if it is 
determined by the central CPET laboratory that peak exercise has 
been achieved in the subject (the only permitted reasons for 
subpeak performance are [1] a decrease in systolic blood pressure 
or [2] severe angina as described in the CPET Laboratory Manual) 
11. Female participants must not be pregnant or lactating and, if 
sexually active, must use one of the following highly effective 
birth control methods from the Screening visit through 3 months 
after the last dose of investigational medicinal product (IMP). 
• 
combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation or 
progestogen-only hormonal contraception associated with 
inhibition of ovulation by oral, implantable, or injectable route 
of administration 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
• 
Female is surgically sterile for 6 months or postmenopausal 
for 1 year. Permanent sterilization includes hysterectomy, 
bilateral oophorectomy, bilateral salpingectomy, and/or 
documented bilateral tubal occlusion at least 6 months prior to 


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Screening. Females are considered postmenopausal if they 
have had amenorrhea for at least 1 year or more following 
cessation of all exogenous hormonal treatments and follicle 
stimulating hormone (FSH) levels are in the postmenopausal 
range. 
Male partners must also use a contraceptive (eg, barrier, condom 
or vasectomy) 
Exclusion Criteria 
A participant who meets any of the following exclusion criteria may 
not participate in this study: 
1. Previously participated in a clinical study with mavacamten 
2. Hypersensitivity to any of the components of the mavacamten 
formulation 
3. Participated in a clinical trial in which the participant received any 
investigational drug (or is currently using an investigational 
device) within 30 days prior to Screening, or at least 5 times the 
respective elimination half-life (whichever is longer) 
4. Known infiltrative or storage disorder causing cardiac hypertrophy 
that mimics oHCM, such as Fabry disease, amyloidosis, or 
Noonan syndrome with LV hypertrophy 
5. Has any medical condition that precludes upright exercise stress 
testing 
6. Has a history of syncope within 6 months prior to screening or 
history of sustained ventricular tachyarrhythmia with exercise 
within 6 months prior to Screening 
7. Has a history of resuscitated sudden cardiac arrest (at any time) or 
known history of appropriate implantable cardioverter-defibrillator 
(ICD) discharge/shock for life-threatening ventricular arrhythmia 
within 6 months prior to Screening (Note: history of anti-
tachycardia pacing (ATP) within 6 months or ever is allowed) 
8. Has paroxysmal, intermittent atrial fibrillation with atrial 
fibrillation present per the investigator’s evaluation of the 
participant’s ECG at the time of Screening 
9. Has persistent or permanent atrial fibrillation not on 
anticoagulation for at least 4 weeks prior to Screening and/or not 
adequately rate-controlled within 6 months prior to Screening 
(Note – patients with persistent or permanent atrial fibrillation who 
are anticoagulated and adequately rate-controlled are allowed) 
10. Current treatment (within 14 days prior to Screening) or planned 
treatment during the study with disopyramide or ranolazine 
11. Current treatment (within 14 days prior to Screening) or planned 
treatment during the study with a combination of β-blockers and 
verapamil or a combination of β-blockers and diltiazem 
12. For individuals on β-blockers, verapamil, or diltiazem, any dose 
adjustment of that medication <14 days prior to Screening or any 


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anticipated change in treatment regimen using these medications 
during the study 
13. Has been successfully treated with invasive septal reduction 
(surgical myectomy or percutaneous alcohol septal ablation 
[ASA]) within 6 months prior to Screening or plans to have either 
of these treatments during the study (note: individuals with 
myectomy or percutaneous ASA procedure performed >6 months 
prior to Screening may be enrolled if study eligibility criteria for 
LVOT gradient criteria are met) 
14. ICD placement or pulse generator change within 2 months prior to 
Screening or planned new ICD placement during the study (pulse 
generator changes, if needed during the study, are allowed) 
15. Has QT interval with Fridericia correction (QTcF) >500 ms at 
Screening or any other ECG abnormality considered by the 
investigator to pose a risk to participant safety (eg, second-degree 
atrioventricular block type II) 
16. Has documented obstructive coronary artery disease (>70% 
stenosis in one or more epicardial coronary arteries) or history of 
myocardial infarction 
17. Has known moderate or severe (as per investigator’s judgment) 
aortic valve stenosis at Screening 
18. Has any acute or serious comorbid condition (eg, major infection 
or hematologic, renal, metabolic, gastrointestinal, or endocrine 
dysfunction) that, in the judgment of the investigator, could lead to 
premature termination of study participation or interfere with the 
measurement or interpretation of the efficacy and safety 
assessments in the study 
19. Has pulmonary disease that limits exercise capacity or systemic 
arterial oxygen saturation 
20. History of malignant disease within 10 years of Screening: 
• 
Participants who have been successfully treated for 
nonmetastatic cutaneous squamous cell or basal cell carcinoma 
or have been adequately treated for cervical carcinoma in situ 
or breast ductal carcinoma in situ (DCIS) can be included in 
the study 
• 
Participants with other malignancies who are cancer-free for 
more than 10 years before Screening can be included in the 
study 
21. Has safety laboratory parameters (chemistry, hematology, 
coagulation, and urinalysis) outside normal limits (according to the 
central laboratory reference range) at Screening as assessed by the 
central laboratory; however, a participant with safety laboratory 
parameters outside normal limits may be included if he or she 
meets all of the following criteria: 


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• 
The safety laboratory parameter outside normal limits is 
considered by the investigator to be clinically not significant 
• 
If there is an alanine aminotransferase or aspartate 
aminotransferase result, the value must be <3 × the upper limit 
of the laboratory reference range 
• 
The body size–adjusted estimated glomerular filtration rate is 
≥30 mL/min/1.73 m2 
22. Has a positive serologic test at Screening for infection with human 
immunodeficiency virus, hepatitis C virus, or hepatitis B virus 
23. Has a history or evidence of any other clinically significant 
disorder, condition, or disease that, in the opinion of the 
investigator, would pose a risk to participant safety or interfere 
with the study evaluation, procedures, or completion 
24. Is currently taking, or has taken within 14 days prior to Screening, 
a prohibited medication, such as a cytochrome P450 (CYP) 2C19 
inhibitor (eg, omeprazole or esomeprazole), a strong CYP 3A4 
inhibitor, or St. John’s Wort (see Appendix 2 for more details). 
Alternatives, such as pantoprazole, are allowed and may be 
discussed with the medical monitor 
25. Prior treatment with cardiotoxic agents such as doxorubicin or 
similar (see Appendix 2) 
26. Unable to comply with the study requirements, including the 
number of required visits to the clinical site 
27. Is a first degree relative of personnel directly affiliated with the 
study at the clinical study site, any study vendor, or the study 
Sponsor 
 
 
 
 
 
: 
 
 
 
 
 
 
 
 
 
 
Primary Efficacy 
Endpoint 
Clinical response defined as achieving: 1) An improvement of at least 
1.5 mL/kg/min in peak oxygen consumption (pVO2) as determined by 
CPET and a reduction of one or more class in NYHA Functional 
Classification or 2) an improvement of 3.0 mL/kg/min or more in 
pVO2 with no worsening in NYHA Functional Class. 
Secondary Efficacy 
Endpoints 
• 
Change from baseline to Week 30 in post-exercise LVOT peak 
gradient 
• 
Proportion of participants with at least 1 class improvement in 
NYHA functional class from baseline to Week 30  


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• 
Change from baseline to Week 30 in (pVO2) as determined by 
CPET 
• 
Change from baseline to Week 30 in participant-reported health-
related quality of life as assessed by the KCCQ score  
• 
Change from baseline to Week 30 in patient-reported severity of 
HCM symptoms as assessed by the HCM Symptom Questionnaire 
score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
-  
Safety Endpoints 
• 
Incidence of major adverse cardiac events (death, stroke, acute 
myocardial infarction) 
• 
Incidence of hospitalizations (both cardiovascular (CV) and non-
CV) 
• 
Incidence of heart failure (HF) events, (includes HF 
hospitalizations and urgent emergency room (ER)/outpatient (OP) 
visits for HF) 
• 
Incidence of atrial fibrillation/flutter (new from screening) 
• 
Incidence of ICD therapy and resuscitated cardiac arrest 
• 
Incidence of Ventricular tachyarrhythmias (includes ventricular 
tachycardia (VT), ventricular fibrillation (VF), and Torsades de 
Pointe) 
• 
Incidence of syncope and seizures 
• 
Frequency and severity of treatment-emergent adverse events 
(TEAEs), treatment-emergent SAEs, and laboratory abnormalities 
(including trends in NT-proBNP) 


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Sample Size and 
Statistical 
Considerations 
Approximately 220 participants will be randomized, with 
110 participants in each of the 2 groups. Randomization will be 
stratified for NYHA functional class, current treatment with β-blocker, 
type of ergometer, and consent for the CMR substudy. The sample size 
should provide adequate power to determine the superiority of 
mavacamten in improving pVO2 and NYHA functional classification 
relative to placebo. The power calculation is derived assuming a true 
clinically meaningful difference of 25% between mavacamten and 
placebo subjects in achieving the clinical response. Based on the 
MYK-461-004, PIONEER-HCM phase 2 study, 50% of the subjects 
receiving mavacamten met the clinical responder definition by the end 
of 12-week treatment period. Assuming the same percentage of 
subjects in the active treatment arm and 25% in placebo arm will 
achieve the clinical response at the end of 30-week dosing period in 
the current study, the proposed sample size of 110 subjects per arm 
will provide 96% power at two-sided 5% statistical significance level. 
Subjects who terminate early or cannot be assessed for the clinical 
response at the end of 30-week dosing period will be considered as 
non-responders. 
Efficacy Analyses 
Primary efficacy endpoints analysis 
The primary efficacy endpoints of clinical response will be analyzed 
using the Cochran-Mantel-Haenszel test for stratified categorical data. 
Early dropouts or participants whose response status is unable to be 
assessed at the end of 30-week dosing period will be classified as non-
responders. More detailed statistical analysis strategies will be 
documented in the Statistical Analysis Plan (SAP). 
Secondary efficacy endpoints analyses 
The general analytical approach for the secondary efficacy endpoints 
are the following: 
• 
To minimize false discovery among the secondary endpoints, 
appropriate methods to control Type 1 errors will be employed; 
further details will be specified in the SAP. 
• 
Categorical endpoints will be analyzed by the Cochran-Mantel-
Haenszel test taking into account of stratification factors or Chi-
square test without adjusting for stratification factors, whenever 
appropriate. 
• 
Continuous variables will be analyzed by analysis of variance 
(ANOVA) model comparing between group means. 


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• 
Ordinal variables, such as NYHA functional class, will be 
converted quantitatively as ordinal scores (I-IV classes to 1-4 
scores, respectively) and analyzed as continuous variables. 
 
 
 
 
 
 
 
 
 
 
Safety Analyses 
Safety data will be analyzed using descriptive statistics without formal 
statistical testing. The safety analysis will focus on the 
treatment-emergent AE period. This period is defined as the time from 
the first administration of the IMP to the last administration of the 
IMP + 56 days. 
 
 
 
 
 
 
 
Study Committees 
• 
Steering Committee 
• 
Clinical Event Adjudication Committee 
• 
Independent Data Monitoring Committee 
 
 


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Figure 1 
Study Schema 
 
 
Abbreviations: CPET, cardiopulmonary exercise testing; ECG, electrocardiogram; PK, pharmacokinetics; 
QD, once daily; stress echo, post-exercise stress echocardiography; TTE, transthoracic echocardiogram; 
wks, weeks. 


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Table 1 
Schedule of Study Procedures 
Assessmenta 
Screeningb 
Day -35 to 
Day -1 
Day 
1 
Week 
4 
(±7 d) 
Week 
6 
(±7 d) 
Week 
8 
(±7 d) 
Week 
12 
(±7 d) 
Week 
14 
(±7 d) 
Week 
18 
(±7 d) 
Week 
22 
(±7 d) 
Week 
26 
(±7 d) 
ETc 
Week 
30 
(±7 d)/ 
EOT 
Week 
34 
(±7 d) 
(call) 
Week 
38 
(±7 d)/ 
EOS 
General Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (in clinic) 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Prior/concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ICD information downloadedf 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
ECGg 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Vital signsh 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Cardiopulmonary Assessments 
Resting TTEi 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Post-exercise stress 
echocardiographyj 
X 
 
 
 
 
 
 
 
 
 
X 
Xj 
 
 
CPETk 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Cardiac monitoring devicel 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Accelerometer attachedm 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Laboratory Assessments 
Hepatitis panel and HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Coagulation panel 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
Chemistry 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
Hematology 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Footnotes and abbreviations defined on last page of table. 


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Table 1 
Schedule of Study Procedures (Cont’d) 
Assessmenta 
Screeningb 
Day -35 to 
Day -1 
Day 
1 
Week 
4 
(±7 d) 
Week 
6 
(±7 d) 
Week 
8 
(±7 d) 
Week 
12 
(±7 d) 
Week 
14 
(±7 d) 
Week 
18 
(±7 d) 
Week 
22 
(±7 d) 
Week 
26 
(±7 d) 
ETc 
Week 
30 
(±7 d)/ 
EOT 
Week 
34 
(±7 d) 
(call) 
Week 
38 
(±7 d)/ 
EOS 
Laboratory Assessments (continued) 
hs-cardiac troponin I 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
NT-proBNPo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
FSHp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(women)q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)q 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
Symptom Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Patient-reported outcomes 
 
 
s 
Investigational Medical Product 
IMP QD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administered at sitet 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
IMP complianceu 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Substudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Abbreviations: AE, adverse event; BP, blood pressure; call, telephone contact; CMR, cardiac magnetic resonance imaging; CPET, cardiopulmonary exercise 
testing; CYP, cytochrome P450; d, day; DNA, deoxyribonucleic acid; ECG, electrocardiogram; EOS, end of study; EOT, end of treatment, ET, early termination; 
FSH, follicle-stimulating hormone; HCM, hypertrophic cardiomyopathy; HIV, human immunodeficiency virus; HR, heart rate; hs, high-sensitivity; 
ICD, implantable cardioverter-defibrillator; ICF, informed consent form; IMP, investigational medicinal product; LVOT, left ventricular outflow tract; 
NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association; PK, pharmacokinetic; PRO, patient-reported outcomes; 
QD, once daily; QTcF, Fridericia correction; SAE, serious adverse event; TTE, transthoracic echocardiography. 
a 
Preferred order of assessments is ECG, vital signs, PK, and TTE, all prior to study drug dosing unless otherwise described below. 
b 
Screening will require more than 1 visit to accommodate all of the study procedures. 


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c 
The ET visit will be scheduled as soon as possible after the participant permanently discontinues study drug. The participant will be encouraged to 
participate in the remaining scheduled study visits, particularly the Week 30 visit and the Week 38/EOS visit. If a participant permanently discontinues 
treatment at or before Week 22, the final visit will be at Week 30. 
d 
At Screening, ET, Week 30/EOT, and Week 38, a complete physical examination will be conducted, including a neurological examination. At all other 
visits, an abbreviated cardiopulmonary physical examination will be conducted, with other systems assessed as directed by interval history. 
e 
Changes in baseline conditions from once the ICF is signed will be recorded as an AE. All changes unless otherwise specified that occur after the 
administration of study drug will be considered treatment-emergent AEs. This assessment will occur either by phone call or an in-person visit. 
f 
For participants who have ICDs, information including rhythm strips and events will be downloaded from the ICDs at baseline, at Week 12, and at Week 30, 
or as clinically indicated after any ICD discharge interrogation occurring during the double-blind treatment period. 
g 
Twelve (12)-lead ECGs will be performed after 10 minutes of rest at Screening and prior to dosing at all onsite study visits (except Weeks 8 and 14). Each 
time an ECG is completed, a 10-second paper ECG will be obtained and maintained in the study participant’s source documentation. QTcF value from Day 1 
ECG will not be used for eligibility or for temporary discontinuation. The Day 1 QTcF value will be used as the baseline to determine percent change at 
future visits when criteria for temporary discontinuation are applied. (Note: If for any reason a D1 QTcF is not determined, then QTcF from screening ECG 
will be used in percent change calculation.) 
h 
At Screening, ET, Week 30/EOT, and Week 38, complete vital signs including temperature, HR, respiratory rate, and BP will be obtained. At all other visits, 
only HR and BP are required. If PK sampling is conducted at a visit, vital signs should be collected before PK sampling. Vital signs should be taken with the 
study participant in the same position at all visits. BP should be taken via an automated recorder after resting for at least 5 minutes. 
i 
Resting TTE should be performed prior to post-exercise stress echocardiography or CPET. Resting TTE images and views will be acquired at each onsite 
visit prior to dosing as detailed in the echo site instruction manual. Instantaneous LVOT peak gradient (resting) and provoked LVOT peak gradient (Valsalva 
maneuver) will be assessed by the core laboratory. Left ventricular ejection fraction (LVEF) will be measured at the clinical site by the certified site 
sonographer and subsequently by the core laboratory. The LVEF site read will be kept blinded from the investigator and other study site personnel, except in 
case of locally measured LVEF≤30%. 
j 
For post-exercise stress echocardiography, participants will undergo a standard symptom-limited exercise test after a 4-hour fast by standardized treadmill or 
bicycle ergometer during Screening and Week 30/EOT prior to dosing. Instantaneous LVOT peak gradient will be assessed immediately post-exercise by 
TTE. Post-exercise stress echocardiography may be performed on a different day than CPET. If the 2 procedures are performed on the same day, participants 
must exercise only once, and participants will undergo CPET and then post-exercise TTE. Post-exercise stress echocardiography should be acquired the 
same day or within 72 hours of the Resting TTE and should also be performed as close as possible to ET if it occurs. If post-exercise stress echocardiography 
and CPET are performed on different days, the same sequence of visits must be performed for both screening and EOT. 
k 
CPET by standardized treadmill or bicycle ergometer will be performed during Screening and at Week 30/EOT prior to dosing. CPET is done after a 4-hour 
fast. Record the fasting status and the date and time of the last dose taken prior to CPET. Any concomitant medication may be administered prior to all 
exercise testing. CPET should also be performed as close as possible to ET if it occurs. 
l 
A cardiac monitoring device will be applied during Screening, Week 12, and at the Week 26 visits and retrieved at the Day 1, Week 14, and Week 30 visits, 
respectively. 
m 
An accelerometer will be fastened to the participant’s wrist at Screening (at least 11 days before Day 1) and at the Week 26 visit to collect data on activity. 
Participants will return the accelerometer at the next study visit for data upload and analysis. 
n 
Participants should not take study drug on day of visit prior to blood draw for PK. PK sample will be collected ≤2 hours before dosing. Additionally, on 
Week 30 (last dose), another PK sample will be collected within 1 to 2 hours postdose. 


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o 
NT-proBNP should be drawn before exercise testing if exercise testing is being performed that day. 
p 
FSH testing at Screening for postmenopausal women to confirm postmenopausal status. 
q 
Pregnancy testing for all females of childbearing potential: serum pregnancy test at Screening; urine pregnancy test at all other visits shown (every 
4-6 weeks), and conduct serum test if any urine test is positive. The Week 34 pregnancy testing will be conducted at home. 
r 
Separate consent is required for HCM genotyping. Note that if a participant with a prior HCM clinical genotype test that was positive for genetic mutation 
consents to provide their results, then no further genotype assessment will be performed; however, participants who have not been tested, participants who 
have tested negative for HCM mutations on clinical panels, and participants who have a positive HCM genotype result but cannot provide the results or will 
not consent to provide the results may consent to have blood drawn on Day 1 for assessment of HCM genotype. 
s 
The pharmacogenetic panel will include CYP 2C19 genotyping and potentially additional DNA sequencing. Pharmacogenetic Screening for CYP 2C19 
genotyping will occur at Screening; samples from screen failures must be destroyed. 
t 
At all onsite visits, study drug will be administered at the investigational site to facilitate collection of PK samples ≤ 2 hours prior to dosing. Note: There is 
no PK sample at Day 1 or Week 14. With the exception of Week 30 when a PK sample is also drawn within 1 to 2 hours postdose, Study drug will be 
administered at the end of the visit when all other assessments have been done, including any drawing of blood. 
u 
All participants will return their study drug dosing containers to the site pharmacy for capsule counts. Refer to the Pharmacy Manual for details. 
v 
The CMR substudy assessment can be completed up to 5 days before the Day 1 visit and up to 5 days before the EOT visit. 
 
 


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Table 2 
Schedule of Patient-reported Outcomes Assessments 
PRO 
Assessmenta 
Screening 
Day -35 to 
Day -1 
Day 1 
Week 4 
(±7 d) 
Week 6 
(±7 d) 
Week 10 
(±7 d) 
(home) 
Week 12 
(±7 d) 
Week 14 
(±7 d) 
Week 18 
(±7 d) 
Week 22 
(±7 d) 
Week 26 
(±7 d) 
Week 30/ 
EOT 
(±7 d) 
Week 38/ 
EOS 
(±7 d) 
 
Xb 
 
 
 
Xc 
 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
 
Xd 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
-
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
-
-
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
-
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Abbreviations: d, day; EOS, end of study; EOT, end of treatment; EQ-5D-5L, EuroQol five dimensions 5-level questionnaire; home, PRO assessments completed 
at home; HCMSQ, Hypertrophic Cardiomyopathy Symptom Questionnaire; KCCQ-23, 23-item Kansas City Cardiomyopathy Questionnaire; PGIC, Patient 
Global Impression of Change questionnaire; PGIS, Patient Global Impression of Severity questionnaire; PRO, patient-reported outcomes; WPAI-SHP, Work 
Productivity and Activity Impairment questionnaire. 
NOTE: Missed PRO assessments by patients outside of study visits are not considered protocol deviations. 
a 
The PRO assessments that are completed at visits, with the exception of Screening, should be completed prior to any other study procedure taking place, 
where possible, and prior to any meaningful discussion about the study or study treatment with investigative site staff. 
b 
Participants will receive a handheld electronic device and training at Screening. During Screening they will complete the HCMSQ daily for a minimum of 
7 days and every day for the first 6 weeks after treatment initiation. 
c 
Participants will complete the HCMSQ on the handheld electronic device daily for a consecutive 7-day (1-week) period prior to the Week 10, 14, 18, 22, 26, 
30 (EOT), and 38 (EOS) time points. 
d 
During Screening, participants will complete the PGIS on the handheld electronic device immediately following completion of the 1st and 7th day of the 
HCMSQ assessment. If the Screening periods is >7 days, the PGIS should also be completed immediately following completion of the 14th, 21st, 28th, and 
35th day of the HCMSQ. 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ......................................2 
PROTOCOL SYNOPSIS...........................................................................................................6 
LIST OF ABBREVIATIONS ..................................................................................................27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
STUDY OBJECTIVES ..........................................................................................35 
3.1 
Primary Objective ............................................................................................35 
3.2 
Secondary Objectives .......................................................................................35 
 
 
 
 
4 
OVERALL STUDY DESIGN AND PLAN ..........................................................36 
4.1 
Study Duration .................................................................................................39 
4.2 
Study Committees ............................................................................................39 
4.2.1 
Steering Committee .............................................................................39 
4.2.2 
Clinical Event Adjudication Committee ..............................................40 
4.2.3 
Independent Data Monitoring Committee ...........................................40 
5 
SELECTION OF STUDY POPULATION ...........................................................40 
5.1 
General Study Population and Clinical Sites ...................................................40 
5.2 
Inclusion Criteria .............................................................................................40 
5.3 
Exclusion Criteria ............................................................................................42 
5.4 
CMR Substudy Inclusion/Exclusion Criteria ...................................................44 
5.5 
Screening and Enrollment ................................................................................44 
6 
RANDOMIZATION AND BLINDING PROCEDURES.....................................45 
6.1 
Randomization .................................................................................................45 
6.2 
Study Blinding .................................................................................................45 
6.3 
Methods for Unblinding ...................................................................................45 
7 
STUDY TREATMENT .........................................................................................45 
7.1 
Mavacamten and Matching Placebo, Administration, and Schedule ..............46 
7.2 
Treatment Compliance .....................................................................................46 
7.3 
Dose Adjustments ............................................................................................46 
7.3.1 
Blinded Dose Adjustments During Double-blind Treatment Period ...46 


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7.3.2 
Blinded Dose Adjustment Leading to Temporary Discontinuation ....49 
7.3.3 
Management of Double-blind Treatment in the Case of LVEF 
≤30% at Study Site ...............................................................................50 
7.3.4 
Management of Double-blind Treatment in the Case of New or 
Worsening Heart Failure ......................................................................51 
7.4 
Hepatotoxicity Stopping and Rechallenge Rules .............................................51 
7.4.1 
Criteria for Permanent Withholding of Study Drug Due to 
Potential Hepatotoxicity .......................................................................51 
7.4.2 
Criteria for Conditional Withholding of Study Drug Due to 
Potential Hepatotoxicity .......................................................................52 
7.4.3 
Criteria for Rechallenge of Study Drug After Potential 
Hepatotoxicity ......................................................................................52 
7.5 
Overdose ..........................................................................................................53 
7.5.1 
Reporting and Follow-up of Overdose ................................................53 
 
 
 
 
 
 
 
 
 
 
8 
RISKS AND PRECAUTIONS ..............................................................................54 
8.1 
General .............................................................................................................54 
8.2 
Pregnancy .........................................................................................................54 
8.2.1 
Avoidance of Pregnancy ......................................................................54 
8.2.2 
Acceptable Forms of Contraception ....................................................54 
8.2.3 
Reporting and Follow-up of Pregnancies ............................................55 
9 
STUDY ASSESSMENTS AND PROCEDURES .................................................55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
9.3 
Safety Assessments ..........................................................................................61 
9.3.1 
Medical History ...................................................................................61 
9.3.2 
Physical Examination...........................................................................61 


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9.3.3 
12-lead ECG .........................................................................................61 
9.3.4 
Cardiac Monitoring Device ..................................................................62 
9.3.5 
Vital Signs ............................................................................................62 
9.3.6 
Other Safety Assessments ....................................................................62 
9.4 
Cardiac Magnetic Resonance Imaging Substudy ............................................63 
9.5 
Participant Restrictions During this Study .......................................................63 
9.6 
Study Procedures by Visit ................................................................................63 
9.7 
Visit Scheduling ...............................................................................................63 
10 
TREATMENT DISCONTINUATION AND WITHDRAWAL FROM 
STUDY ..................................................................................................................64 
10.1 
Treatment Discontinuation ...............................................................................64 
10.1.1 
Temporary Treatment Discontinuation ................................................64 
10.1.2 
Permanent Treatment Discontinuation ................................................64 
10.1.3 
Criteria for Permanent Treatment Discontinuation ..............................65 
10.1.4 
Management of Participants After Permanent Treatment 
Discontinuation ....................................................................................65 
10.2 
Withdrawal from Study....................................................................................66 
10.2.1 
Withdrawal of Consent for Ongoing Study Participation ....................66 
10.2.2 
Replacement of Participants Who Withdraw from the Study ..............67 
11 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS ................................................................................................................67 
11.1 
Definitions........................................................................................................67 
11.1.1 
Adverse Event ......................................................................................67 
11.1.2 
Serious Adverse Event .........................................................................68 
11.2 
Adverse Event Reporting and Descriptions .....................................................69 
11.2.1 
Reporting Period and Follow-up ..........................................................69 
11.2.2 
Adverse Event Attributes .....................................................................69 
11.3 
Reporting and Evaluation of Serious Adverse Events .....................................70 
11.4 
Reporting Adverse Events of Special Interest .................................................71 
12 
STATISTICAL METHODS ..................................................................................71 
12.1 
Determination of Sample Size .........................................................................71 
12.2 
Study Endpoints ...............................................................................................71 
12.2.1 
Primary Efficacy Endpoints .................................................................72 
12.2.2 
Secondary Efficacy Endpoints .............................................................72 
 
 
 
 
12.2.5 
Safety Endpoints ..................................................................................73 
 
 
 
 


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12.4 
Statistical Analysis ...........................................................................................73 
12.4.1 
Analysis Populations ............................................................................74 
12.4.2 
General Considerations ........................................................................74 
12.4.3 
Participant Disposition .........................................................................74 
12.4.4 
Demographics and Baseline Characteristics ........................................74 
12.4.5 
Extent of Study Treatment Exposure and Compliance ........................74 
12.4.6 
Efficacy Analyses ................................................................................75 
 
 
12.4.8 
Safety Analyses ....................................................................................76 
 
 
12.4.10 
Interim Analysis ...................................................................................80 
 
 
13 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS ........................80 
13.1 
Compliance Statement .....................................................................................80 
13.2 
Informed Consent.............................................................................................80 
13.3 
Ethics Committee .............................................................................................81 
14 
ADMINISTRATIVE PROCEDURES ..................................................................82 
14.1 
Sponsor’s Responsibilities ...............................................................................82 
14.1.1 
Participant Confidentiality ...................................................................82 
14.1.2 
Study Supplies .....................................................................................83 
14.1.3 
Investigator Training ............................................................................83 
14.1.4 
Ongoing Communication of Safety Information During the Study .....83 
14.1.5 
Study Monitoring .................................................................................84 
14.1.6 
Study Auditing and Inspecting.............................................................84 
14.2 
Investigator’s Responsibilities .........................................................................84 
14.2.1 
Screening Log ......................................................................................84 
14.2.2 
Mavacamten Accountability ................................................................84 
14.2.3 
Reporting and Recording of Study Data ..............................................85 
14.2.4 
Source Data and Source Documents ....................................................85 
14.2.5 
Participant Identification Information ..................................................86 
14.2.6 
Records Retention ................................................................................86 
14.2.7 
Protocol Deviations ..............................................................................86 
14.2.8 
Blood Sample Collection/Storage ........................................................86 
14.3 
Clinical Trial Insurance ....................................................................................87 
14.4 
Protocol Amendments and Study Administrative Letters ...............................87 
15 
DATA QUALITY ASSURANCE .........................................................................87 
16 
ADMINISTRATIVE CONSIDERATIONS ..........................................................88 


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16.1 
Use of Computerized Systems .........................................................................88 
16.2 
Study Records ..................................................................................................88 
17 
PUBLICATION .....................................................................................................89 
 
 
LIST OF TABLES 
Table 1 
Schedule of Study Procedures ...................................................................17 
 
 
 
 
 
 
 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema.............................................................................................16 
LIST OF APPENDICES 
Appendix 1 
Laboratory Assessments ............................................................................93 
 
 
Appendix 3 
Potential Drug-Induced Liver Injury Reporting and Additional 
Assessments Reporting ..............................................................................95 
Appendix 4 
Investigator’s Signature Amendment 5 .....................................................97 
 
 


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LIST OF ABBREVIATIONS 
ACCF 
American College of Cardiology Foundation 
AE 
adverse event 
AESI 
adverse event of special interest 
AHA 
American Heart Association 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ASA 
alcohol septal ablation 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CEAC 
Clinical Event Adjudication Committee 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CMH 
Cochran-Mantel-Haenszel 
CMR 
cardiac magnetic resonance imaging 
CPET 
cardiopulmonary exercise test or testing 
CRF 
case report form 
CV 
cardiovascular  
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
EC 
ethics committee; refers to an IRB or IEC or equivalent 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ER 
emergency room 
EM 
extensive metabolizers 
EQ-5D-5L 
EuroQol five dimensions 5-level questionnaire 
EOS 
end of study 
EOT 
end of treatment 
ESC 
European Society of Cardiology 
ET 
early termination 
EV 
expired ventilation 
FDA 
The United States Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCM 
hypertrophic cardiomyopathy 
HCMSQ 
hypertrophic cardiopathy symptom questionnaire 
HF 
heart failure 
HIV 
human immunodeficiency virus 
HLGT 
high-level group term 
HLT 
high-level term 
HR 
heart rate 


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IB 
Investigator’s Brochure 
ICD 
implantable cardioverter-defibrillator 
 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IXRS 
interactive response system 
KCCQ-23 
23-item Kansas City Cardiomyopathy Questionnaire 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
LVOT 
left ventricular outflow tract 
MAD 
multiple ascending-dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
mitral regurgitation 
NASH 
nonalcoholic steatohepatitis 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
oHCM 
obstructive hypertrophic cardiomyopathy 
OP 
outpatient 
PD 
pharmacodynamics(s) 
PGIC 
Patient Global Impression of Change questionnaire 
PGIS 
Patient Global Impression of Severity 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcomes 
PT 
preferred term 
pVO2 
peak oxygen consumption 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval with Fridericia correction 
RER 
respiratory exchange ratio 
RNA 
ribonucleic acid 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SC 
Steering Committee 
SCD 
sudden cardiac death 
SD 
standard deviation 


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SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reactions 
T 
time (variable) 
t1/2 
terminal half-life 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TTE 
transthoracic echocardiography, transthoracic echocardiogram 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
VCO2 
carbon dioxide production 
VE 
expired ventilation 
VF 
ventricular fibrillation 
VT 
ventricular tachycardia 
VO2 
oxygen uptake 
WPAI-SHP 
Work Productivity and Activity Impairment questionnaire 


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 -
 
 
 
 
 


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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is: 
• To compare the effect of a 30-week course of mavacamten with placebo on clinical 
response comprising of exercise capacity and clinical symptoms in participants with 
symptomatic oHCM 
 
3.2 
Secondary Objectives 
The secondary efficacy objectives of this study are: 
• To compare the effect of a 30-week course of mavacamten with placebo on symptoms 
and LVOT obstruction as determined by Doppler echocardiography 
• To compare the effect of a 30-week course of mavacamten with placebo on exercise 
capacity, clinical symptoms and Patient Reported Outcomes individually 


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• To assess the safety and tolerability of mavacamten 
• To assess the PK characteristics of mavacamten 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
4 
OVERALL STUDY DESIGN AND PLAN 
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter, international, 
parallel-group study to evaluate the safety, tolerability, and efficacy of mavacamten 
compared with placebo (1:1) in participants with symptomatic oHCM. Approximately 
220 participants will be enrolled. 
 
 Randomization will be stratified 
according to NYHA functional classification (II or III), current treatment with β-blocker (yes 
or no), planned type of ergometer used during the study (treadmill or exercise bicycle), and 
consent for the CMR substudy (yes or no). 
The study will comprise 3 periods (Figure 1). 
Screening period (Day -35 to Day -1): Participants will undergo a variety of general, 
cardiopulmonary, laboratory, symptom, and PRO assessments over 1 to 2 days (Table 1 and 
Table 2) in order to assess eligibility criteria, including presence of HCM and presence of 
obstruction (at rest or provoked). The investigator should also confirm that participants can 
adequately perform a Valsalva maneuver. Key Screening tests include ECG; TTE conducted 
at rest, with Valsalva maneuver, and post-exercise; and CPET. The following screening 
assessments may be repeated, as long as they fall within the 35-days screening window: 
blood tests, ECG, and/or TTE. Repeat assessments are allowed if central core labs require a 
repeat submission due to quality and in order to better assess inclusion/exclusion values. 
Screening test results as reported by core laboratories (electrocardiogram core laboratory, 
echocardiography core laboratory, and CPET core laboratory) will be used to confirm 
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CPET and post-exercise TTE may be conducted on the same day or separate days during
the Screening period. If CPET and post-exercise TTE are conducted on the same day,
participants must be exercised only once for both procedures, and participants will
undergo CPET followed by post-exercise TTE. If the participants undergo CPET and
post-exercise TTE on different days, then participants will first undergo resting, Valsalva,
and post-exercise TTE (and send the echocardiogram to the core laboratory to determine
LVOT gradients for each) and undergo CPET on a later day. If CPET and post-exercise
TTE are performed on different days, the same sequence of visits must be used for both
screening and EOT.
•
Participants who are receiving treatment for their oHCM condition should be on optimal
medical therapy for their condition as determined by the investigator and informed by
HCM treatment guidelines (eg, β-blocker, verapamil, or diltiazem). This treatment should
be stable and well-tolerated for at least 2 weeks prior to Screening. Concomitant
medications at Screening should be maintained at a stable dose throughout the study,
unless safety or tolerability concerns arise.
•
A participant may also be considered for enrollment if the investigator has determined
that receiving no treatment for their underlying oHCM condition is a valid option (eg, in
case of prior intolerance or contra-indication to β-blockers). In such cases, there should
be no plan to initiate treatment (with β-blocker, verapamil, or diltiazem) after
randomization in the study.
Participants who screen fail may be considered for rescreening based on the investigator’s 
discretion, taking into consideration the reason(s) for screen fail. One attempt at rescreening 
will be allowed, and all procedures must be repeated. 
Double-blind treatment period (Day 1 [randomization] to Week 30/EOT): Participants 
who meet all eligibility criteria will first be randomized via an interactive response system 
(IXRS) in a 1:1 ratio to receive treatment with mavacamten 5 mg starting dose or matching 
placebo QD. 
Overall, the 30-week, double-blind treatment period includes a total of 10 scheduled clinic 
visits, allowing the maintenance of participant contact every 2 to 4 weeks (Table 1 and 
Table 2). All clinic visits will include but are not limited to: clinical evaluation (symptoms, 
PRO assessments, adverse event (AE)/SAE assessments, concomitant medications). At all 
visits except the Week 8 and Week 14 visits, ECGs, TTEs, and laboratory assessments will 
also be conducted. Blood for PK (trough plasma concentrations) will be drawn at all visits 
except Day 1 and Week 14. Results of TTEs performed at each scheduled visit following 
randomization should be kept blinded to the investigator and study site personnel. An 
exception may occur if LVEF ≤30% is measured at the site, then the investigator will be 
notified and study drug will be permanently discontinued (see Section 7.3.3). 
After randomization, participants will first be seen at Week 4 for an initial evaluation of 
clinical tolerability and safety. PK sample collection and blinded TTE will be performed at 
this visit. In the unlikely event that the results from Week 4 exceed PK/PD criteria 
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(700 ng/mL < trough PK < 1000 ng/mL), the dose will be decreased at Week 6 to 2.5 mg via 
the IXRS (see Table 3). 
Participants will subsequently be seen at Week 6 and Week 12 for repeat evaluation. Blinded 
assessments including trough PK, and TTE measures of LVEF and LVOT gradient with 
Valsalva will be performed to guide dose adjustment via the IXRS. At Week 8 and Week 14, 
the dose will be adjusted (dose increase, dose decrease, dose remain unchanged) based upon 
results of Week 6 and Week 12 assessments, respectively, as specified in Section 7.3.1. 
For added safety, a Week 8 blood sample will be drawn to determine trough plasma PK. If 
PK is greater than 700 and less than 1000 ng/mL, then an unscheduled visit will be arranged 
2 weeks later to reduce dose as specified in Section 7.3.3. At any time if PK plasma 
concentration ≥ 1000 ng/mL, then study drug will be temporarily discontinued. 
After Week 14, there are no additional scheduled dose titrations. Blinded assessments at 
Weeks 18, 22, and 26 can inform dose reduction or temporary discontinuation of study drug 
based on predefined criteria detailed in Section 7.3.2. Whenever a mavacamten dose is 
decreased, the participant will continue on the reduced dose to the EOT (Week 30) unless 
further safety concerns or intolerability arise. 
At Week 30/EOT, participants will complete post-exercise TTE (between Week 26 and 
Week 30) and CPET (at Week 30). For any participants permanently discontinuing treatment 
prior to Week 30, an early termination (ET) visit should be conducted as soon as possible, 
including CPET and post-exercise TTE. Participants with ET will also be encouraged to 
complete all remaining study visits and assessments, including Week 30 (see Section 10.1.4). 
Post-treatment follow-up period (Week 30/EOT to Week 38/end of study [EOS]): After 
the end of the double-blind treatment period (Week 30), participants will be contacted by 
phone at Week 34 and return at Week 38 for an EOS visit. At the EOS visit, baseline resting 
assessments will be repeated. This posttreatment follow-up period applies only to participants 
who are receiving study drug after Week 22. 
Description of Patient-reported Outcomes 
PRO assessments will be completed on an electronic device provided to each participant 
during the Screening period (see Sections 9.1.3 and 9.1.4). Data from these PRO assessments 
will not be made available to the investigators and other site personnel throughout the study. 
Participants will first be informed of this when they fill out the consent form that is required 
in order to participate in the trial. The form will include information explaining that the PRO 
information gathered via the device is not shared with their healthcare provider and they 
should therefore report any concerning symptoms directly to their physician. Participants will 
then be reminded of this each time they go to complete the assessment on their handheld 
device. When the participant logs onto their handheld device to complete the assessments, a 
message screen will be shown advising the participant to consult their healthcare provider if 
they have any concerning symptoms. The participant will not be able to continue with the 
PRO assessments until they have acknowledged that they have read this message. The exact 
message text states: 


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Please note: If you are having any symptoms, health issues, or other concerns, please be 
sure to discuss these with your doctor or nurse. The answers you provide to the questions 
are for research purposes only and are not being routinely shared with the members of 
your healthcare team. Please note, however, that you are always free to share any and all 
information with your doctor including information about the answers you will provide in 
this questionnaire that may help address your concerns. 
Description of Other Procedures and Assessments 
Participants with implantable cardioverter-defibrillators (ICDs) will have their data 
downloaded at baseline, at Week 12, and at Week 30, or as clinically indicated whenever 
device discharge is interrogated and/or prior to any device reset. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Study Duration 
The expected study duration is approximately 43 weeks: up to 5 weeks for Screening, a 
30-week treatment period, and an 8-week posttreatment follow-up period (±7 days). 
4.2 
Study Committees 
4.2.1 
Steering Committee 
The Steering Committee (SC) will play an active role in providing scientific guidance and 
advice to the Sponsor related to the design, conduct, results analysis, and publication strategy 


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for the MYK-461-005 EXPLORER-HCM study. The SC will be composed of members who 
are experts in cardiovascular disease, including HCM, with relevant clinical and 
methodological expertise. The SC will include 2 co-chairs, approximately 5 members, and 
Sponsor representatives. All SC members will remain blinded to treatment assignments 
(unless unblinding is required for participant safety) until the conclusion of the study. 
Specific responsibilities will be further described in the SC Charter. 
4.2.2 
Clinical Event Adjudication Committee 
The Clinical Event Adjudication Committee (CEAC) will be assembled to ensure quality and 
timely event reporting. The role of the CEAC will be to adjudicate a pre-specified set of 
safety endpoints, including major adverse cardiac events (eg, death, stroke, acute myocardial 
infarction) as listed in Section 9.3. The committee will be composed of experienced 
cardiovascular specialists and experts who will review all pertinent blinded, clinical, and 
diagnostic source documentation and independently adjudicate any cardiovascular (CV) 
events. The processes to identify coded events for submission to the committee members for 
adjudication and their completion of electronic case report forms (eCRFs) will be described 
in a separate CEAC Charter. The CEAC full committee will meet quarterly or as needed to 
review discordant cases and conduct their responsibilities as outlined in the CEAC Charter. 
The CEAC Charter and associated data management plan will also describe how the 
communication of information to and from the CEAC will be handled to ensure timely 
delivery of adjudicated data for Independent Data Monitoring Committee (IDMC) meetings. 
4.2.3 
Independent Data Monitoring Committee 
An IDMC will meet at regular intervals to review ongoing study data. The role of the IDMC 
will be to act in an advisory capacity to the Sponsor with respect to safeguarding the interest 
of study participants, assessing interim unblinded safety data, and advising the Sponsor on 
important emerging study conduct issues. The IDMC may formulate recommendations in 
relation to the evaluation procedures and methodologies being employed to survey and detect 
potential safety signals. Meeting frequency, membership, and conduct will be described in 
the IDMC Charter. 
5 
SELECTION OF STUDY POPULATION 
5.1 
General Study Population and Clinical Sites 
Approximately 220 participants with symptomatic oHCM are expected to enroll in this study 
at up to ~90 clinical sites worldwide. 
5.2 
Inclusion Criteria 
Each participant must meet the following criteria to be enrolled in this study. 
1. Able to understand and comply with the study procedures, understand the risks involved 
in the study, and provide written informed consent according to federal, local, and 
institutional guidelines before the first study-specific procedure 


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2. Is at least 18 years old at Screening 
3. Body weight is greater than 45 kg at Screening 
4. Has adequate acoustic windows to enable accurate TTEs (refer to Echocardiography Site 
Instruction Manual) 
5. Diagnosed with oHCM consistent with current AACF/AMA and ESC guidelines, ie, 
satisfy both criteria below (criteria to be documented by the echocardiography core 
laboratory): 
a. Has unexplained LV hypertrophy with nondilated ventricular chambers in the absence 
of other cardiac (eg, hypertension, aortic stenosis) or systemic disease and with 
maximal LV wall thickness ≥15 mm (or ≥13 mm with positive family history of 
HCM) as determined by core laboratory interpretation, and 
b. Has LVOT peak gradient ≥50 mmHg during Screening as assessed by 
echocardiography at rest, after Valsalva maneuver, or post-exercise (confirmed by 
echocardiography core laboratory interpretation) 
6. Has documented LVEF ≥55% by echocardiography core laboratory read of Screening 
TTE at rest 
7. Has LVOT gradient with Valsalva maneuver at Screening TTE of ≥30 mmHg, 
determined by echocardiography core laboratory 
8. Has NYHA Functional Class II or III symptoms at Screening 
9. Has documented oxygen saturation at rest ≥90% at Screening 
10. Is able to perform an upright CPET and has a respiratory exchange ratio (RER) ≥1.0 at 
Screening per central reading; if the RER is between 0.91 and 1.0, the participant may be 
enrolled only if it is determined by the central CPET laboratory that peak exercise has 
been achieved in the subject (the only permitted reasons for subpeak performance are [1] 
a decrease in systolic blood pressure (SBP) or [2] severe angina as described in the CPET 
Laboratory Manual) 
11. Female participants must not be pregnant or lactating and, if sexually active, must use 
one of the following highly effective birth control methods from the Screening visit 
through 3 months after the last dose of investigational medicinal product (IMP). 
• combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation or progestogen-only hormonal contraception associated with 
inhibition of ovulation by oral, implantable, or injectable route of administration 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
• Female is surgically sterile for 6 months or postmenopausal for 1 year. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, 
and/or documented bilateral tubal occlusion at least 6 months prior to Screening. 


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Females are considered postmenopausal if they have had amenorrhea for at least 1 
year or more following cessation of all exogenous hormonal treatments and follicle 
stimulating hormone levels (FSH) are in the postmenopausal range. 
Male partners must also use a contraceptive (eg, barrier, condom or vasectomy) 
5.3 
Exclusion Criteria 
A participant who meets any of the following criteria will be excluded from the study. 
1. Previously participated in a clinical study with mavacamten 
2. Hypersensitivity to any of the components of the mavacamten formulation 
3. Participated in a clinical trial in which the participant received any investigational drug 
(or is currently using an investigational device) within 30 days prior to Screening, or at 
least 5 times the respective elimination half-life (whichever is longer) 
4. Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM, 
such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy 
5. Has any medical condition that precludes upright exercise stress testing 
6. Has a history of syncope within 6 months prior to screening or history of sustained 
ventricular tachyarrhythmia with exercise within 6 months prior to Screening 
7. Has a history of resuscitated sudden cardiac arrest (at any time) or known history of 
appropriate ICD discharge/shock for life-threatening ventricular arrhythmia within 
6 months prior to Screening (Note: history of anti-tachycardia pacing (ATP) within 6 
months or ever is allowed) 
8. Has paroxysmal, intermittent atrial fibrillation with atrial fibrillation present per the 
investigator’s evaluation of the participant’s ECG at the time of Screening 
9. Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks 
prior to Screening and/or not adequately rate controlled within 6 months of Screening 
(Note – patients with persistent or permanent atrial fibrillation who are anticoagulated 
and adequately rate-controlled are allowed) 
10. Current treatment (within 14 days prior to Screening) or planned treatment during the 
study with disopyramide or ranolazine 
11. Current treatment (within 14 days prior to Screening) or planned treatment during the 
study with a combination of β-blockers and verapamil or a combination of β-blockers and 
diltiazem 
12. For individuals on β-blockers, verapamil, or diltiazem, any dose adjustment of that 
medication <14 days prior to Screening or an anticipated change in treatment regimen 
using these medications during the study 
13. Has been successfully treated with invasive septal reduction (surgical myectomy or 
percutaneous ASA) within 6 months prior to Screening or plans to have either of these 
treatments during the study (note: individuals with myectomy or percutaneous ASA 


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performed >6 months prior to Screening may be enrolled if study eligibility criteria for 
LVOT gradient criteria are met) 
14. ICD placement or pulse generator change within 2 months prior to Screening or planned 
new ICD placement during the study (pulse generator changes, if needed during the 
study, are allowed) 
15. Has QT interval with Fridericia correction (QTcF) >500 ms at Screening or any other 
ECG abnormality considered by the investigator to pose a risk to participant safety 
(eg, second-degree atrioventricular block type II) 
16. Has documented obstructive coronary artery disease (>70% stenosis in one or more 
epicardial coronary arteries) or history of myocardial infarction 
17. Has known moderate or severe (as per investigator’s judgment) aortic valve stenosis at 
Screening 
18. Has any acute or serious comorbid condition (eg, major infection or hematologic, renal, 
metabolic, gastrointestinal, or endocrine dysfunction) that, in the judgment of the 
investigator, could lead to premature termination of study participation or interfere with 
the measurement or interpretation of the efficacy and safety assessments in the study 
19. Has pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation 
20. History of malignant disease within 10 years of Screening: 
• Participants who have been successfully treated for nonmetastatic cutaneous 
squamous cell or basal cell carcinoma or have been adequately treated for cervical 
carcinoma in situ or breast ductal carcinoma in situ (DCIS) can be included in the 
study 
• Participants with other malignancies who are cancer-free for more than 10 years 
before Screening can be included in the study 
21. Has safety laboratory parameters (chemistry, hematology, coagulation, and urinalysis) 
outside normal limits (according to the central laboratory reference range) at Screening as 
assessed by the central laboratory; however, a participant with safety laboratory 
parameters outside normal limits may be included if he or she meets all of the following 
criteria: 
• The safety laboratory parameter outside normal limits is considered by the 
investigator to be clinically not significant 
• If there is an alanine aminotransferase or aspartate aminotransferase result, the value 
must be <3 × the upper limit of the laboratory reference range 
• The body size–adjusted estimated glomerular filtration rate is ≥30 mL/min/1.73 m2 
22. Has a positive serologic test at Screening for infection with human immunodeficiency 
virus, hepatitis C virus, or hepatitis B virus 
23. Has a history or evidence of any other clinically significant disorder, condition, or disease 
that, in the opinion of the investigator, would pose a risk to participant safety or interfere 
with the study evaluation, procedures, or completion 


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24. Is currently taking, or has taken within 14 days prior to Screening, a prohibited 
medication, such as a cytochrome P450 (CYP) 2C19 inhibitor (eg, omeprazole or 
esomeprazole), a strong CYP 3A4 inhibitor, or St. John’s Wort (see Appendix 2 for more 
details). Alternatives, such as pantoprazole are allowed and may be discussed with the 
medical monitor 
25. Prior treatment with cardiotoxic agents such as doxorubicin or similar (see Appendix 2) 
26. Unable to comply with the study requirements, including the number of required visits to 
the clinical site 
27. Is a first degree relative of personnel directly affiliated with the study at the clinical study 
site, any study vendor, or the study Sponsor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.5 
Screening and Enrollment 
An informed consent form (ICF) must be signed and dated by the participant before any 
study-specific tests or procedures may be performed. 
Each participant will be assigned a unique identification number (subject number) when 
informed consent has been obtained. The subject number will be generated and assigned by 
the IXRS. Participants will be considered enrolled once a subject number has been assigned. 
The subject number will be used to identify the participant throughout the study and should 
appear on all study-related documentation. Subject numbers will not include identifiable 
information. The investigator will ensure that informed consent is obtained from each 
participant before any study specific procedures are performed. 
Participants that fail to meet all inclusion criteria or present with an exclusion criterion may 
be re-screened. Refer to IXRS Manual for re-Screening criteria and procedures. 


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6 
RANDOMIZATION AND BLINDING PROCEDURES 
6.1 
Randomization 
Participants who meet the inclusion/exclusion criteria will be randomized via an IXRS in a 
1:1 ratio to receive double-blind treatment with either mavacamten 5 mg or matching placebo 
QD. Randomization will be stratified according to NYHA functional classification (II or III), 
current treatment with β-blocker (yes or no), type of ergometer (treadmill or exercise 
bicycle), and consent for the CMR substudy (yes or no). 
6.2 
Study Blinding 
Participants will be randomized to receive mavacamten or matching placebo in a 
double-blind manner such that the principal investigator, site staff including the pharmacist, 
and the participant will not know which study drug is being administered. In addition, the 
Sponsor, the central and core laboratories, and clinical site monitors will be blinded to 
assigned treatment. Mavacamten and matching placebo will be identical in appearance in 
order to preserve the blind. Study drug (mavacamten or matching placebo) will be labeled 
with a unique identifying number that will be assigned to a participant through the IXRS. 
Blinded results (ie, echocardiography results, and PK data) will be transferred to the IXRS by 
the respective core laboratories in order to perform dose adjustments and dose 
discontinuations in a blinded manner. In addition, sham dose discontinuation and 
unscheduled visits, if necessary, will be performed in the placebo arm in order to keep the 
blind. However, site personnel who perform specific tasks such as reviewing 
echocardiograms for safety may be unblinded (see Study Reference Manual). In the case of 
LVEF ≤30% the investigator will be notified as described in Section 7.3.3. The 
pharmacovigilance team will be unblinded for suspected unexpected serious adverse reaction 
(SUSAR) reporting. The IDMC may also be unblinded to treatment allocation and all safety 
and efficacy data. 
6.3 
Methods for Unblinding 
All efforts should be made to keep participants blinded to treatment assignment. However, 
participants may be unblinded to treatment assignment upon request from the investigator 
and agreement by the Sponsor if knowledge of treatment assignment will impact future 
treatments or clinical care of the participant. Unblinding by the investigator independently of 
the Sponsor also may occur if an AE or toxicity necessitates identification of the medication 
for the welfare of the participant. Please refer to the Suvoda Interactive Web Response 
System Manual for the unblinding process and contact information. 
7 
STUDY TREATMENT 
Study drug is defined as mavacamten (MYK-461) or placebo. 
All randomized study participants will receive either mavacamten or placebo in a 
double-blinded manner. 


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7.1 
Mavacamten and Matching Placebo, Administration, and Schedule 
Mavacamten capsules and matching placebo have the same appearance. The study drug 
presentation is size 2, blue opaque capsules printed with a yellow band on the body and black 
band on the cap. Each capsule contains white to off-white powder. The active capsules are 
supplied in 4 strengths: 2.5 mg, 5 mg, 10 mg, and 15 mg. 
Mavacamten active and placebo capsules have been manufactured according to current Good 
Manufacturing Practice (cGMP) regulations. They will be supplied in high-density 
polyethylene bottles with induction seals and child-resistant caps at 30 count per bottle. All 
study drug will be labeled according to applicable local regulatory guidelines. 
The mavacamten active and placebo capsules must be stored at 2°C to 25°C (36°F to 77°F) 
in the packaging supplied by MyoKardia. Study medication at the investigational site will be 
stored in a secure area with access limited to authorized study personnel. 
Study drug will be supplied to participants in 30-count high-density polyethylene bottles that 
are appropriately labeled. Refer to Table 1 for the complete schedule of study drug 
administration. Participants will take study drug as directed by the study investigator. The 
participants will be instructed to store the study drug capsules and bottles in a cool, dry place. 
Study drug should be taken with approximately 8 ounces (48 tablespoons or ~235 mL) of 
water. 
7.2 
Treatment Compliance 
Compliance with study drug will be monitored by capsule count at all study visits. Refer to 
the Pharmacy Manual for details. 
Participants should be instructed to take the study drug at approximately the same time every 
day (±8 hours). If the dosing window is missed, the participant should not take study drug 
that day. Participants should never receive 2 doses of study drug within an 8-hour period. 
On study visit days, participants should wait to take study drug until after they reach the 
clinic and have a PK blood sample taken as indicated in the schedule of study procedures 
(Table 1). Any concomitant medication may to be administered prior to all exercise testing. 
7.3 
Dose Adjustments 
7.3.1 
Blinded Dose Adjustments During Double-blind Treatment Period 
7.3.1.1 
Dose Titration Period (Day 1 to Week 14) 
The double-blind treatment period will include a two-step dose titration scheme at Week 8 
and Week 14 designed to achieve safe and effective dosing for each participant based on 
their own PK/PD response parameters (Figure 1 and Table 3). 
In this study, the starting dose of study drug is mavacamten 5 mg or matching placebo QD, 
and each participant will receive this dose of study drug from Day 1 through Week 8 unless a 


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PK/PD criterion is met at Week 4, in which case the dose will be reduced at Week 6 
(Table 3). 
At Weeks 8 and 14, participants will undergo dose adjustment (dose increase, dose decrease, 
or dose unchanged) based on their results from PK/PD assessments at Week 6 and Week 12, 
respectively (Table 3). Note that Table 3 is provided for IXRS programming. Sites and 
investigators will not be actively adjusting doses. All dose adjustments will occur in a 
double-blind manner via IXRS, and all participants, whether receiving mavacamten or 
matching placebo, will undergo assessments that could lead to a blinded dose adjustment. 
However, note that participants who are on placebo will remain on placebo (in blinded 
fashion) unless the participant has a temporary discontinuation as described in Section 7.3.2 
or a permanent treatment discontinuation as described in Section 7.3.3 and Section 10.1.3. 
For added safety, a Week 8 blood sample will be drawn to determine trough plasma PK. If 
PK is greater than 700 and less than 1000 ng/mL, then an unscheduled visit will be arranged 
2 weeks later to reduce dose (see Table 3). Dose reduction will occur via IXRS. To avoid 
potential bias the IXRS will randomly select a participant from the placebo arm to undergo 
an unscheduled follow-up visit (see also Section 6.2). 
If the mavacamten dose is decreased at any time during the study, then the participant will 
continue on the reduced dose to the EOT (Week 30) unless safety concerns or intolerability 
arise requiring further dose reduction or dose discontinuation. 
Based on PK modeling informed by prior mavacamten clinical studies, and depending on the 
demographics of enrolled patients, it is estimated that the following percentages of 
participants will reach the target steady-state concentrations for the following doses: 2.5 mg 
(< 1%), 5 mg (5–20%), 10 mg (40–50%), and 15 mg (30–55%). 
If the PK/PD criteria for down-titration are met, then dose reduction will be implemented as 
follows: 


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7.3.1.2 
Dosing Period (Week 14 to Week 30) 
After the second dose titration at Week 14, there are no further up-titrations; the intent is for 
dose to remain unchanged unless for safety or other reasons for premature discontinuation 
(see Section 7.3.2 and Section 10.1). After Week 14, participants will return to the clinical 
site for monitoring at scheduled 4-week intervals (Weeks 18, 22, 26, and 30 [±7 days]). At 
each visit, AEs, concomitant medications, and symptoms will be assessed, and ECG, plasma 
PK, and TTE will be performed for ongoing safety monitoring. Compliance with study drug 
will also be monitored by capsule count at each visit. If PK/PD criteria are met, then an 
unscheduled visit 2 weeks later will be required to reduce dose as shown in Table 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
7.3.2 
Blinded Dose Adjustment Leading to Temporary Discontinuation 
In addition to the blinded dose adjustments described above (which are not preceded by dose 
discontinuation), at any time (T) during the treatment period, dosing may be temporarily 
discontinued in the case of exaggerated pharmacologic effect (systolic dysfunction), higher 
than expected plasma concentration, or excessive QTcF prolongation as described below. 
If participant has a resting LVEF <50%, plasma drug concentration ≥1000 ng/mL, or QTcF 
stopping criteria described below, as determined by the echocardiography central laboratory, 
PK analysis laboratory, or ECG core laboratory, respectively, it will be communicated to the 
investigator and Sponsor that a criterion for temporary discontinuation has been met. Upon 
receipt of this information, the study site/investigator will contact the participant by 
telephone and instruct the participant to discontinue study drug and to return for an onsite 
visit within 2 to 4 weeks (T+2 to 4 weeks). This could correspond to a scheduled or 
unscheduled visit. Note that to avoid potential bias the IXRS will randomly select 
participant(s) from the placebo arm to undergo an unscheduled follow-up visit (see also 
Section 6.2). 


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Criteria for temporary discontinuation due to QTcF prolongation are as follows and depend 
on QRS width as determined by the ECG core laboratory: 
• If QRS is narrow (<120 ms), then temporary discontinuation criteria are the smaller 
of: a 15% increase from baseline QTcF OR QTcF ≥520 ms 
• If QRS is wide (≥120 ms), then temporary discontinuation criteria are the smaller of: 
a 15% increase from baseline QTcF OR QTcF ≥550 ms 
At the follow-up visit (T+2 to 4 weeks), ECG, plasma PK, and TTE will be repeated and 
another unscheduled visit will be planned for 2 weeks later (T+4 to 6 weeks). If LVEF ≥50% 
AND plasma drug concentration <1000 ng/mL AND QTcF duration is below programmed 
discontinuation rules, then the study drug will be restarted at a lower dose (at T+6 weeks) for 
remainder of the study as follows (previous dose → restart dose): 
• Placebo → placebo 
• 2.5 mg → placebo 
• 5 mg → 2.5 mg 
• 10 mg → 5 mg 
• 15 mg → 10 mg 
 
If LVEF, plasma drug concentration and/or QTcF persist out of range at the follow-up visit, 
then study drug will be switched permanently to placebo. 
7.3.3 
Management of Double-blind Treatment in the Case of LVEF ≤30% at 
Study Site 
Results of TTE performed by study site sonographers at each scheduled visit following 
randomization should be kept blinded to the investigator and other study site personnel. An 
exception may occur if LVEF ≤ 30% is measured at the site. Under these circumstances, the 
sonographer should review and re-measure the findings with at least one other non-study 
professional qualified in echocardiography assessment who is not the investigator (eg, echo 
laboratory director, other experienced sonographer or non-study cardiologist). If the result is 
confirmed (LVEF ≤ 30%), then the investigator will be immediately notified and study drug 
will be discontinued. 
Low LVEF ≤ 30%, as measured by local site, is one of the criteria for permanent treatment 
discontinuation (Section 10.1.3), as this finding will lead to Investigator being unblinded. It 
should be subsequently managed as described in Section 10.1.4. 


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7.3.4 
Management of Double-blind Treatment in the Case of New or Worsening 
Heart Failure 
If a participant experiences heart failure related to systolic dysfunction, no further study drug 
should be administered and administration of therapeutic doses of a β-adrenergic agonist 
(eg, 5 to 10 µg/kg/min dobutamine infusion) should be considered. Additional supportive 
measures, eg, IV volume supplementation and/or the use of arterial vasoconstrictor agents 
(α-adrenergic agonists) should complement the use of a β-adrenergic agonist. Aside from this 
specific advice regarding the role of a β-adrenergic agonist, appropriate care will be 
determined by the treating medical personnel. 
New or worsening heart failure associated with systolic dysfunction is one of the criteria for 
permanent treatment discontinuation (Section 10.1.3) and should be subsequently managed 
as described in Section 10.1.4. 
7.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Participants with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL], or 
international normalized ratio or signs/symptoms of hepatitis may meet the criteria for 
withholding of study medication or other protocol-required therapies. Withholding is either 
permanent or conditional depending on the clinical circumstances discussed below (as 
specified in the United States (US) Food and Drug Administration (FDA) Guidance for 
Industry–Drug Induced Liver Injury: Premarketing Clinical Evaluation, July 2009). 
7.4.1 
Criteria for Permanent Withholding of Study Drug Due to Potential 
Hepatotoxicity 
Study drug should be discontinued permanently and the participant should be followed 
according to the recommendations in Appendix 3 for possible drug-induced liver injury 
(DILI), if all the criteria below are met: 
• TBL >2 × upper limit of normal (ULN) or international normalized ratio >1.5 
• AND increased AST or ALT, if the baseline value was <ULN and AST or ALT elevation 
is >3 × ULN 
• AND no other cause for the combination of laboratory abnormalities is immediately 
apparent. Important potential causes for abnormal AST/ALT or TBL values include, but 
are not limited to, the following: 
◦ 
Obstructive gall bladder or bile duct disease 
◦ 
Viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella) 
◦ 
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right sided heart failure 


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◦ 
Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
◦ 
Heritable disorders causing impaired glucuronidation (eg, Gilbert syndrome); 
α-1 antitrypsin deficiency 
◦ 
Autoimmune hepatitis 
◦ 
Nonalcoholic steatohepatitis (NASH) or other fatty liver disease 
If an alternative cause for hepatotoxicity is identified or less stringent conditions developed 
than what is noted above, the investigator will determine whether study drug and other 
protocol-required therapies should be permanently or temporarily discontinued based on 
participant population and/or severity of the hepatotoxicity or event, as deemed appropriate 
for the safety of the participant. 
7.4.2 
Criteria for Conditional Withholding of Study Drug Due to Potential 
Hepatotoxicity 
For participants who do not meet the criteria for permanent withholding of study medication 
outlined above, study drug should be withheld if ANY of the following criteria are met, and 
the participant should be evaluated for DILI: 
• Elevation of either AST or ALT, regardless of baseline AST or ALT value, if: 
o >8 × ULN at any time 
o >5 × ULN and <8 × ULN for ≥2 weeks 
o >5 × ULN and <8 × ULN and unable to adhere to enhanced monitoring schedule 
• OR: clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant pain/tenderness, fever, nausea, vomiting, jaundice, 
rash or eosinophilia >5%). If such signs or symptoms are coupled with ALT or AST 
elevations >3× ULN, study medication should be withheld 
• OR: TBL >3× ULN at any time 
OR: ALP >8× ULN at any time 
 
Study drug should be withheld pending an investigation into alternative causes of DILI. If 
study drug is withheld, the participant should be followed according to recommendations in 
Appendix 3 for possible DILI. Rechallenge may be considered if an alternative cause, such as 
acute hepatitis B infection, is discovered and the laboratory abnormalities resolve to normal 
or baseline (Section 7.4.3). 
7.4.3 
Criteria for Rechallenge of Study Drug After Potential Hepatotoxicity 
The decision to rechallenge the participant should be discussed and unanimously agreed by 
the investigator and Sponsor. 


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If signs or symptoms recur with rechallenge, then study drug will be permanently 
discontinued. Participants who clearly meet the criteria for permanent discontinuation (as 
described in Section 7.4.1) should never be rechallenged. 
7.5 
Overdose 
An overdose is defined as taking more capsules of study drug than directed. An overdose 
may be suspected by the investigator or spontaneously reported by the participant. An 
overdose may be symptomatic or asymptomatic. 
In the event of suspected overdose, the investigator should contact the medical monitor. No 
further double-blind treatment should be administered. The participant should be closely 
monitored clinically for AEs/SAEs, with supportive measures undertaken as clinically 
indicated. If necessary, corrective measures such as initiation of inotropic support with 
adrenergic agents, levosimendan, and/or PDE III inhibitors and other supportive measures as 
described in the 2013 ACCF/AHA Guideline for the Management of Heart Failure 
  
 and in the 2016 ESC Guidelines for the Diagnosis and Treatment of 
Acute and Chronic Heart Failure 
 [Table 12.5]) should be 
implemented. 
7.5.1 
Reporting and Follow-up of Overdose 
If a participant should experience an overdose, the investigator will report the overdose 
within 24 hours, even if there are no signs or symptoms associated with the overdose in the 
participant. Follow-up on the participant’s condition will be conducted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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. 
8 
RISKS AND PRECAUTIONS 
8.1 
General 
Based on nonclinical data and the available clinical data, the most likely risks are those 
associated with higher exposures resulting in an excessive decrease in cardiac contractility 
(reduced LVEF), which could result in the development of signs or symptoms of systolic 
heart failure. 
Safety testing in other mammalian species has demonstrated that dose-limiting toxicity is 
related to exaggerated pharmacologic effect and not to off-target adverse effects. For 
overdose, see Section 7.5. 
8.2 
Pregnancy 
8.2.1 
Avoidance of Pregnancy 
Women of childbearing potential must use appropriate methods of birth control as listed in 
Section 8.2.2. Women of nonchildbearing potential are defined as women who are 
permanently (surgically) sterilized or are postmenopausal. Permanent sterilization includes 
hysterectomy, bilateral oophorectomy, and bilateral tubal occlusion or ligation at least 
6 months prior. Women are considered postmenopausal if they have had amenorrhea for at 
least 1 year or more following cessation of all exogenous hormonal treatments and FSH 
levels are in the postmenopausal range. 
8.2.2 
Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those that result in a low failure rate 
(<1% per year) when used consistently and correctly. From the time of Screening through 
3 months after the last dose of study drug, female participants should practice true abstinence 
or use effective means of contraception as follows: 


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• combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation or progestogen-only hormonal contraception associated with 
inhibition of ovulation by oral, implantable, or injectable route of administration 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
• Female is surgically sterile for 6 months or postmenopausal for 1 year. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, 
and/or documented bilateral tubal occlusion at least 6 months prior to Screening. Females 
are considered postmenopausal if they have had amenorrhea for at least 1 year or more 
following cessation of all exogenous hormonal treatments and follicle stimulating 
hormone levels (FSH) are in the postmenopausal range. 
Male partners must also use a contraceptive (eg, barrier, condom or vasectomy) 
8.2.3 
Reporting and Follow-up of Pregnancies 
All pregnancies in female participants and female partners of male participants receiving at 
least 1 dose of study drug must be reported if they occur anytime from first dose to 3 months 
after the last dose of study drug. The investigator is responsible for informing MyoKardia 
within 24 hours of knowledge of the pregnancy even if no AE has occurred. The participant 
will be asked to provide information on the outcome of the pregnancy, including premature 
termination. Spontaneous miscarriage and congenital abnormalities will be reported as SAEs. 
9 
STUDY ASSESSMENTS AND PROCEDURES 
The investigator is responsible for ensuring that all staff involved in the study are familiar 
and comply with the content of this section. 
The following describes the study procedures to be performed during the study. Additional 
details are provided in Table 1 and Table 2 of this document. When several assessments are 
to be conducted at the same time point, the preferred order of assessments is ECG, vital 
signs, PK, and then TTE all prior to study drug dosing. The order of assessments may vary 
slightly at specific time points (eg, additional 1-hour postdose PK sampling on Day 1 and 
Week 30/EOT) to facilitate the most contemporaneous performance of the required 
assessments. Unscheduled or additional safety assessments may be performed if necessary, in 
the opinion of the investigator. Whenever possible discussion with the medical monitor is 
encouraged. 
For assessments that require the participants to be in a semi-recumbent or supine position, 
assessments should be conducted with participants in the same position at all time points. 


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9.3 
Safety Assessments 
Safety will be assessed throughout the study. Safety assessments include medical history, 
physical examinations, ECGs, vital signs, observed and participant-reported AEs, pregnancy 
testing, and safety laboratory results. Any abnormal findings judged by the investigator to be 
clinically important will be recorded as an AE. 
The following safety endpoints will be adjudicated by the CEAC: Death, stroke, acute 
myocardial infarction, all hospitalizations (CV and non-CV), heart failure (HF) events 
(includes HF hospitalizations and urgent emergency room (ER)/outpatient (OP) visits for 
HF), atrial fibrillation/flutter (new from screening), ICD therapy, resuscitated cardiac arrest, 
ventricular tachyarrhythmias (includes ventricular tachycardia (VT) and ventricular 
fibrillation (VF); also any Torsades de Pointe identified during CEAC review). 
9.3.1 
Medical History 
A complete medical history will be recorded at the Screening visit, which will include 
evaluation (past or present) of the following: general, head and neck, eyes, ears, nose, throat, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, gynecological/urogenital, 
musculoskeletal/extremities, skin, neurological/psychiatric, endocrine/metabolic, 
hematologic/lymphatic, allergies/drug sensitivities, past surgeries, substance abuse, or any 
other diseases or disorders as well as participation in clinical studies (study medication 
and/or device or other therapy). 
9.3.2 
Physical Examination 
At selected visits, a complete physical examination will be conducted including a 
neurological examination (gross motor and deep tendon reflexes), height (Screening only) 
and weight, and assessment of the following: general appearance, skin, head and neck, 
mouth, lymph nodes, thyroid, abdomen, musculoskeletal, cardiovascular, and respiratory 
systems. At all other visits, an abbreviated cardiopulmonary physical examination will be 
conducted, with other systems assessed as directed by interval history. 
Height (cm) and body weight (kg) will be measured at Screening, and body mass index 
(kg/m2) will be calculated. Participants will be required to remove their shoes and wear 
clothing as specified by the clinical site. 
Body weight will be captured in clinic at Screening and Week 30. 
9.3.3 
12-lead ECG 
12-lead ECG evaluations will be performed after 10 minutes of rest at Screening and at all 
onsite study visits except for the Day 1, Week 8 and 14 visits. On visits during the treatment 


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period ECGs will be taken prior to dosing. All ECG data will be sent to a central cardiac 
laboratory and transmitted to IXRS. 
The investigator may perform 12-lead ECG safety assessments if he/she considers it is 
required for any other safety reason. These assessments should be recorded as an 
unscheduled assessment. 
9.3.4 
Cardiac Monitoring Device 
At 3 time points during the study, participants will wear a small device to collect continuous 
HR and rhythm data for approximately 48 hours (Table 1). The monitoring device uses 
surface electrodes, internal electronics to capture a continuous ECG waveform, removable 
memory card to store data over 48 hours, and a battery to power the device (see manual). 
Following a period of data collection, the memory card will be transported to a core 
laboratory where the continuous ECG waveforms will be uploaded for analysis. The analysis 
will provide full disclosure capabilities for HR and heart rhythm over the period during 
which the device was properly applied and functioning. The device will be used to explore 
the pattern of HR and heart rhythm before and during treatment with study drug. 
9.3.5 
Vital Signs 
Vital signs are to be assessed at each onsite study visit except the Week 8 and 14 visits. At 
Screening, ET, Week 30/EOT, and Week 38, complete vital signs including temperature, HR, 
respiratory rate, and blood pressure (BP) will be obtained. At all other visits, only HR and BP 
are required. 
Vital signs will be obtained with the participant in the same position; BP will be taken after 
resting for at least 5 minutes via an automated recorder. 
At all visits, vital signs will be taken prior to dosing. Alert values will be flagged. Refer to 
the Study Laboratory Manual for additional details. 
9.3.6 
Other Safety Assessments 
Refer to Section 11 for information on AE assessment and Section 7.6.3 for concomitant 
therapy assessments. 
Safety laboratory results will be assessed in an ongoing manner. A central safety laboratory 
will be used. Laboratory parameters are provided in Appendix 1. 
Serum pregnancy testing will be performed at Screening for all females of childbearing 
potential. In addition, urine pregnancy testing either in clinic or at home will be conducted 
every 4–6 weeks throughout the study. Confirmatory serum testing will be performed if any 
urine test is positive. 


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9.4 
Cardiac Magnetic Resonance Imaging Substudy 
For qualified participating sites, participants will have the option to participate in the CMR 
substudy. Approximately 80 participants will be enrolled (~40 per treatment group). 
Participants will undergo CMR up to 5 days prior to Day 1 and up to 5 days prior to Week 
30. Refer to the CMR Substudy Reference Manual for additional details. 
9.5 
Participant Restrictions During this Study 
The following restrictions apply for the specified times during the study period. If a 
participant does not comply with these restrictions or tests positive in any laboratory tests 
(eg, drug, alcohol, pregnancy), he or she may be excluded or withdrawn from the study. 
• Starting 72 hours prior to the first dose until the final follow-up visit, participants should 
not engage in unaccustomed intensive exercise except during protocol-specified exercise 
tests 
• Starting at Screening, participants will be required to abstain from blood or plasma 
donation until 3 months after the final study visit 
• Starting on Day 1 until the final follow-up visit, participants will be asked to abstain from 
grapefruit or grapefruit juice, Seville oranges, and quinine (eg, tonic water) 
 
Contraception requirements are discussed in Section 8.2. 
9.6 
Study Procedures by Visit 
Study procedures are presented by visit in Table 1 and Table 2. Every effort should be made 
to avoid protocol deviations. 
At the investigator’s discretion, unscheduled visits may be conducted for the assessment of 
AEs, new or worsening symptoms, physical examinations, vital signs, laboratory tests, 
ECGs, and/or TTEs. The investigator should make best effort to contact the medical monitor 
before conducting an unblinded TTE if possible. Refer also to Section 7.3.2. All information 
collected from unscheduled visits will be recorded on the eCRF and included in the clinical 
database. 
9.7 
Visit Scheduling 
All visits should occur within the visit window (±7 days). If an evaluation is missed, 
reschedule and perform it as close as possible to the original date. 


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10 
TREATMENT DISCONTINUATION AND WITHDRAWAL FROM 
STUDY 
In general, every effort should be made to keep a participant on double-blind treatment for as 
long as possible during the study unless a safety concern arises. Treatment Discontinuation 
may either be temporary or permanent and if permanent, the degree to which a study 
participant withdraws can vary. Each of these circumstances are described below. 
10.1 
Treatment Discontinuation 
10.1.1 
Temporary Treatment Discontinuation 
Temporary treatment discontinuation 
• Will be implemented when a predefined safety threshold has been met (see Section 7.3.2) 
• May be considered by the investigator in the case of an AE/SAE or for another reason 
 
As a general rule, any discontinuation of study drug should be initially considered temporary 
unless permanent treatment discontinuation is mandated by the protocol (see Section 10.1.3). 
If a temporary treatment discontinuation was caused by a safety threshold being met, blinded 
treatment will be resumed approximately 4 to 6 weeks later, either at a lower dose or with 
permanent switch to placebo, transmitted via IXRS (see Section 7.3.2). 
In the case of discontinuation for an AE/SAE, the investigator should make a best effort to 
resume study drug as soon as practically possible, assuming there are no safety concerns 
(ie, the investigator is satisfied that in his or her medical judgment, the study drug is unlikely 
to be responsible for the event concerned). 
All temporary treatment interruptions should be recorded in the eCRF. 
10.1.2 
Permanent Treatment Discontinuation 
After a temporary treatment discontinuation, if a safety concern has not resolved or stabilized 
or the investigator suspects that study drug is responsible, the investigator may consider a 
treatment discontinuation as permanent. The investigator should make best effort to contact 
the monitoring team before considering any treatment discontinuation as permanent. 
Permanent treatment discontinuation should be considered a last resort. Every effort should 
be made to collect important safety data if feasible and the study participant agrees. 
In all cases, participants should be encouraged to discuss stopping study drug with the 
investigator or the investigator’s designee so that questions can be addressed, concomitant 
therapy can be adjusted if needed, and a follow-up assessment be arranged. 
Any permanent treatment discontinuation should be recorded in the eCRF. 


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10.1.3 
Criteria for Permanent Treatment Discontinuation 
The following reasons will lead to permanent treatment discontinuation: 
• Pregnancy 
• LVEF ≤30% as determined by local site 
• New or worsening heart failure associated with systolic dysfunction 
• Any breaking of the study blind requested by the investigator 
• Continued administration of study drug is considered by the investigator to be detrimental 
to the participant’s safety or well-being 
• If all the criteria are met for possible DILI (see Section 7.4.1) 
• The participant requests to discontinue study drug 
• The Sponsor requests that the participant permanently discontinues study drug 
 
10.1.4 
Management of Participants After Permanent Treatment Discontinuation 
If a participant permanently discontinues treatment prior to Week 30/EOT, the participant 
will be asked to undergo an ET visit as soon as possible after stopping study drug, using the 
procedure normally planned for the EOT visit, including post-exercise echocardiogram and 
CPET. Subsequently, every effort will be made to have the participant return to the site at the 
times corresponding to his or her remaining scheduled visits (ie, until the end of the study 
and including final CPET study at Week 30), or through the recovery or stabilization of any 
AE to be followed as specified in this protocol, whichever comes last. 
Under circumstances of permanent treatment discontinuation, study participants can: 
• Withdraw from treatment (permanent treatment discontinuation) and agree to participate 
in ET, EOT, and EOS visits. Participants are eligible to complete ET, EOT, and EOS 
visits only if they have received 22 weeks or more of study drug. If they have received 
less than 22 weeks of study drug, they are eligible to participate in the ET visit and visits 
up to EOT (week 30) but not beyond week 30. 
• Withdraw from treatment (permanent treatment discontinuation) and agree to participate 
in the ET and EOT visit. This is the preferred follow-up for participants who have 
received less than 22 weeks of study drug. 
• Withdraw from treatment (permanent treatment discontinuation) and agree to participate 
in the ET visit. This is the preferred follow-up for participants who have received study 
drug, regardless of treatment duration and who do not wish to be followed beyond ET 
visit. 


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• Withdraw from treatment (permanent treatment discontinuation) and all follow-up (see 
Section 10.2) 
 
In case of difficulties to comply and return for all study visits until Week 30, every effort 
should be made to have the participant return for as many study visits as possible, especially 
the Week 30 visit with final CPET. 
For participants who do not withdraw consent for ongoing study participation but fail to 
return to the site, the investigator should make every effort to contact the participant 
(eg, contacting participant’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, particularly vital status. 
Attempts to contact such participants must be documented in the participant’s records 
(eg, number of attempts and dates of attempted telephone contact and receipt for sending a 
registered letter). Then participants will receive a phone call from the investigator at 
Week 38 for vital status assessment. 
10.2 
Withdrawal from Study 
10.2.1 
Withdrawal of Consent for Ongoing Study Participation 
Participants may withdraw from the study before study completion if they decide to do so, at 
any time and for any reason. Withdrawal of consent for treatment (permanent treatment 
discontinuation) described above should be distinguished from withdrawal of consent for 
ongoing study participation with scheduled visits and from withdrawal of consent for 
non-participant contact follow-up (eg, medical records check). 
Participants who withdraw from the study should be explicitly asked about the reason and the 
contribution of any possible AE(s) that led to their decision, and any AE information elicited 
should be documented. The participant may withdraw consent verbally or in writing. If the 
consent is withdrawn verbally, the site should document it appropriately. Preferably the 
participant should withdraw consent in writing and, if the participant or the participant’s 
representative refuses or is physically unavailable, the site should document and sign the 
reason for the participant’s failure to withdraw consent in writing. 
All study withdrawals should be recorded by the investigator in the appropriate eCRF and in 
the participant’s medical records when considered as confirmed. The date of the withdrawal 
and the reason should be documented. 
The Statistical Analysis Plan (SAP) will specify how these participants lost to follow-up will 
be considered for their primary endpoints. 
Participants who have withdrawn from the study cannot be re-randomized (treated) in the 
study. Their inclusion and treatment numbers must not be reused. 


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10.2.2 
Replacement of Participants Who Withdraw from the Study 
Participants who withdraw from the study after receiving an initial dose of treatment will not 
be replaced. If a participant withdraws after randomization and before dosing, that participant 
may be replaced. The replacement participant will undergo the same stratification procedure 
as a new participant; no special replacement randomization schedule is necessary. 
11 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS 
11.1 
Definitions 
11.1.1 
Adverse Event 
An AE is any untoward medical occurrence, or the deterioration of a preexisting medical 
condition (other than the condition that is being treated by the study) associated with the use 
of a study medication in humans, whether or not it is considered related to the study 
medication. An AE (also referred to as an adverse experience) can therefore be any 
unfavorable and unintended sign (eg, tachycardia, enlarged liver, clinically important or 
abnormal laboratory result), participant-reported symptom (eg, nausea, chest pain), or 
evidence of any disease activity temporally associated with the use of a study medication, 
whether or not related to the study medication. 
In clinical studies, an AE can include an undesirable medical condition occurring at any time 
after the participant has signed informed consent, including run-in or washout periods, even 
if no specific treatment has been administered. 
Preexisting medical conditions (other than natural progression of the disease being studied) 
judged by the investigator or participant to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period will be reported as 
AEs or SAEs as appropriate. 
Imaging-based assessments of a decrease in contractility are not considered AEs unless 
associated with symptoms or signs of clinical concern on the part of the investigator. Such 
events should be categorized as an AE defined in terms of those symptoms or signs. 
An AE or SAE can also be a complication that occurs as a result of protocol-mandated 
procedures (eg, invasive procedures such as biopsies). 
For MyoKardia to collect additional information about clinically important laboratory results 
or diagnostic tests (eg, blood, ECG, imaging), at a minimum, the following abnormalities 
should be captured on the AE eCRF: 
• Any test result that meets the definition of an SAE 
• Any clinically important test abnormality that suggests a disease and/or organ toxicity is 
worsening or is new (eg, >3× deviation from the upper or lower limit of the analyzing 
laboratory reference range, or as otherwise specified in the protocol) 


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• Any test abnormality that requires the participant to have study medication discontinued 
or interrupted or in the clinical judgment of the investigator 
• Any test abnormality that requires the participant to receive specific corrective therapy, 
close observation, more frequent follow-up assessment, or further diagnostic 
investigation 
 
The term AE is used generally to include any AE whether serious or nonserious. 
11.1.1.1 
Events Not Meeting the Definition of Adverse Event 
Events that do not meet the definition of AE include the following: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease under study, unless judged by 
the investigator to be more severe than expected for the participant’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 participant’s 
condition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that led to 
the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
• Hospitalization for a preexisting condition, provided that all of the following criteria are 
met:  
o The subject has not experienced an AE. 
o The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery or procedure became necessary because of the expected normal 
progression of the disease. 
11.1.2 
Serious Adverse Event 
An SAE is an AE that fulfills one or more of the following criteria in the opinion of the 
investigator or MyoKardia: 
• Results in death 
• Is immediately life-threatening (places the participant at immediate risk of death from the 
event as it occurred) 
• Requires in-participant hospitalization or prolongation of existing hospitalization 


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• Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it may require medical or surgical intervention to prevent one of the outcomes 
listed above 
11.2 
Adverse Event Reporting and Descriptions 
11.2.1 
Reporting Period and Follow-up 
AEs will be assessed from the time the participant provides informed consent through the 
duration of the study. Preexisting medical conditions that increase in severity from the first 
dose of study medication will be reported as AEs. Preexisting medical conditions that 
increase in severity after providing informed consent but before the first dose of study 
medication will be reported as medical history. 
Any AEs that are unresolved at the participant’s last visit in the study are followed by the 
investigator until resolved or stabilized and are considered irreversible, or the participant has 
died. 
MyoKardia retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
11.2.2 
Adverse Event Attributes 
The following attributes will be recorded for each AE. Additional attributes may be collected 
as required by MyoKardia. 
11.2.2.1 
Description 
All AEs spontaneously reported by the participant or reported in response to the open 
question from the study personnel “Have you had any health problems since you were last 
asked?”, or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms (eg, anemia, not low hemoglobin). However, if a diagnosis is 
known and there are other signs or symptoms that are not generally part of the diagnosis, the 
diagnosis and each sign or symptom will be recorded separately. 
Death is an outcome and not the name of the event. In this situation, the event that led to the 
death is the name of the event. If the cause of death is unknown, “found dead” is an 
acceptable description. 


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11.2.2.2 
Start Date/Time and Stop Date/Time 
The date (and time during the period of residency) that the AE started and the date (and time 
during the period of residency) that the event ended will be recorded. For events that 
continue for long periods of time, recording the end date as the day the event stabilized will 
be acceptable. 
11.2.2.3 
Relationship to Study Treatment (Suspected Adverse Reactions) 
The investigator should assess causality by answering either “yes” or “no” to the question “Is 
there a reasonable possibility that the event may have been caused by the IMP/study 
medication?” 
11.2.2.4 
Intensity 
Record the intensity or severity of the event using the following guide: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
• Life-threatening (urgent intervention indicated) 
• Fatal (event led to death) 
 
11.2.2.5 
Seriousness 
Record SAE criteria described in Section 11.1.2 or indicate that the AE is not serious. 
It is important to distinguish between category (AE vs SAE) and intensity (mild, 
moderate, or severe) of AEs. 
Severity is a measure of intensity (Section 11.2.2.4), whereas seriousness is defined by the 
criteria in Section 11.1.2. 
An AE of severe intensity need not necessarily be considered serious. For example, nausea 
that persists for several hours may be considered severe nausea but not an SAE. On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be an SAE. 
11.2.2.6 
Outcome 
Record the outcome of the event based on the options provided on the eCRF. 
11.3 
Reporting and Evaluation of Serious Adverse Events 
All SAEs occurring during the treatment-emergent period (defined as the period from the 
first administration of study drug to 56 days [5 half-lives] after the last administration of 
study drug [corresponding to Week 30]) regardless of causality will be reported by the 


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investigator or designee to MyoKardia/designee within 24 hours of knowledge of the event 
or sequelae. Deaths and SAEs occurring after the treatment-emergent period and considered 
related to study medication or study procedure must also be reported. SAE reporting 
instructions are provided in the Study Reference Manual. 
SUSARs are SAEs that qualify for mandatory expedited reporting to regulatory authorities 
when the SAE is suspected to be caused by the study treatment and is considered unexpected 
(ie, not defined as expected in the current IB, clinical protocol, or approved labeling for 
marketed products). In this case, MyoKardia or designee will report to the relevant regulatory 
authority(ies) and forward a formal notification describing the SUSAR to investigators, 
according to regulatory requirement. Each investigator must then notify his/her ethics 
committee (EC) of the SUSAR as required by local regulatory authorities and in accordance 
with their EC policy. 
11.4 
Reporting Adverse Events of Special Interest 
Overdose, pregnancy, and LVEF ≤30% as determined by local site read echocardiogram are 
considered Adverse Events of Special Interest (AESI). If AESI occurs, this must be reported 
within 24 hours to MyoKardia. 
12 
STATISTICAL METHODS 
12.1 
Determination of Sample Size 
Approximately 220 participants will be randomized, with 110 participants in each of the 
2 groups. Randomization will be stratified for NYHA functional classification (II or III), 
current treatment with β-blocker (yes/no), type of ergometer (treadmill or exercise bicycle), 
and consent for the CMR substudy (yes or no). The sample size should provide adequate 
power to determine the superiority of mavacamten in improving pVO2 and NYHA functional 
class relative to placebo (see Section 12.2.1). The power calculation is derived assuming a 
true clinically meaningful difference of 25% between mavacamten and placebo participants 
in achieving the clinical response. Based on the MYK-461-004 PIONEER-HCM phase 2 
study, 50% of the participants receiving mavacamten met the clinical responder definition by 
the end of 12-week treatment period. Assuming the same percentage of participants in the 
active treatment arm and 25% in placebo arm will achieve the clinical response at the end of 
30-week dosing period in the current study, the proposed sample size of 110 participants per 
arm will provide 96% power at two-sided 5% statistical significance level. Participants who 
terminate early or cannot be assessed for the clinical response at the end of 30-week dosing 
period will be considered as non-responders. 
12.2 
Study Endpoints 
The study design is a randomized two-arm double-blinded trial, and the conceptual analytical 
approach is to compare the mavacamten treatment arm with the placebo arm. 


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12.2.1 
Primary Efficacy Endpoints 
• Clinical response defined as achieving: 1) An improvement of at least 1.5 mL/kg/min in 
peak oxygen consumption (pVO2) as determined by CPET and a reduction of one or 
more class in NYHA Functional Classification or 2) an improvement of 3.0 mL/kg/min 
or more in pVO2 with no worsening in NYHA Functional Class. 
12.2.2 
Secondary Efficacy Endpoints 
• Change from baseline to Week 30 in post-exercise LVOT peak gradient 
• Proportion of participants with at least 1 class improvement in NYHA functional class 
from baseline to Week 30 
• Change from baseline to Week 30 in pVO2 as determined by CPET 
• Change from baseline to Week 30 in participant-reported health-related quality of life as 
assessed by the KCCQ score 
• Change from baseline to Week 30 in patient-reported severity of HCM symptoms as 
assessed by the HCMSQ score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.2.5 
Safety Endpoints 
• Incidence of major adverse cardiac events (death, stroke, acute myocardial infarction) 
• Incidence of hospitalizations (both cardiovascular (CV) and non-CV)) 
• Incidence of heart failure (HF) events, (includes HF hospitalizations and urgent 
emergency room (ER)/outpatient (OP) visits for HF) 
• Incidence of atrial fibrillation/flutter (new from screening) 
• Incidence of ICD therapy and resuscitated cardiac arrest 
• Incidence of Ventricular tachyarrhythmias (includes VT, VF, and Torsades de Pointe) 
• Incidence of syncope and seizures 
• Frequency and severity of treatment-emergent adverse events (TEAE), treatment-
emergent SAEs, and laboratory abnormalities (including trends in NT-proBNP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.4 
Statistical Analysis 
Before database lock, final SAPs for clinical data and PK data will be prepared that contain 
full details of all planned analyses. The analyses presented here represent an outline of the 
intended methodology. 


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12.4.1 
Analysis Populations 
Six analysis populations are defined in this study: 
• Intention-to-treat (ITT) Population: all randomized participants regardless of whether 
they receive study drug, with analyses conducted according to the randomized treatment 
assignment 
• Per Protocol Population: all randomized participants who reached Week 30 visit and 
completed all efficacy assessments, with analyses conducted by actual treatment received 
• Safety Analysis Population: all randomized participants who receive at least 1 dose of 
study drug, with analyses conducted by actual treatment received 
• PK Analysis Population: all randomized participants who receive at least 1 dose of study 
drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.4.2 
General Considerations 
Descriptive summary statistics for continuous variables will include the number of 
participants, mean, standard deviation (SD) or standard error, median, minimum, and 
maximum. Nominal categorical variables will be summarized using counts and percentages. 
Ordinal variables may be analyzed as continuous variables as if they were continuously 
scaled. 
12.4.3 
Participant Disposition 
The number and percentage of participants who complete and discontinue as well as reasons 
for early discontinuation will be presented. 
12.4.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
12.4.5 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 


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The duration of study drug exposure is defined as last dose date – first dose date + 1 day, 
regardless of intermittent discontinuations. 
A given administration will be considered noncompliant if the participant did not take the 
planned dose of treatment as required by the protocol. No imputation will be performed for 
participants with missing or incomplete data. 
Treatment compliance, above-planned and under-planned dosing percentages will be 
summarized descriptively (number [n], mean, SD, median, minimum, and maximum). The 
participants with compliance <80% will be fully described and summarized. In addition, 
number and percentage of participants with at least 1 dosing administration will be given, as 
well as the number and percentage of participants with 0, (0, 20%), and >20% under-planned 
dosing administrations. 
12.4.6 
Efficacy Analyses 
All efficacy analyses will be performed on the ITT population, with sensitivity analysis also 
performed on the Per Protocol Population. 
12.4.6.1 
Primary Efficacy Endpoint Analyses 
The primary efficacy endpoints of clinical response will be analyzed using the Cochran-
Mantel-Haenszel (CMH) test for stratified categorical data. Early dropouts or participants 
whose response status is unable to be assessed at the end of 30-week dosing period will be 
classified as non-responders. More detailed statistical analysis strategies will be documented 
in the SAP. 
12.4.6.2 
Secondary Efficacy Endpoints Analyses 
The general analytical approach for the secondary efficacy endpoints are as follows: 
• To minimize false discovery among the secondary endpoints appropriate methods will be 
employed to control the familywise Type 1 error. Further details will be specified in the 
SAP. 
• Categorical endpoints will be analyzed by comparing the respective proportions of the 
2 treatment groups using CMH tests with adjusting for stratification factors, or 
Chi-square tests without adjusting for stratification factors, whenever appropriate. 
• Continuous variables will be analyzed by analysis of variance (ANOVA) evaluating the 
treatment group differences against the null of zero difference. 
• Ordinal variables, such as NYHA functional class, will be converted quantitatively as 
ordinal scores (I-IV classes to 1-4 scores, respectively) and analyzed as continuous 
variables. 
Specific details will be provided in the SAP. 


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12.4.8 
Safety Analyses 
All safety analyses will be performed on the Safety Population using the following common 
rules: 
• The baseline value is defined as the last available value before the first administration of 
study drug 
• For quantitative safety parameters based on central laboratory measurements, descriptive 
statistics will be used to summarize results and change from baseline values by visit and 
treatment group; resulting changes may be presented in shift tables or scattergrams 
• The analysis of the safety variables will be descriptive and no hypothesis testing is 
planned 
The safety analysis will focus on the treatment-emergent period, which is defined as the time 
from the first administration of study drug to the last administration of study drug + 56 days. 
12.4.8.1 
Adverse Events 
AEs will be mapped to system organ classes and preferred terms (PTs) using the Medical 
Dictionary for Regulatory Activities (MedDRA). AEs will be monitored during the study and 
the data analyzed with respect to overall incidence as well as severity and potential 
relationship of AEs to study medication. AEs with onset during the treatment-emergent 
period, or with an onset before the first dose of study medication that increases in severity or 
becomes serious during the treatment-emergent period, will be considered 
treatment-emergent. 
Adverse event incidence tables will present the number and percentage of participants 
experiencing at least one TEAE by system organ class (SOC) (sorted by internationally 
agreed order), high-level group term (HLGT), high-level term (HLT) and PT in alphabetical 
order for each treatment group. Multiple occurrences of the same event in the same 


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participant will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each treatment group. 
Adverse event incidence tables will be provided by treatment group for all types of TEAEs: 
all TEAEs, all treatment-emergent SAEs and all TEAEs leading to permanent treatment 
discontinuation. 
Potential Drug-induced Liver Injury 
The incidence of liver-related AEs will be summarized by treatment group. The selection of 
PTs will be based on standardized MedDRA query hepatic disorder. 
Deaths 
The following deaths summaries will be generated: 
• Number and percent of participants who died by study period (treatment-emergent 
period, on-study) summarized on the safety population by treatment received 
• Death in non-randomized participants or randomized and not treated participants 
• TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
investigator) by primary SOC, HLGT, HLT, and PT showing number and percent of 
participants sorted by internationally agreed order of SOC and alphabetic order of HLGT, 
HLT, and PT 
 
Pregnancy 
The following pregnancy summaries will be generated: 
• Number of participants or partners of participants who became pregnant summarized by 
treatment received 
• Outcomes of the pregnancies and analysis of the outcomes 
• TEAE experienced during the pregnancy by primary SOC, HGLT, HLT, and PT showing 
the number and percent of participants sorted by internationally agreed order of SOC and 
alphabetic order of HLGT, HLT, and PT 
 
Overdose 
The following summaries for reports of overdose will be generated: 
• Number of participants who experienced overdose summarized by treatment received 
• Analysis of the cause and occurrence of the overdose 


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• TEAE experienced during the overdose by primary SOC, HGLT, HLT, and PT showing 
the number and percent of participants sorted by internationally agreed order of SOC and 
alphabetic order of HLGT, HLT, and PT 
 
12.4.8.2 
12-lead Electrocardiogram 
The RR, PR, QRS, and QT intervals will be measured and read by a central laboratory. HR 
will be calculated as 60/ (RR × 1000) (with RR expressed in msec) and rounded to the 
nearest integer. 
Correction for Heart Rate 
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. 
Each individual ECG QT value will be corrected for HR. The measured QT data will be 
corrected for HR using QTcF as per the following formulae/method (with QT, RR and QTc 
expressed in msec): 
Fridericia’s Correction: 
 
ECG Numeric Variables 
HR, PR, QRS, and QTcF will be summarized using descriptive statistics. QRS duration, 
manually over-read, will be used to determine which threshold criterion rules to apply for 
temporary discontinuation based on QTcF (eg, QRS duration <120 msec or QRS duration 
≥120 msec). See Section 7.3.2. The change from baseline of these ECG parameters at each 
time point will be listed for each participant. For each time point of measurement, the 
changes from baseline will be summarized using descriptive statistics. 
Categorical Analysis 
The incidence count and percentage of participants with any postdose QTcF values of 
>500 msec, >520 msec, and >550 msec will be tabulated for all participants. Participants 
with QTcF values >520 msec will be listed with corresponding baseline values, ∆QTcF, and 
baseline and treatment HR. The incidence count and percentage of participants with ∆QTcF 
increase from baseline of >30 msec and >60 msec will be tabulated. 
Morphology Findings 
New ECG morphologies for each participant not present on any ECG at baseline for that 
participant will be summarized for all observation time points combined. 
The number and percentage of participants having T-wave morphology changes and/or the 
occurrence of abnormal U-waves that represent the appearance or worsening of the 
morphological abnormality from baseline will be reported. 


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Concentration-QTc Analyses 
A concentration-QTc regression analysis, based on data collected from the ECG recordings 
after drug administration and concentration values for each participant at each matching time 
point, will be performed. The concentration-ECG relationship will be first evaluated by some 
descriptive plots to investigate any potential delayed or sustained effects and explore the 
shape of the relationship. Then, linear or nonlinear models will be implemented to estimate 
the slope and 95% confidence interval of the relationship. Predictions at selected 
concentration values will be computed within the model. 
12.4.8.3 
Laboratory Data 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of 
all laboratory variables (laboratory values and changes from baseline), will be calculated for 
each visit (baseline and post-baseline time points) and presented by treatment group. 
Listings of participants with laboratory values that are out of the reference range will be 
produced. 
Potential Drug-induced Liver Injury 
The liver function tests, namely ALT, AST, ALP, and TBL, are used to assess possible 
drug-induced liver toxicity. 
A graph of distribution of peak values of ALT versus peak values of TBL will be presented. 
Note that the ALT and TBL values are presented on a logarithmic scale. The graph will be 
divided into 4 quadrants with a vertical line corresponding to 3 × ULN for ALT and a 
horizontal line corresponding to 2 × ULN for TBL. 
The normalization (to ≤1 × ULN or return to baseline if baseline >ULN) of elevated liver 
function tests will be summarized by categories of elevation (3 × ULN, 5 × ULN, 10 × ULN, 
20 × ULN for ALT and AST, 1.5 × ULN for ALP, and 1.5 × ULN and 2 × ULN for TBL), 
with the following categories of normalization: never normalized, normalized after 
permanent discontinuation of study drug. Note that a participant will be counted only under 
the maximum elevation category (1-3 × ULN, 3-5 × ULN, 5-10 × ULN, 10-20 × ULN, 
>20 × ULN). 
12.4.8.4 
Vital Signs Data 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of 
all vital sign variables (values and changes from baseline), will be calculated for each visit 
(baseline and post-baseline time points) and presented by treatment group. 
Listings of participants with vital signs values that are out of the reference range will be 
produced. 


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12.4.8.5 
Other Safety Analyses 
Abnormal physical examination results will be listed. Concomitant medications will be 
summarized. 
 
 
 
 
 
-
-
 
 
 
  
 
 
 
 
 
. 
12.4.10 
Interim Analysis 
No interim analysis is planned. 
 
 
 
 
 
 
13 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
13.1 
Compliance Statement 
This study will be conducted in accordance with the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) Guidelines; US Title 21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, and 
312; European Union (EU) GCP; cGMP; the principles enunciated in the Declaration of 
Helsinki; and all human clinical research regulations in the countries where the study is to be 
conducted. 
13.2 
Informed Consent 
The ICFs used for the study must comply with the Declaration of Helsinki, US 21 CFR 
Part 50, ICH GCP guidelines, and any other local regulations. The investigator, or a person 
delegated by the investigator, must explain the medical aspects of the study including the 
nature of the study and the treatment, orally and in writing, in such a manner that the 
potential participant is aware of potential benefits and risks. Potential participants must be 
informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. Participants, or a legal guardian if the participant is unable to, must 
give informed consent in writing. 
Prior to participation in any study-related procedures, participants must sign and date an 
EC-approved written ICF in a language the participant can understand. The informed consent 


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process must be conducted, documented in the source document (including the date), and the 
form must be signed before the participant undergoes any study-specific procedures. 
The language in the written information about the study should be as nontechnical as 
practical and should be understandable to the potential participant. Before informed consent 
is obtained, the investigator should provide the potential participant ample time and 
opportunity to inquire about the study and to decide whether or not to participate. 
All questions about the study should be answered to the satisfaction of the participant. The 
written ICF should be signed and personally dated by the participant and by the person who 
conducts the informed consent discussion. All participants will receive a copy of his/her 
signed and dated ICF. 
13.3 
Ethics Committee 
The term EC used in this document refers to an Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) or equivalent. The EC must review and, if appropriate, 
approve the following documents, as applicable: 
• Study protocol and amendment(s) 
• Written ICF(s) and consent form updates 
• Participant recruitment procedures/documents (eg, advertisements) 
• Written information to be provided to participants 
• IB and available safety information (Note: ECs do not approve IBs but are responsible for 
acknowledging receipt) 
• Information about payments and compensation available to participants 
 
The EC approval must be in writing, clearly identifying the study (by protocol date and/or 
version), the documents reviewed, including informed consent, and date of the review. The 
investigator has the responsibility to provide MyoKardia with the written EC approval prior 
to initiating any study-related procedures. 
The investigator also has the responsibility to inform the EC of the following according to 
the EC’s policy: 
• All SUSARs (as described in Section 11.3) 
• Any new information that may affect adversely the safety of the participants or the 
conduct of the trial 
• Protocol deviations 
• A synopsis of the study report upon study completion 


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Documentation of subsequent reviews of the study must also be forwarded to MyoKardia. 
14 
ADMINISTRATIVE PROCEDURES 
14.1 
Sponsor’s Responsibilities 
MyoKardia reserves the right to terminate the study at any time. MyoKardia and the 
investigators will assure that adequate consideration is given to the protection of the 
participants’ interests. MyoKardia retains the right to terminate the study and remove all 
study materials from a clinical site at any time. Specific circumstances that may precipitate 
such termination are: 
• Request by Health Authority to terminate the study 
• Unsatisfactory participant enrollment with regard to quality or quantity 
• Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on participants, maintain adequate study records or 
inaccurate, incomplete, or late data recording on a recurrent basis 
• The incident or severity of AEs in this or other studies indicating potential health hazard 
caused by the study treatment 
 
14.1.1 
Participant Confidentiality 
The processing of personal data in pursuit of this study will be limited to those data that are 
reasonably necessary to investigate the utility of the study medications used in this study. 
These data will be processed with adequate precautions to ensure confidentiality according to 
applicable laws. 
MyoKardia ensures that the personal data are: 
• Collected for a specified and legitimate purpose 
• Processed fairly and lawfully 
• Accurate and up to date 
 
Explicit consent for the processing of personal data will be obtained prospectively from the 
participating participant. 
MyoKardia, whose responsibilities require access to personal data, agrees to keep the identity 
of participants confidential. This confidentiality will be maintained throughout the complete 
data processing. 


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Participants will be entitled to request confirmation of the existence of personal data held by 
MyoKardia and will have the right to rectify erroneous or inaccurate data up until database 
lock. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.1.3 
Investigator Training 
All clinical sites will have a center-specific study initiation meeting to ensure the center staff 
understands the protocol, study requirements and procedures, and data capture processes. 
This training will take place before the first participant is enrolled. Each clinical site will be 
provided with information regarding GCP and regulations specific to the conduct of the 
clinical studies. Each clinical site will be responsible for ensuring that new team members are 
adequately trained and the training is documented. 
14.1.4 
Ongoing Communication of Safety Information During the Study 
MyoKardia will provide the investigator(s) with documentation of SAEs from this study and 
other studies that are related to mavacamten study drug and are unexpected (refer to 
Section 11.3), as appropriate. The investigator(s) must forward this documentation to the EC 
as described in Section 11.3. 


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MyoKardia will also notify the investigator(s) about any other significant safety findings that 
could alter the safety profile of the IMP from what is described in the protocol and 
significantly affect the safety of participants, affect the conduct of the study, or alter the EC’s 
opinion about the continuation of the study. 
14.1.5 
Study Monitoring 
MyoKardia will monitor this clinical study through remote data checks and monitoring visits 
to check the adequacy of clinical site staff and facilities, and to ensure adherence to the 
protocol, study procedures, and applicable regulations. The clinical site monitor will also 
assess proper eCRF completion and source document retention. The investigator(s) and 
clinical site staff are expected to provide adequate space for monitoring visits and to allocate 
sufficient time to permit adequate review of the study’s progress. The investigator(s) will 
permit study-related monitoring, audits, EC review, and regulatory inspection(s), providing 
direct access to source data/documents and study-related facilities (eg, pharmacy, diagnostic 
laboratories). 
14.1.6 
Study Auditing and Inspecting 
MyoKardia may audit the study conduct, compliance with the protocol, and accuracy of the 
data in 1 or more clinical sites. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, and inspections 
by MyoKardia, EC, government regulatory authority(ies), and MyoKardia’s quality 
assurance personnel or its designees by providing direct access to source data/documents 
after appropriate notification from MyoKardia. 
14.2 
Investigator’s Responsibilities 
14.2.1 
Screening Log 
The investigator must keep a record that lists all participants who signed an informed consent 
and the reason for noninclusion if the potential participant does not ultimately enroll and 
receive IMP. 
14.2.2 
Mavacamten Accountability 
The investigator must ensure that the study drug at the investigational site is kept secured and 
accounted for with access limited to only those individuals authorized by the investigator. 
The investigator, his/her designee, or pharmacist must also maintain adequate records of 
distribution, dispensing, and destruction of all study drug at the end of the study. The study 
drug records must be readily available for inspection by the site monitor and/or auditor. Only 
those sites with institutional, local, state, or federal restrictions in the destruction of material 
will be allowed to return study drug to the depot. No study drug can be destroyed or returned 
to depot until the clinical site monitor has verified the accuracy of the study drug records at 
the clinical site. 


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14.2.3 
Reporting and Recording of Study Data 
Data will be captured and compiled using procedures developed by MyoKardia or designee. 
Electronic data capture (EDC) technology will be used for this study. Clearly record all 
requested study data on the eCRF and other forms as required. Whenever possible, record the 
reason for missing data in the source document. Only individuals who are identified on the 
study personnel responsibility/signature log and who have received appropriate training on 
the EDC system may enter or correct data in the eCRF. Incomplete or inconsistent data on 
the eCRF will result in data queries that require resolution by the investigator or designee. 
Corrections to the eCRF, including the reason for the change, will be automatically 
documented through the EDC system’s audit trail. 
Participant source data must be maintained as original records or a certified copy (ie, copy of 
original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original). The investigator and 
affiliated institution should take measures to prevent the accidental or premature destruction 
of documents. Data collected on the eCRF must match the source documents. 
An eCRF must be completed for each participant who receives at least 1 dose of IMP. All 
entries into the eCRF are ultimately the responsibility of the investigator before approving 
them via an electronic signature. The investigator is responsible for ensuring accurate, 
authentic, and complete records for each participant. 
An electronic copy of the eCRF casebooks will be sent to the clinical site for retention with 
other study documents after full completion of the study. 
14.2.4 
Source Data and Source Documents 
The nature and location of all source documents will be identified to ensure that all sources 
of original data required to complete the eCRF are known to the company and clinical site 
staff. The source documents are to be accessible for verification by the clinical site monitor. 
Source documents should at minimum include the following information for each participant: 
• Participant identification and contact information (name, date of birth, sex, address, 
phone) 
• Documentation verifying participant eligibility (ie, medical history, physical 
examination) 
• Informed consent process documentation and ICF 
• Record of all visits and other contacts 
• Record of all AEs and other safety parameters and all event attributes 
• Record of all concomitant therapy (including start/stop dates, indication for use, dose) 
• Date of study completion and reason for early discontinuation, if applicable 


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The author of an entry in the source documents should be identifiable as well as the date of 
the entry. Direct access to source documentation (medical records) must be allowed for the 
purpose of verifying that the data recorded in the eCRF are consistent with the original 
source data. The investigator will provide certified copies of the participant’s medical records 
in the event that clinical site’s policy does not permit direct access to the electronic medical 
records. 
14.2.5 
Participant Identification Information 
To permit easy identification of the individual participant during and after the study, the 
investigator is responsible for keeping an updated log that contains the participant 
identification information. This document will be reviewed by the clinical site monitor for 
completeness. However, to ensure the participant’s confidentiality, the document will be 
maintained at the clinical site and no copy will be made. 
14.2.6 
Records Retention 
MyoKardia will inform the investigator in writing when it is acceptable to dispose of any 
study records. To enable evaluation and/or audits from regulatory authorities or MyoKardia, 
the investigator agrees to keep records, including the identity of all participants 
(eg, participant identification code list and all source documents), all original signed ICFs, 
copies of all eCRFs, original laboratory reports, detailed records of study medication 
disposition, and all essential documents for the conduct of a clinical study. To comply with 
international regulations, the records should be retained by the investigator for at least 
2 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing application in an ICH region, or until at least 2 years 
have elapsed since the formal discontinuation of clinical development of the IMP. However, 
the investigator may need to retain these documents for a longer period if required by the 
local regulatory requirements or by an agreement with MyoKardia. 
14.2.7 
Protocol Deviations 
Unless there is a safety concern, there should be no deviations from the study protocol. In the 
event of a safety concern, the investigator or designee must document and explain the reason 
for any deviation from the approved protocol. The investigator may implement a deviation 
from, or a change to, the protocol to eliminate an immediate hazard to participants without 
prior EC approval. Immediately after the implemented deviation or change, the investigator 
must submit a report explaining the reasons for the protocol deviation to the EC and 
MyoKardia, if required. The medical monitor will notify the study monitor of the decision. 
14.2.8 
Blood Sample Collection/Storage 
Blood samples that are collected as part of routine medical care or as part of protocol 
procedures may be stored and analyzed for PK or PD analyses. 


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After the study, samples may be used for additional investigation to help identify factors that 
may influence response to therapy. Such samples will be used in compliance with guidelines 
defined by US FDA Guidance on Informed Consent for In Vitro Dialogistic Device Studies 
Using Leftover Human Specimens That are Not Individually Identifiable (issued 
25 Apr 2006) and European Medicines Agency’s Reflection Paper on Pharmacogenomic 
Samples, Testing and Data Handling 
14.3 
Clinical Trial Insurance 
Clinical trial insurance has been undertaken according to the laws of the countries in which 
the study will be conducted. An insurance certificate will be made available to the 
participating clinical sites upon request. 
14.4 
Protocol Amendments and Study Administrative Letters 
Study procedures will not be changed without the mutual agreement of the investigator and 
MyoKardia. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the 
study protocol. 
The amendment should be approved by the EC and the appropriate regulatory authority(ies), 
before implementation, as appropriate. Local requirements should be followed for revised 
protocols. 
If a protocol amendment requires a change to the ICF, the EC will need to approve the 
revised ICF before the revised form is used. 
If there are nonsubstantial changes such as clarification of statement or corrections to 
obvious errors/typos/inconsistencies in the protocol, or change to logistical or administrative 
aspects, then MyoKardia may issue an Administrative Letter. If local regulations require any 
administrative change, it will be communicated to or approved by the EC. 
15 
DATA QUALITY ASSURANCE 
Quality assurance and quality control systems will be implemented and maintained per 
Standard Operating Procedures by MyoKardia, as appropriate, to ensure that this clinical 
study is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, ICH E6 GCP: Consolidated Guidance and the applicable 
regulatory requirements. 


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16 
ADMINISTRATIVE CONSIDERATIONS 
16.1 
Use of Computerized Systems 
This study will require the use of the following electronic data collection methods: 
• EDC system to capture protocol-required participant data: clinical sites will enter data 
from source documents onto eCRFs for each study visit using a web-based interface. 
Study monitors and data management personnel will use this system to review data and 
generate queries and reports as needed 
• Cardiac clinical data management systems will be used to analyze ECG, CPET, 
echocardiographic, and CMR data from digital equipment used by clinical site personnel 
to collect participant data 
• IXRS to dispense IMP and transfer data in double-blind manner 
• Electronic clinical outcomes assessment equipment to allow participants to complete the 
HCMSQ and other PRO questionnaires 
 
In addition, other central data management systems/databases and software may be used to 
collect and analyze study data: 
• Laboratory Information Systems or proprietary systems will be used by laboratories for 
storing and/or analyzing bioanalytical laboratory data collected throughout the study 
• Statistical software will be used for the statistical analysis of the study data as outlined in 
the SAP 
 
Information on the above systems will be provided to the investigator, clinical site personnel, 
and other personnel as appropriate. Measures will be taken to ensure data security and 
accuracy; including, but not limited to, user training, granting of user accounts and privileges 
to trained and authorized personnel in a role-based manner, username/password/electronic 
signature requirements enforcement, programmed and manual edit checks as outlined in data 
validation specifications, computer generated audit trails, centralized data management, and 
routine study monitoring. The systems used will be compliant with US 21 CFR Part 11 and 
Annex 11 to the Rule Governing Medicinal Products in the European Union and the data 
collected will be archived (at minimum) for the period specified by applicable regulatory 
requirements. 
16.2 
Study Records 
The investigator and affiliated institution shall maintain the study documents and records as 
specified in “Essential Documents for the Conduct of a Clinical Trial” (ICH E6 Section 8), 
and as required by the applicable regulatory requirement(s). This includes, but is not limited 
to, the protocol, eCRFs, AE reports, participant source data (original records or certified 


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copies), correspondence with health authorities and EC, consent forms, investigator’s 
curriculum vitae, monitor visit logs, laboratory reference ranges and laboratory certification 
or quality control procedures, and laboratory director curriculum vitae. 
The eCRF must be completed at the time of, or shortly after the participant’s visit or upon 
receipt of test results. Information will be provided to clinical site staff on the proper way to 
complete the eCRF. 
A copy of each participant’s eCRF will be maintained by the investigator. 
17 
PUBLICATION 
The data and results of the study will be owned solely by MyoKardia and shall be 
confidential information of MyoKardia, participant to the investigator’s publication rights, all 
as outlined in the agreement between the investigator/institution and MyoKardia regarding 
the conduct of the clinical study (the “Clinical Study Agreement”). It is understood by the 
investigator that MyoKardia may use the information developed in this study in connection 
with the development of MyoKardia’s proprietary IMP and, therefore, may disclose such 
information as necessary or useful to other clinical investigators or regulatory agencies. To 
allow for the use of the information derived from the study, the investigator understands that 
he/she has an obligation to provide and disclose all study results and all data developed 
during this study to MyoKardia. 
Any publication or presentation of the results or data of this clinical study by the investigator 
may only be made in strict compliance with the provision of the Clinical Study Agreement. 
The investigator understands that it is not MyoKardia’s intention to prevent publication of 
the data generated in the study; rather, MyoKardia reserves the right to control the form and 
timing of such publication for commercial reasons and desires to confirm the scientific 
accuracy of such information prior to such publication or presentation.


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APPENDIX 1 
LABORATORY ASSESSMENTS 
The following safety laboratory parameters will be measured by the central laboratory: 
Hematology/Coagulation 
Serum Chemistry 
Urinalysisa 
• CBC, including differential 
count 
• Sodium 
• Specific gravity 
• Potassium 
• pH 
• Platelet count 
• Chloride 
• Protein 
• INR 
• Bicarbonate 
• Glucose 
• aPTT 
• Calcium 
• Leukocyte esterase 
 
• Magnesium 
• Blood 
 
• BUN 
 
 
• Creatinine 
 
 
• ALP 
 
 
• ALT 
 
 
• AST 
 
 
• Total bilirubin 
 
 
• CPK 
 
 
• Glucose 
 
 
• Protein 
 
 
• Albumin 
 
ALT, alanine aminotransferase; ALP, alkaline phosphatase; aPTT, activated partial thromboplastin time; 
AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; CPK, creatine 
phosphokinase; INR, international normalized ratio. 
a 
Urine microscopy will be performed if there is a significant abnormality in the dipstick. 
 
At the investigator’s discretion, safety laboratory assessments may be repeated on Day -1 to 
confirm study eligibility before dosing of study medication. 
In addition, NT-proBNP and hs-troponin I will be measured by the central laboratory and 
reviewed by the IDMC on a regular basis throughout the study. 
The following nonsafety laboratory parameters will be measured at Screening: 
• Hepatitis panel (HVB and HVC) 
• HIV test 
• FSH 
 


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APPENDIX 3 
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING 
AND ADDITIONAL ASSESSMENTS REPORTING 
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases of 
concurrent aspartate/alanine (AST/ALT) and total bilirubin (TBL) elevation according to the 
criteria specified in Section 7.4 (3 × upper limit of normal [ULN] for AST/ALT and 
2 × ULN for TBL in participants with no underlying liver disease and eligibility criteria 
requiring normal liver function at baseline) require the following: 
• The event is to be reported to MyoKardia as an SAE within 24 hours of discovery or 
notification of the event (ie, before additional etiologic investigations have been 
concluded) 
 
The appropriate case report form (CRF) (eg, Adverse Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities are to be 
completed and sent to MyoKardia. 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Section 11.1.2. 
Additional Clinical Assessments and Observation 
All participants in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI or who experience 
AST/ALT elevations > 3 × ULN are to undergo a period of “close observation” until 
abnormalities return to normal or to the participant’s baseline levels. Assessments that are to 
be performed during this period include the following: 
• Repeat liver chemistries within 24-48 hours (ALT, AST, alkaline phosphatase [ALP], 
TBL); in cases of TBL > 2 × ULN or AST/ALT much greater than 3 × ULN, retesting is 
to be performed within 24 hours 
◦ For participants that are far away from the trial site, it may be difficult for the 
participants to return to the trial site promptly. In this case, the participants should be 
retested locally, but normal laboratory ranges should be recorded, results should be 
made available to trial investigators immediately, and the data should be included in 
the case reports 
 
Participants are to be monitored at least twice weekly; testing frequency may decrease to 
once per week or less if laboratory abnormalities stabilize or the investigational product(s) or 
protocol-required therapies have been discontinued AND the participant is asymptomatic. 
• Obtain prothrombin time/international normalized ratio, fractionated bilirubin, and any 
other potentially relevant laboratory evaluations of liver function or disease 
• Obtain complete blood count with differential to assess for eosinophilia 


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• Obtain appropriate blood sampling for pharmacokinetic (PK) analysis if this has not 
already been collected 
• Obtain a more detailed history of the following: 
◦ 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 medications (including nonprescription medicines and herbal and 
dietary supplements) 
• Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A, B, C, 
D, E, Epstein-Barr virus, herpes simplex virus, etc.); evaluate for other potential causes of 
DILI, including but not limited to: nonalcoholic steatohepatitis (NASH), 
hypoxic/ischemic hepatopathy, and biliary tract disease 
• Obtain gastroenterology or hepatology consult 
• Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider 
these tests in cases of concurrent transaminase and TBL elevation as specified in 
Section 7.4 
• Follow the participant until all laboratory abnormalities return to baseline or normal. The 
“close observation period” is to continue for a minimum of 4 weeks after investigational 
product(s) or protocol-required therapies discontinuation 
 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 


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APPENDIX 4 
INVESTIGATOR’S SIGNATURE AMENDMENT 5 
I have read and understood the contents of the clinical protocol, MYK-461-005, A 
Randomized, Double-blind, Placebo-controlled Clinical Study to Evaluate Mavacamten 
(MYK-461) in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy 
(EXPLORER-HCM), and I agree to the following: 
• To assume responsibility for the proper conduct of this clinical study at this clinical site 
and to conduct the study in compliance with this protocol, any future amendments and 
with any other study conduct procedures provided by MyoKardia/designee 
• That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practices (GCP) and all other applicable regulatory requirements to obtain 
written and dated approval for the Ethics Committee (eg, Institutional or Central Review 
Board [IRB] or Independent Ethics Committee [IEC]) for the study protocol, written 
informed consents, consent form updates, study participant recruitment procedures and 
any other written information to be provided to the study participants before initiating 
this clinical study 
• Not to implement any changes to, or deviations from the protocol without prior 
agreement from MyoKardia and review and documented approval from the EC, except to 
eliminate an immediate hazard to the study participants, or when change(s) involves only 
logistical or administrative aspects of the clinical study 
• To permit direct monitoring and auditing by MyoKardia or MyoKardia’s representatives 
and inspection by the appropriate regulatory authority(ies) 
• That I am thoroughly familiar with the appropriate use of the Investigational Medicinal 
Product (IMP) and other study medication(s) (if applicable), as described in this protocol, 
and any other information provided by MyoKardia or designee, including, but not limited 
to the current Investigator’s Brochure (IB) or equivalent document and marketed 
prescription information (if applicable) 
• To provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically and safely 
• To ensure that all persons assisting in this study are adequately informed about the 
protocol, IMP/study medication(s) and their clinical study-related duties and functions 
 
 
 
Signed: ____________________________________ 
Date: ___________________ 
(sign name with credentials) 
Printed Name: ______________________________ 

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor Name 
MyoKardia, A Bristol Myers Squibb Company 
NCT Number 
NCT03470545 
Sponsor Trial ID 
MYK-461-005 
Official Study Title 
A Randomized, Double-blind, Placebo-controlled 
Clinical Study to Evaluate Mavacamten (MYK-
461) in Adults With Symptomatic Obstructive 
Hypertrophic Cardiomyopathy 
Document Date 
21 April 2020 
 


MYK-461-005:  Statistical Analysis Plan 
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Page 1  
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
MYK-461-005 (EXPLORER-HCM) 
Protocol Title: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED CLINICAL STUDY TO EVALUATE 
MAVACAMTEN (MYK-461) IN ADULTS WITH 
SYMPTOMATIC OBSTRUCTIVE HYPERTROPHIC 
CARDIOMYOPATHY 
Indication: 
Hypertrophic Cardiomyopathy 
Phase: 
3 
Investigational 
Medicinal Product: 
Mavacamten (MYK-461) or matching placebo 
Sponsor: 
MyoKardia, Inc. 
 
 
 
Protocol Version 
Date 
Amendment 5  
October 2019 
SAP Version 
Date 
Version 2 
21 April 2020 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains trade secrets or otherwise confidential and/or proprietary information 
of MyoKardia, Inc. Access to and use of this information is strictly limited and controlled by 
MyoKardia, Inc. Acceptance of this document constitutes agreement by the recipient that the 
contents will be not be copied, distributed, or otherwise disclosed to third parties, and will 
not be used in any way, except as expressly authorized by MyoKardia, Inc. 
 
 


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SIGNATURE PAGE 
 
Protocol Number: 
MYK-461-005 (EXPLORER-HCM) 
Protocol Title: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED CLINICAL STUDY TO EVALUATE 
MAVACAMTEN (MYK-461) IN ADULTS WITH 
SYMPTOMATIC OBSTRUCTIVE HYPERTROPHIC 
CARDIOMYOPATHY 
SAP Version: 
Date: 
Version 2.0 
21 April 2020 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
 
 
 
2. 
STUDY OBJECTIVES ..............................................................................................10 
2.1. 
Primary Objective .......................................................................................................10 
2.2. 
Secondary Objectives .................................................................................................10 
 
 
 
 
 
 
3. 
OVERALL STUDY DESIGN AND PLAN ...............................................................10 
4. 
RANDOMIZATION AND BLINDING PROCEDURES .........................................11 
4.1. 
Randomization ............................................................................................................11 
4.2. 
Study Blinding ............................................................................................................11 
4.3. 
Methods for Unblinding .............................................................................................11 
5. 
DETERMINATION OF SAMPLE SIZE ...................................................................11 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................12 
6.1. 
Study Endpoints ..........................................................................................................13 
6.2. 
Analysis Populations ..................................................................................................15 
6.3. 
Stratification Factors and Subgroups ..........................................................................16 
6.4. 
Missing Data ...............................................................................................................17 
6.5. 
Multiplicity Control ....................................................................................................18 
7. 
SUBJECT DISPOSITION ..........................................................................................18 
7.1. 
Demographics and Baseline Characteristics ...............................................................19 
7.2. 
Extent of Study Treatment Exposure and Compliance ...............................................19 
7.3. 
Protocol Deviations ....................................................................................................19 
7.4. 
Medical History and Concomitant Medications .........................................................19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10. 
SAFETY ANALYSES ...............................................................................................28 
10.1. 
Adverse Events ...........................................................................................................28 
10.1.1. 
Deaths .........................................................................................................................29 
10.1.2. 
Pregnancy ...................................................................................................................29 
10.1.3. 
Overdose .....................................................................................................................29 
10.2. 
12-lead Electrocardiogram ..........................................................................................29 
10.2.1. 
Correction for Heart Rate ...........................................................................................29 
10.2.2. 
ECG Numeric Variables .............................................................................................30 
10.2.3. 
Categorical Analysis ...................................................................................................30 
10.2.4. 
Morphology Findings .................................................................................................30 
10.2.5. 
Concentration-QTcF Analyses ...................................................................................30 
10.3. 
Safety Laboratory Data ...............................................................................................30 
10.3.1. 
Potential Drug-induced Liver Injury ..........................................................................30 
10.4. 
Vital Signs Data ..........................................................................................................31 
10.5. 
Cardiac Rhythm Monitoring (Including Holter Monitor) ..........................................31 
10.6. 
Other Safety Analysis .................................................................................................31 
 
 
 
 
 
 
13. 
INTERIM ANALYSIS ...............................................................................................32 
14. 
SUMMARY OF CHANGES IN THE PROTOCOL PLANNED 
ANALYSES ...............................................................................................................32 
 
 
 
APPENDIX 1. ................................................................................................................................34 
APPENDIX 2. ................................................................................................................................39 


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LIST OF TABLES 
Table 1: 
Responder Thresholds for HCMSQ ............................................................................25 
Table 2: 
Responder Thresholds for KCCQ-23 .........................................................................25 
Table 3: 
Accelerometry Data Analysis Windows .....................................................................26 
Table 4: 
Schedule of Study Procedures ....................................................................................35 
Table 5: 
Analysis Window Definition for NYHA class and NT-proBNP ................................39 
Table 6: 
Analysis Window Definition for CPET, Stress Echo and CMR 
Measurements .............................................................................................................39 
Table 7: 
Analysis Window Definition for Resting TTE ...........................................................39 
Table 8: 
Analysis Window Definition for hs-Cardiac Troponin I ............................................40 
Table 9: 
Analysis Window Definition for PGIS and PGIC ......................................................40 
Table 10: Analysis Window Definition for WPAI-SHP, EQ-5D-5L, and KCCQ-23 ................40 
Table 11: Analysis Window Definition for HCMSQ .................................................................41 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................34 
 
 


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LIST OF ABBREVIATIONS 
A 
peak velocity of late transmitral flow 
ADAU 
Average Daily Accelerometry Unit 
AE 
adverse event 
AESI 
adverse event of special interest 
AF 
atrial fibrillation 
AHA 
American Heart Association 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BSA 
body surface area 
CEAC 
Clinical Event Adjudication Committee 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CMR 
cardiac magnetic resonance 
CPET 
cardiopulmonary exercise testing 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
E 
peak velocity of early diastolic transmitral flow 
eꞌ 
peak velocity of early diastolic septal and lateral mitral annular motion 
ECG 
electrocardiogram 
ECHO 
echocardiography 
eCRF 
electronic case report form 
EQ-5D-5L 
EuroQol 5-dimensions 5-levels questionnaire 
EOS 
end of study 
EOT 
end of treatment 
ESC 
European Society of Cardiology 
ET 
early termination 
FDA 
The United States Food and Drug Administration 
HCM 
hypertrophic cardiomyopathy 
HCMSQ 
Hypertrophic Cardiomyopathy Symptom Questionnaire 
HF 
Heart failure 
HR 
heart rate 


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ICD 
implantable cardioverter-defibrillator 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IPD 
important protocol deviations 
ITT 
intention-to-treat 
IXRS 
interactive response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LAVI 
Left atrial volume index 
LLOQ 
lower limit of quantitation 
LV 
left ventricular 
LVEDVI 
LV end-diastolic volume index 
LVEF 
left ventricular ejection fraction 
LVOT 
left ventricular outflow tract 
MedDRA 
Medical Dictionary for Regulatory Activities 
nHCM 
nonobstructive hypertrophic cardiomyopathy 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
NSVT 
nonsustained ventricular tachycardia 
NYHA 
New York Heart Association 
oHCM  
obstructive hypertrophic cardiomyopathy 
PAP 
Psychometric Analysis Plan 
PD 
pharmacodynamic(s) 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcomes 
PT 
preferred term 
pVO2 
peak oxygen consumption 
QD 
once daily 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
steering committee 


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SD 
standard deviation 
SOC 
system organ class 
SRT 
septal reduction therapy 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TTE 
transthoracic echocardiography, transthoracic echocardiogram 
ULN 
upper limit of normal 
US 
United States 
VCO2 
carbon dioxide production 
VE 
volume expired 
VT 
ventricular tachycardia 
WPAI-SHP 
Work Productivity and Activity Impairment Questionnaire-Specific Health 
Problem 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to compare the effect of a 30-week course of mavacamten 
with placebo on clinical response comprising exercise capacity and clinical symptoms in 
participants with symptomatic oHCM. 
2.2. 
Secondary Objectives 
The secondary efficacy objectives of this study are: 
 To compare the effect of a 30-week course of mavacamten with placebo on 
symptoms and LVOT obstruction as determined by Doppler echocardiography 
 To compare the effect of a 30-week course of mavacamten with placebo on exercise 
capacity, clinical symptoms, and patient-reported outcomes (PRO) individually 
 To assess the safety and tolerability of mavacamten 
 To assess the pharmacokinetic (PK) characteristics of mavacamten 
 
 
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3. 
OVERALL STUDY DESIGN AND PLAN 
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter, international, 
parallel group study to evaluate the safety, tolerability, and efficacy of mavacamten compared 
with placebo (1:1) in participants with symptomatic oHCM. Approximately 220 participants will 
be enrolled. This includes ~80 participants (~40 per treatment group) who consent to participate 
in a CMR substudy at selected sites. Randomization will be stratified according to New York 
Heart Association (NYHA) functional classification (II or III) (i.e. NYHA class II or III), current 
treatment with β-blocker (yes or no), planned type of ergometer used during the study (treadmill 
or exercise bicycle), and consent for the CMR substudy (yes or no). 
The expected study duration is approximately 43 weeks: up to 5 weeks for screening, a 30-week 
treatment period, and an 8-week post-treatment follow-up period (±7 days). 
 


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4. 
RANDOMIZATION AND BLINDING PROCEDURES 
4.1. 
Randomization 
Participants who meet the inclusion/exclusion criteria will be randomized via an interactive 
response system (IXRS) in a 1:1 ratio to receive double-blind treatment with either 
mavacamten 5 mg or matching placebo QD. Randomization will be stratified according to 
NYHA class (II or III), current treatment with β-blocker (yes or no), type of ergometer (treadmill 
or exercise bicycle), and consent for the CMR substudy (yes or no). 
4.2. 
Study Blinding 
Participants will be randomized to receive mavacamten or matching placebo in a double-blind 
manner such that the principal investigator; site staff, including the pharmacist; and the 
participant will not know which study drug is being administered. In addition, the sponsor, the 
central and core laboratories, and clinical site monitors will be blinded to assigned treatment. 
Mavacamten and matching placebo will be identical in appearance to preserve the blind. Study 
drug (mavacamten or matching placebo) will be labeled with a unique identifying number that 
will be assigned to a participant through the IXRS. 
Blinded results (ie, echocardiography results, and PK data) will be transferred to the IXRS by the 
respective core laboratories in order to perform dose adjustments and dose discontinuations in a 
blinded manner. In addition, sham dose discontinuation and unscheduled visits, if necessary, will 
be performed in the placebo arm to preserve the blind. However, site personnel who perform 
specific tasks, such as reviewing echocardiograms for safety, may be unblinded (see Study 
Reference Manual). In the case of LVEF ≤ 30% the investigator will be notified as described in 
Section 7.3.3 of the protocol. The pharmacovigilance team will be unblinded for suspected 
unexpected serious adverse reaction (SUSAR) reporting. The IDMC may also be unblinded to 
treatment allocation and all safety and efficacy data. 
4.3. 
Methods for Unblinding 
All efforts should be made to keep participants blinded to treatment assignment. However, 
participants may be unblinded to treatment assignment upon request from the Investigator and 
agreement by the sponsor if knowledge of treatment assignment will impact future treatments or 
clinical care of the participant. Unblinding by the investigator independently of the sponsor also 
may occur if an adverse event (AE) or toxicity necessitates identification of the study drug for 
the welfare of the participant. Please refer to the Suvoda Interactive Web Response System 
Manual for the unblinding process and contact information. 
5. 
DETERMINATION OF SAMPLE SIZE 
Approximately 220 participants will be randomized, with 110 participants in each of the 
2 groups. Randomization will be stratified for NYHA class (II or III), current treatment with 
β-blocker (yes/no), type of ergometer (treadmill or exercise bicycle), and consent for the CMR 
substudy (yes or no). The sample size should provide adequate power to determine the 
superiority of mavacamten in improving peak oxygen consumption (pVO2) and NYHA class 
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assuming a true clinically meaningful difference of 25% between mavacamten and placebo 
participants in achieving the clinical response. Based on the MYK-461-004 PIONEER-HCM 
Phase 2 study, 50% of the participants receiving mavacamten met the clinical responder 
definition by the end of 12-week treatment period. Assuming the same percentage of participants 
in the active treatment arm and 25% in placebo arm will achieve the clinical response at the end 
of the 30-week dosing period in the current study, the proposed sample size of 110 participants 
per arm will provide 96% power at the 2-sided 5% statistical significance level. Participants who 
terminate early or cannot be assessed for the clinical response at the end of the 30-week dosing 
period will be considered nonresponders. 
6. 
GENERAL STATISTICAL CONSIDERATIONS 
The primary analysis will be conducted through the 30-week treatment period. Data collected 
through this time point will be cleaned and locked prior to conducting the primary analysis. 
Once all participants have completed their Week 38/end of study (EOS) visit, all data will be 
cleaned and locked, and analyses using this data will be used to inform study objectives relating 
to follow-up safety and reversibility of drug effect. 
SAS® version 9.4 or higher will be used for statistical analyses, tabulations, and graphical 
presentations. 
In general, descriptive summaries will be presented by treatment group (placebo and 
mavacamten) for values at each visit.  The descriptive summary for continuous variables will 
also be provided for the change from baseline and, if appropriate, for the change from week 30 to 
week 38.  Summaries of continuous variables will include the number of subjects (N), mean, 
standard deviation (SD), median, Q1, Q3, minimum, and maximum. For variables with highly 
skewed distribution (e.g. log-normal distribution), geometric mean and %CV will also be 
reported in descriptive summaries.  Inferential analysis for those variables may be performed 
after log-transformation as deemed appropriate.  Descriptive summaries for categorical variables 
will include the number and percentage of subjects. Unless otherwise stated, denominators for 
percentages will be the number of subjects in the analysis population.  
Between-group comparisons will focus on the comparative performance of mavacamten versus 
placebo. All statistical tests will be conducted at a 2-sided significance level of 0.05. 
In general, baseline is defined as the last nonmissing value on or before the first dose date and 
time (as applicable). For certain data types (eg, accelerometer, PROs, cardiac rhythm monitoring, 
etc.), special considerations may be required. Refer to the specific data section for details.  
Unless otherwise noted, nonsafety (ie. efficacy, pharmacodynamics [PD]) information displayed 
“by visit” will utilize analysis visits as defined by the analysis visit window as opposed to the 
visits at which the information was collected (ie, nominal visit). Data collected at unscheduled or 
early termination (ET) visits will also be mapped to analysis visits. The analysis day for the 
purposes of deriving the analysis visit windows are derived as follows (reference date is the 
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 If date of information (year, month, and day) is completely missing, analysis day 
cannot be calculated and will be treated as missing. If the date is partially missing, 
date will be imputed according to the rules outlined in Section 6.4. 
 If date is < reference date, analysis day = date of information – reference date. If 
date ≥ reference date, analysis day = (date of information – reference date) + 1. 
The visit windows for efficacy and PD assessments will be defined according to their respective 
collection schedules. The rule for defining the analysis window is +/-14 days from the target visit 
date for all post-baseline visits, except for Week 30 and Week 38, which have +/- 28 day 
windows. If 2 adjacent visit windows overlap, the limits of the windows will be adjusted to the 
midpoint between the 2 visits.  The specific window definitions for each endpoint are available 
in Appendix 2 Table 3 to Table 9.   
For efficacy and PD analyses, if a value does not fall within an analysis window, it will not be 
included in the summary analysis. However, these values will be included in data listings and 
SAS data sets.  For post-baseline data, when more than 1 value is available within the same 
analysis visit, the value collected closest to the target visit day will be used for analysis. If 
2 values are the same distance to the closest to target visit day (for example, 1 value is before and 
the other value is after the target day), then the latest value will be selected as the analysis value. 
For a specific analysis window, if the latest collected time point has 2 or more values collected, 
then for continuous data, the average among these results will be derived, and for categorical 
data (eg, yes or no) the clinically ‘worse’ value will be selected. 
Safety data and PK data will be summarized by the nominal visit (per protocol), and unscheduled 
visits will be presented in listings only. If a participant had treatment early terminated (ET) and 
had additional visits after the ET visit, those visits will be relabeled as FU (ie, follow-up)-1, FU-2, 
and FU-3, etc. at 4-week intervals following the ET visit.   
6.1. 
Study Endpoints 
Primary Efficacy Endpoints: 
The primary efficacy endpoint was a clinical response at Week 30 defined as achieving:  
1. An improvement of at least 1.5 mL/kg/min in pVO2 as determined by cardiopulmonary 
exercise testing (CPET) and a reduction of one or more class in NYHA class  
OR 
2. An improvement of 3.0 mL/kg/min or more in pVO2 with no worsening in NYHA class. 
Secondary Efficacy Endpoints: 
 Change from baseline to Week 30 in post-exercise LVOT peak gradient 
 Change from baseline to Week 30 in pVO2 as determined by CPET 
 Proportion of subjects who had at least 1 class of NYHA improvement from baseline 
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 Change from baseline to Week 30 in patient-reported health-related QoL as assessed 
by the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score 
(CSS) 
 Change from baseline to Week 30 in patient-reported severity of HCM symptoms as 
assessed by the Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) 
shortness-of-breath (SoB) subscore 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  


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6.2. 
Analysis Populations 
Four analysis populations are defined in this study: 
 Intention-to-treat (ITT) Population: All randomized subjects, regardless of whether 
they receive study drug, with analyses conducted according to randomized treatment 
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 Safety Analysis Population: All randomized subjects who receive at least 1 dose of 
study drug with analyses conducted by actual treatment received.  
 PK Analysis Population: All randomized subjects who receive at least 1 dose of 
mavacamten 
 
 
 
 
 
 
 
 
6.3. 
Stratification Factors and Subgroups 
The baseline values for the following stratification factors will be summarized using descriptive 
statistics: 
 NYHA class (II or III) 
 Current treatment with β-blocker (yes or no) 
 Type of ergometer (treadmill or exercise bicycle) 
 Consent for the CMR substudy (yes or no). 
The assigned (IXRS) and actual (CRF) stratification factors will be summarized and listed for 
mis-stratified participants.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 


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6.4. 
Missing Data 
In general, missing data will not be imputed unless specifically stated in this SAP. For mixed-
model repeated-measure analyses, missing data are handled implicitly by the model.  For the 
responder analysis of primary and secondary endpoints, refer Section 8.1 and 8.2 for the specific 
handling rules.  
Handling of Missing Data: 
 For values below the lower limit of quantitation (LLOQ), 1/2 LLOQ will be imputed 
unless otherwise specified. 
 For values above the upper limit of quantitation (ULOQ), ULOQ + 1 unit of 
significant digit will be imputed unless otherwise specified. 
 In general, for missing or partial dates the following is noted: 
o Start Dates: 
 If day is missing, then impute it to be the start of the month (eg, 
01MMMYYYY); except if the month and year is equal to the first dose 
date month and year then impute the day to be the same day as the first 
dose date. 
 If month is missing, then impute it to be the start of the year (eg, 
01JANYYYY), except if the year is equal to the first dose date year then 
impute the day and month to be the same as the first dose date. 
 If year is missing, then do not impute. 
o End Dates: 
 If day is missing, then impute it to be the end of the month (eg, 
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assessment date month and year then the day should be imputed to the last 
assessment date day. 
 If month is missing, then impute it to be the end of the year (eg, 
31DECYYYY), except if the year is equal to the last assessment date year 
then the day and month should be imputed to the last assessment date day 
and month. 
 If year is missing then do not impute. 
o For all other type of dates: 
 If only day is missing, then impute it to be the start of the month (eg, 
01MMMYYYY). 
 If month and day are missing, then impute it to be the start of the year (eg, 
01JANYYYY). 
 If year is missing, then do not impute. 
6.5. 
Multiplicity Control 
A sequential testing procedure will be used for multiplicity control. If the primary endpoint is not 
statistically significantly different between treatment groups, none of the tests for secondary 
endpoints will be considered statistically significant despite the nominal p-values. Contingent 
upon significance in the primary endpoint, each of the secondary efficacy endpoints will be 
tested sequentially in the following order, at a 2-sided alpha level of 0.05: 
1. Change from baseline to Week 30 in post-exercise LVOT peak gradient 
2. Change from baseline to Week 30 in pVO2 as determined by CPET 
3. Proportion of subjects who had at least 1 class of NYHA improvement from baseline at 
Week 30  
4. Change from baseline to Week 30 in patient-reported health-related QoL as assessed by 
the KCCQ-23 CSS 
5. Change from baseline to Week 30 in patient-reported severity of HCM symptoms as 
assessed by the HCMSQ SoB subscore 
If any of the endpoints are not statistically significantly different between treatment groups, the 
tests for all subsequent endpoints will not be considered statistically significant despite the 
nominal p-values. 
7. 
SUBJECT DISPOSITION 
The number and percentage of subjects who complete and who prematurely discontinue study 
drug or study, as well as the reasons for premature discontinuation, will be summarized by 
randomized treatment assignment for the ITT Population.  The reason for screen failure will be 
summarized for all screened subjects. 


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7.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by randomized 
treatment assignment for the ITT Population. 
Body surface area (BSA) will be derived using the Du Bois method.   
Cytochrome P450 (CYP) 2C19 genotypes and phenotypes will also be summarized.   
7.2. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received for the Safety Analysis Population. 
The duration of study drug exposure is defined as last dose date – first dose date + 1 day, 
regardless of intermittent interruptions. Adjusted duration will also be derived by taking 
protocol-defined interruptions into account. 
Compliance will be calculated based on the total cumulative dose received divided by the total 
expected cumulative dose. Compliance of taking pills will be calculated based on the total 
number of pills taken divided by the adjusted duration. 
Treatment exposure and compliance will be summarized using descriptive statistics.  The 
compliance of participants with compliance < 80% and those with compliance > 100% will be 
summarized.  
Actual dose adjustments that occurred during the study and expected dose adjustments based on 
protocol-specified criteria will be listed by subject and time point. Any inconsistencies will be 
flagged. 
7.3. 
Protocol Deviations 
Prior to Week 38 database lock, all protocol deviations will be reviewed and confirmed by the 
sponsor. All important protocol deviations will be presented in a by-subject data listing. 
Important protocol deviations (IPDs) will be identified by the sponsor and summarized. 
International Council for Harmonisation (ICH) E3 guidance defines IPD as a subset of protocol 
deviations that may significantly impact the completeness, accuracy, and/or reliability of the 
study data or that may significantly affect a participant’s rights, safety, or well-being. 
7.4. 
Medical History and Concomitant Medications 
Medical history, HCM history, concomitant and prior medications will be summarized and listed 
by treatment group for Safety Analysis Population. 
 
 
 
 
 
 
 
 
 
 
 
 


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10. 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Population using the following 
common rules: 
 The baseline value is defined generally as the last available value before the first 
administration of study drug. 
 The analysis of the safety variables will be descriptive and no hypothesis testing is 
planned. 
The safety analyses will focus on the treatment emergent period, which is defined as the time 
from the first administration of study drug to the last administration of study drug plus 56 days. 
A by-subject listing of all AEs will be provided. 
10.1. 
Adverse Events 
AEs will be mapped to system organ classes (SOCs) and preferred terms (PTs) using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 21.0. AEs will be monitored during the 
study, and AE data will be analyzed with respect to overall incidence, as well as severity and 
relationship of AEs to study drug. AEs with onset during the treatment emergent period or with 
onset before the first dose of study drug that increase in severity or become serious during the 
treatment-emergent period will be considered TEAEs.  
AE summary tables will present the number and percentage of subjects experiencing at least one 
TEAE by SOC and PT by treatment group for the Safety Analysis Population. Multiple 
occurrences of the same event in the same participant will be counted only once in the tables. In 
addition, the AE summary tables will also be presented by SOC, PT, and severity grade.   
AE summary tables will be provided by treatment group for all types of TEAEs: all TEAEs, all 
treatment-emergent serious AEs, study drug related AEs (per investigator assessment), study 
drug related SAEs, all TEAEs leading to permanent treatment discontinuation, and all TEAEs 
leading to death. Similarly, AE incidence during the pre-treatment period (ICF signed date up to 
the first administration of study drug) will be summarized by SOC and PT. Adverse events of 
special interest (AESI; per protocol) will be summarized for frequency of occurrence and 
symptomatic responses.   
TEAEs may also be summarized by Standardised MedDRA Queries (SMQs) or other groupings 
deemed relevant based on AESIs and SAEs observed in the study. Selected TEAEs (e.g. atrial 
fibrillation, atrial flutter, heart failure, syncope, presyncope and dizziness) will be summarized 
and listed by historical medical conditions and treatment group. By-subject listings of all AEs, 
SAEs, TEAEs leading to treatment interruption or discontinuation or study discontinuation will 
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10.1.1. 
Deaths 
The following death summaries will be generated in a summary table or listed in a by-subject 
data listing: 
 Number and percentage of subjects who died by treatment group for the Safety 
Analysis Population  
 Death in non-randomized subjects or randomized but not treated subjects 
 TEAEs leading to death (death as an outcome on the AE eCRF page as reported by 
the investigator) by primary SOC and PT showing number and percentage of subjects 
10.1.2. 
Pregnancy 
The following pregnancy summaries will be generated: 
 Number of participants who became pregnant summarized by treatment group 
 Outcomes of the pregnancies and analysis of the outcomes 
 TEAE experienced during the pregnancy by primary SOC and PT showing the 
number and percent of participants  
10.1.3. 
Overdose 
Overdose is defined per protocol as taking more capsules of study drug than directed.  The 
following overdose information will be provided: 
 Number of subjects who experienced overdose summarized by treatment group 
 Listing of the cause and occurrence of the overdose 
 Summary of TEAEs as symptomatic response to overdose by primary SOC and PT 
showing the number and percent of subjects 
10.2. 
12-lead Electrocardiogram 
12-lead electrocardiogram (ECG) data will be summarized for all subjects in the Safety Analysis 
Population, for subjects without pacing, and for subjects with baseline QRS <120 ms versus 
≥120 ms in the analyses described in this section.  
The RR, PR, QRS, and QT intervals will be measured and read by a central laboratory. HR will 
be calculated as 60/(RR × 1000) (with RR expressed in msec) and rounded to the nearest integer. 
10.2.1. 
Correction for Heart Rate 
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. Each 
individual ECG QT value will be corrected for HR. The measured QT data will be corrected for 
HR using Fridericia-corrected QT interval (QTcF) as per the following formulae/method (with 
QT, RR, and QTc expressed in msec): 


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Fridericia’s correction: 
 
10.2.2. 
ECG Numeric Variables 
HR, PR, QRS, and QTcF and changes from baseline will be summarized by treatment group 
using descriptive statistics. The change from baseline of these ECG parameters at each time 
point will be listed for each subject.  
10.2.3. 
Categorical Analysis 
The number and percentage of subjects with maximun post-dose QTcF values > 450 msec, 
> 480 msec, >500 msec, > 520 msec, and >550 msec will be summarized by treatment group. 
Participants with QTcF values > 500 msec will be listed along with corresponding baseline 
values, QTcF, and baseline and treatment HR. The number and percentage of subjects with 
QTcF increase from baseline > 30 msec and > 60 msec will be summarized by treatment group. 
10.2.4. 
Morphology Findings 
ECG morphologies for each subject will be listed. 
10.2.5. 
Concentration-QTcF Analyses 
The relationship between mavacamten concentration and ∆QTcF will first be evaluated by a 
scatterplot of time-matched concentration and ∆QTcF data. A linear mixed model will be used to 
estimate the slope and 95% CI of the concentration-QTcF relationship. For the linear mixed-
effects model, the fixed effects can include but not limited to concentration and sex, and subject 
will be included as a random effect. Compound symmetry will be implemented for the variance-
covariance structure. 
10.3. 
Safety Laboratory Data 
Safety laboratory data will be summarized by treatment group and visit using descriptive 
statistics. 
Shift tables reflecting changes from baseline (ie, normal to low, high, etc.) will be presented in 
lieu of descriptive statistics of changes from baseline. Listings of laboratory values will be 
generated and the results that are out of the reference range will be flagged.   
10.3.1. 
Potential Drug-induced Liver Injury 
The liver function tests, namely alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase (ALP), and total bilirubin (TBL) are used to assess possible 
drug -induced liver injury (DILI). 
A graph of distribution of peak values of ALT versus peak values of TBL will be presented. ALT 
and TBL values will be presented on a logarithmic scale. The graph will be divided into 
4 quadrants with a vertical line corresponding to 3 × the upper limit of normal (ULN) for ALT 
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The number and percentage of subjects with elevated liver function tests (based on safety 
laboratory data) during the TEAE period will be summarized by categories of elevation 
(>3 × ULN, >5 × ULN, >10 × ULN, >20 × ULN for ALT and AST, >1.5 × ULN for ALP, and 
>1.5 × ULN and >2 × ULN for TBL), along with the following categories of normalization (i.e. 
return to ≤1 × ULN, or return to baseline if baseline > ULN): never normalized, normalized after 
permanent discontinuation of study drug, normalized during treatment period and elevated after 
permanent discontinuation of study drug. Potential Hy’s law cases will be investigated by 
summarizing the number of subjects with elevated ALT or AST (>3 x ULN) and with elevated 
total bilirubin (>2 x ULN) where transaminase elevation coincides with or precedes BILI 
elevation.  
10.4. 
Vital Signs Data 
Vital signs, including heart rate (HR), systolic blood pressure, and diastolic blood pressure, 
values and changes from baseline will be summarized by treatment group and visit using 
descriptive statistics.  
10.5. 
Cardiac Rhythm Monitoring (Including Holter Monitor) 
The summary statistics of maximum HR, atrial fibrillation (Afib) percentage time, and VT 
(sustained or non-sustained) frequency will be calculated for each cumulative 48-hour Holter 
monitoring period and summarized by treatment group and visit. For each of the cardiac event 
type (Afib and VT), the number of subjects with ≥ 1 occurrence will be summarized.  The 
percentage of time in Afib and number of VT episodes per subject will also be summarized. 
Additional parameters (eg, supraventricular tachycardia, premature ventricular contractions, 
pauses) may be summarized and analyzed as appropriate. 
10.6. 
Other Safety Analysis 
Listing of patients with ICD therapy (shock) and appropriateness of therapy as per event 
adjudication will be provided. 
Abnormal physical examination results will be listed by subject and clinical significance. 
The number of subjects who met treatment discontinuation criteria per protocol, as well as who 
met each temporary study drug interruption, will be summarized by treatment and criteria met. 
 
 
 
 
 
 
 
 
 
 
 


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13. 
INTERIM ANALYSIS 
No interim analysis is planned for this study. Week 30 analysis is the primary analysis to 
evaluate the efficacy, and week 38 analysis is the safety follow up analysis. 
14. 
SUMMARY OF CHANGES IN THE PROTOCOL PLANNED 
ANALYSES 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 1.  
Figure 1: 
Study Schema 
 
Abbreviations: CPET, cardiopulmonary exercise testing; ECG, electrocardiogram; PK, pharmacokinetics; QD, once 
daily; stress echo, post-exercise stress echocardiography; TTE, transthoracic echocardiogram; wks, weeks. 
 


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Table 4: 
Schedule of Study Procedures 
Assessmenta 
Screeningb 
Day -35 to 
Day -1 
Day 
1 
Week 
4 
(±7 d) 
Week 
6 
(±7 d) 
Week 
8 
(±7 d) 
Week 
12 
(±7 d) 
Week 
14 
(±7 d) 
Week 
18 
(±7 d) 
Week 
22 
(±7 d) 
Week 
26 
(±7 d) 
ETc 
Week 
30 
(±7 d)/ 
EOT 
Week 
34 
(±7 d) 
(call) 
Week 
38 
(±7 d)/ 
EOS 
General Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight (in clinic) 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Prior/concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ICD information downloadedf 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
ECGg 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Vital signsh 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Cardiopulmonary Assessments 
Resting TTEi 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Post-exercise stress 
echocardiographyj 
X 
 
 
 
 
 
 
 
 
 
X 
Xj 
 
 
CPETk 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Cardiac monitoring devicel 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Accelerometer attachedm 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Laboratory Assessments 
Hepatitis panel and HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Coagulation panel 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
Chemistry 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
Hematology 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
hs-cardiac troponin I 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
NT-proBNPo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 


MYK-461-005:  Statistical Analysis Plan 
MyoKardia, Inc. 
Version 2.0 
 
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Table 4: 
Schedule of Study Procedures (Continued) 
Assessmenta 
Screeningb 
Day -35 to 
Day -1 
Day 
1 
Week 
4 
(±7 d) 
Week 
6 
(±7 d) 
Week 
8 
(±7 d) 
Week 
12 
(±7 d) 
Week 
14 
(±7 d) 
Week 
18 
(±7 d) 
Week 
22 
(±7 d) 
Week 
26 
(±7 d) 
ETc 
Week 
30 
(±7 d)/ 
EOT 
Week 
34 
(±7 d) 
(call) 
Week 
38 
(±7 d)/ 
EOS 
FSHp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(women)q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)q 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
Symptom Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA functional classification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Patient-Reported Outcomes 
 
s 
Investigational Medical Product 
IMP QD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administered at sitet 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
IMP complianceu 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Substudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Abbreviations: AE, adverse event; BP, blood pressure; call, telephone contact; CMR, cardiac magnetic resonance imaging; CPET, cardiopulmonary exercise 
testing; CYP, cytochrome P450; d, day; DNA, deoxyribonucleic acid; ECG, electrocardiogram; EOS, end of study; EOT, end of treatment, ET, early termination; 
FSH, follicle-stimulating hormone; HCM, hypertrophic cardiomyopathy; HIV, human immunodeficiency virus; HR, heart rate; hs, high-sensitivity; 
ICD, implantable cardioverter-defibrillator; ICF, informed consent form; IMP, investigational medicinal product; LVOT, left ventricular outflow tract; 
NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association; PK, pharmacokinetic; PRO, patient-reported outcomes; 
QD, once daily; QTcF, Fridericia correction; SAE, serious adverse event; TTE, transthoracic echocardiography. 
a 
Preferred order of assessments is ECG, vital signs, PK, and TTE, all prior to study drug dosing unless otherwise described below. 
b 
Screening will require more than 1 visit to accommodate all of the study procedures. 
c 
The ET visit will be scheduled as soon as possible after the participant permanently discontinues study drug. The participant will be encouraged to 
participate in the remaining scheduled study visits, particularly the Week 30 visit and the Week 38/EOS visit. If a participant permanently discontinues 
treatment at or before Week 22, the final visit will be at Week 30. 
d 
At Screening, ET, Week 30/EOT, and Week 38, a complete physical examination will be conducted, including a neurological examination. At all other 
visits, an abbreviated cardiopulmonary physical examination will be conducted, with other systems assessed as directed by interval history. 
 


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Table 4: 
Schedule of Study Procedures (Continued) 
e 
Changes in baseline conditions from once the ICF is signed will be recorded as an AE. All changes unless otherwise specified that occur after the 
administration of study drug will be considered treatment-emergent AEs.  This assessment will occur either by phone call or an in-person visit. 
f 
For participants who have ICDs, information including rhythm strips and events will be downloaded from the ICDs at baseline, at Week 12, and at Week 30, 
or as clinically indicated after any ICD discharge interrogation occurring during the double-blind treatment period. 
g 
Twelve (12)-lead ECGs will be performed after 10 minutes of rest at Screening and prior to dosing at all onsite study visits (except Weeks 8 and 14). Each 
time an ECG is completed, a 10-second paper ECG will be obtained and maintained in the study participant’s source documentation. QTcF value from Day 1 
ECG will not be used for eligibility or for temporary discontinuation. The Day 1 QTcF value will be used as the baseline to determine percent change at 
future visits when criteria for temporary discontinuation are applied. (Note: If for any reason a D1 QTcF is not determined, then QTcF from screening ECG 
will be used in percent change calculation.) 
h 
At Screening, ET, Week 30/EOT, and Week 38, complete vital signs including temperature, HR, respiratory rate, and BP will be obtained. At all other visits, 
only HR and BP are required. If PK sampling is conducted at a visit, vital signs should be collected before PK sampling. Vital signs should be taken with the 
study participant in the same position at all visits. BP should be taken via an automated recorder after resting for at least 5 minutes. 
i 
Resting TTE should be performed prior to post-exercise stress echocardiography or CPET. Resting TTE images and views will be acquired at each onsite 
visit prior to dosing as detailed in the echo site instruction manual. Instantaneous LVOT peak gradient (resting) and provoked LVOT peak gradient (Valsalva 
maneuver) will be assessed by the core laboratory. Left ventricular ejection fraction (LVEF) will be measured at the clinical site by the certified site 
sonographer and subsequently by the core laboratory. The LVEF site read will be kept blinded from the investigator and other study site personnel, except in 
case of locally measured LVEF≤30%. 
j 
For post-exercise stress echocardiography, participants will undergo a standard symptom-limited exercise test after a 4-hour fast by standardized treadmill or 
bicycle ergometer during Screening and Week 30/EOT prior to dosing. Instantaneous LVOT peak gradient will be assessed immediately post-exercise by 
TTE. Post-exercise stress echocardiography may be performed on a different day than CPET. If the 2 procedures are performed on the same day, participants 
must exercise only once, and participants will undergo CPET and then post-exercise TTE. Post-exercise stress echocardiography should be acquired the 
same day or within 72 hours of the Resting TTE and should also be performed as close as possible to ET if it occurs. If post-exercise stress echocardiography 
and CPET are performed on different days, the same sequence of visits must be performed for both screening and EOT. 
k 
CPET by standardized treadmill or bicycle ergometer will be performed during Screening and at Week 30/EOT prior to dosing. CPET is done after a 4-hour 
fast. Record the fasting status and the date and time of the last dose taken prior to CPET. Any concomitant medication may be administered prior to all 
exercise testing. CPET should also be performed as close as possible to ET if it occurs. 
l 
A cardiac monitoring device will be applied during Screening, Week 12, and at the Week 26 visits and retrieved at the Day 1, Week 14, and Week 30 visits, 
respectively. 
m 
An accelerometer will be fastened to the participant’s wrist at Screening (at least 11 days before Day 1) and at the Week 26 visit to collect data on activity. 
Participants will return the accelerometer at the next study visit for data upload and analysis. 
n 
Participants should not take study drug on day of visit prior to blood draw for PK. PK sample will be collected 2 hours before dosing. Additionally, on 
Week 30 (last dose), another PK sample will be collected within 1 to 2 hours postdose. 
o 
NT-proBNP should be drawn before exercise testing if exercise testing is being performed that day. 
p 
FSH testing at Screening for postmenopausal women to confirm postmenopausal status. 
q 
Pregnancy testing for all females of childbearing potential: serum pregnancy test at Screening; urine pregnancy test at all other visits shown (every 
4-6 weeks), and conduct serum test if any urine test is positive. The Week 34 pregnancy testing will be conducted at home. 


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Version 2.0 
 
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Table 4: 
Schedule of Study Procedures (Continued) 
r 
Separate consent is required for HCM genotyping. Note that if a participant with a prior HCM clinical genotype test that was positive for genetic mutation 
consents to provide their results, then no further genotype assessment will be performed; however, participants who have not been tested, participants who 
have tested negative for HCM mutations on clinical panels, and participants who have a positive HCM genotype result but cannot provide the results or will 
not consent to provide the results may consent to have blood drawn on Day 1 for assessment of HCM genotype. 
s 
The pharmacogenetic panel will include CYP 2C19 genotyping and potentially additional DNA sequencing. Pharmacogenetic Screening for CYP 2C19 
genotyping will occur at Screening; samples from screen failures must be destroyed. 
t 
At all onsite visits, study drug will be administered at the investigational site to facilitate collection of PK samples ≤ 2 hours prior to dosing. Note: There is 
no PK sample at Day 1 or Week 14. With the exception of Week 30 when a PK sample is also drawn within 1 to 2 hours postdose, Study drug will be 
administered at the end of the visit when all other assessments have been done, including any drawing of blood. 
u 
All participants will return their study drug dosing containers to the site pharmacy for capsule counts. Refer to the Pharmacy Manual for details. 
v 
The CMR substudy assessment can be completed up to 5 days before the Day 1 visit and up to 5 days before the EOT visit. 
 
 
 


MYK-461-005:  Statistical Analysis Plan 
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Version 2.0 
 
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APPENDIX 2.  
Table 5: 
Analysis Window Definition for NYHA class and NT-proBNP 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Baseline 
Screening <= analysis day <=1 
1 
Week 4 
15 < analysis day <= 36 
29 
Week 6 
36 < analysis day <= 50 
43 
Week 8 
50 < analysis day <= 71 
57 
Week 12 
71 < analysis day <= 92 
85 
Week 14 
92 < analysis day <=113 
99 
Week 18 
113< analysis day <=141 
127 
Week 22 
141< analysis day <=169 
155 
Week 26 
169<analysis day <=197 
183 
Week 30 
197<analysis day <=239 
211 
Week 38 
239<analysis day <=295 
267 
Table 6: 
Analysis Window Definition for CPET, Stress Echo and CMR Measurements 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Baseline 
Screening <= analysis day <=1 
1 
Week 30 
183 < analysis day <= 239 
211 
Table 7: 
Analysis Window Definition for Resting TTE 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Baseline 
Screening <= analysis day <=1 
1 
Week 4 
15 < analysis day <= 36 
29 
Week 6 
36 < analysis day <= 57 
43 
Week 12 
71 < analysis day <= 99 
85 
Week 18 
113< analysis day <=141 
127 
Week 22 
141< analysis day <=169 
155 
Week 26 
169<analysis day <=197 
183 
Week 30 
197<analysis day <=239 
211 
Week 38 
239<analysis day <=295 
267 
 


MYK-461-005:  Statistical Analysis Plan 
MyoKardia, Inc. 
Version 2.0 
 
Page 40  
 
Table 8: 
Analysis Window Definition for hs-Cardiac Troponin I 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Baseline 
Screening <= analysis day <=1 
1 
Week 6 
29< analysis day <=57 
43 
Week 18 
113<analysis day <=141 
127 
Week 30 
197 < analysis day<=239 
211 
Week 38 
239<analysis day<=295 
267 
Table 9: 
Analysis Window Definition for PGIS and PGIC 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Baseline 
Screening <= analysis day <=1 
1 
Week 6 
29 < analysis day <= 57 
43 
Week 10 
57 < analysis day <= 85 
71 
Week 14 
85 < analysis day <=113 
99 
Week 18 
113< analysis day <=141 
127 
Week 22 
141< analysis day <=169 
155 
Week 26 
169<analysis day <=197 
183 
Week 30 
197<analysis day <=239 
211 
Week 38 
239<analysis day <=295 
267 
Table 10: 
Analysis Window Definition for WPAI-SHP, EQ-5D-5L, and KCCQ-23 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Baseline 
Screening <= analysis day <=1 
1 
Week 6 
29 < analysis day <= 57 
43 
Week 12 
71 < analysis day <= 99 
85 
Week 18 
113< analysis day <=155 
127 
Week 30 
197<analysis day <=239 
211 
Week 38 
239<analysis day <=295 
267 
 


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MyoKardia, Inc. 
Version 2.0 
 
Page 41  
 
Table 11: 
Analysis Window Definition for HCMSQ 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Baseline 
Screening <= analysis day <= 1 
1 
Week 4 
15 <= analysis day < 36 
29 
Week 6 
36 <= analysis day < 57 
43 
Week 10 
57 <= analysis day < 85 
71 
Week 14 
85 <= analysis day < 113 
99 
Week 18 
113 <= analysis day < 141 
127 
Week 22 
141 <= analysis day < 169 
155 
Week 26 
169 <= analysis day < 197 
183 
Week 30 
197 <= analysis day < 239 
211 
Week 38 
239 <= analysis day < 295 
267 


MYK-461-005:  Statistical Analysis Plan 
MyoKardia, Inc. 
Version 2.0 
 
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