Clinical trial NCT05174416
Conditions: Obstructive Hypertrophic Cardiomyopathy
Keywords: Mavacamten
Sponsor: LianBio LLC
Start date: 2022-01-04; Completion date: 2024-07-22
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Mavacamtenis a novel, small molecule, selective allosteric inhibitor of cardiac-specific myosin, for the treatment of patients with symptomatic oHCM. This study will assess the efficacy and safety of mavacamten in Chinese adults with symptomatic oHCM.

Detailed description:
This is a randomized, double-blinded, placebo-controlled clinical study witha long-term extension to evaluate the efficacy and safety of mavacamten in Chinese adults with symptomatic oHCM. Approximately 81eligible participants will be enrolled and randomized in a 2:1 ratio (mavacamten:placebo). Participants will receive mavacamten or matching placebofor 30 weeks indouble-blinded manner. After 30-week double-blinded placebo-controlled treatment, eligible participants will receive mavacamten for additional 48 weeks (placebogroup: switch from placebo to mavacamten, mavacamten group: maintain on mavacamten).

Arms: arm 1: Mavacamten Capsules arm 2: Matching Placebo Capsules
Interventions: intervention 1: Mavacamten intervention 2: Placebo
Intervention descriptions: intervention 1: Mavacamten Capsules intervention 2: Matching PBO capsules during placebo controlled period，and mavacamten capsules during long term extension period

Protocol documents:
Prot_000.pdf: 
Protocol No.: LB2001-301 
Confidential 
V3.0/ Dec 25, 2023 
 
 
 
Clinical Study Protocol 
A Phase III, Randomized, Double-blinded, Placebo-controlled Clinical 
Study with A Long-term Extension to Evaluate the Efficacy and Safety of 
Mavacamten in Chinese Adults with Symptomatic Obstructive 
Hypertrophic Cardiomyopathy 
 
 
 
 
 
Investigational product 
Mavacamten Capsules 
Protocol No. 
LB2001-301  
Version and date 
3.0/ Dec 25, 2023 
Phase of development 
III 
Registration Category 
Chemical Drug Class 1 
Proposed Indication 
Obstructive Hypertrophic Cardiomyopathy 
Sponsor 
MyoKardia, Inc. 
Sponsor Contact 
Victoria Florea, MD 
Clinical Trial physician 
Address: 1000 Sierra Point Parkway, Brisbane, CA 
94005 USA 
Phone: +1 786 9993957 
Email: victoria.florea@bms.com 
 
Sean Little 
Clinical Scientist 
Address: 3401 Princeton Pike, Lawrenceville, NJ 08648 
USA 
Phone: +1 330 5694258 
Email: sean.little@bms.com 
Sponsor Address 
 1000 Sierra Point Parkway Brisbane, CA 94005, USA 
China Operation 
Affiliate 
 Bristol-Myers Squibb (China) Investment Co., Ltd. 
China Operation 
Affiliate Adress 
 1717 West Nanjing Road Shanghai 200040, P.R. China 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
 II 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
The information contained in this document is owned by MyoKardia, Inc. This document has 
provided some confidential information to you in accordance with the agreed and signed and 
Disclosure and Nondisclosure Agreement. Without a prior written permission, this document or its 
any copy or any information contained in its cannot be disclosed to any third party (except those 
being participant to the Disclosure and Nondisclosure Agreement and coordinating to carry out the 
research works in the organization).


Protocol No.: LB2001-301 
Confidential 
V3.0/ Dec 25, 2023 
I 
 
Version History 
 
Version Number 
Version Date 
Content of the Main Revisions and 
Reason for Revision 
3.0 
Dec 25, 2023 
Sponsor and China Operation Affiliate 
information updates 
2.0 
 
 
 
 
 
 
 
 
 
April 18, 2022 
1. 
Exclusion criteria #20: clarified that 
exclusion criteria for serologic hepatitis 
B virus test is hepatitis B surface 
antigen positive. 
2. 
Exclusion criteria #21: updated as 
excluding participants with current 
COVID-19 infection or with severe 
complications, due to the change of 
clinical manifestations of the new type 
of COVID-19 virus; 
3. 
Section 4.3.2: clarified that the 
unscheduled visit in the text of "an 
unscheduled visit will be arranged 2 
weeks later to reduce dose" is drug 
dispensing visit only. 
4. 
Section 7.4.3: clarified that the "T+4 to 
6 weeks" visit is drug dispensing visit 
only if performing as unscheduled visit. 
5. 
Appendix 4: clarified and updated as: 1) 
How will TTE be performed in the local 
hospital; 2) The safety monitoring 
requirement for maintaining the study 
drug when the participants are unable to 
return to the study site; 3) The study 
drug will be resumed if the study drug is 
interrupted for < 6 weeks and 
monitoring can be resumed before 
Week 20; 4) Washout requirements to 
re-enter the study; and 5) Patients in 
LTE phase will not allowed to re-enter 
the study. 
6. 
Corrigendum: the protocol number in 
the header is "LB2001-301". 
1.0 
May 26, 2021 
NA 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 1 
 
Synopsis 
Title  
A Phase III, Randomized, Double-blinded, Placebo-controlled Clinical 
Study with A Long-term Extension to Evaluate the Efficacy and Safety 
of Mavacamten in Chinese Adults with Symptomatic Obstructive 
Hypertrophic Cardiomyopathy 
Short Title 
EXPLORER-CN 
Protocol No. 
LB2001-301 
Sponsor 
 MyoKardia, Inc. 
China 
Operation 
Affiliate 
 Bristol-Myers Squibb (China) Investment Co., Ltd. 
Clinical 
Phase 
III 
Investigation
al Product 
• 
Name: Mavacamten Capsules 
• 
Dosage form: Capsules 
• 
Strength: 1 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg 
• 
Storage condition: 2℃ to 25℃ (36℉ to 77℉)  
Study Period 
The study will be composed of 4 periods as below: 
• 
Screening period: up to 4 weeks 
• 
Double-blinded, placebo-controlled treatment period: 30 weeks 
• 
Long-term extension (LTE) period: 48 weeks, including a double-
blinded LTE phase and an open-label LTE phase 
• 
Post treatment follow-up period: 8 weeks (or 20 weeks for poor 
CYP2C19 metabolizer) 
Objectives and Endpoints: The efficacy, safety, and pharmacokinetics (PK) objectives 
and endpoints of the study are as follows: 
Objectives 
Endpoints 
Efficacy 
• 
Primary Efficacy 


Protocol No.: LB2001-301 
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Page 2 
 
To compare the effect of a 30-week 
course 
of 
mavacamten 
with 
placebo 
on 
Valsalva 
left 
ventricular outflow tract (LVOT) 
peak gradient as determined by 
Doppler echocardiography 
• 
Change from baseline to Week 30 in Valsalva 
LVOT peak gradient 
• 
Secondary Efficacy 
To compare the effect of a 30-week 
course 
of 
mavacamten 
with 
placebo on LVOT obstruction 
• 
Change from baseline to Week 30 in resting 
LVOT peak gradient 
• 
Proportion of participants achieving a Valsalva 
LVOT peak gradient < 30 mmHg at Week 30 
• 
Proportion of participants achieving a Valsalva 
LVOT peak gradient < 50 mmHg at Week 30 
To compare the effect of a 30-week 
course 
of 
mavacamten 
with 
placebo on clinical symptoms 
• 
Proportion of participants with at least 1 class 
improvement 
in 
NYHA 
functional 
classification from baseline to Week 30 
To compare the effect of a 30-week 
course 
of 
mavacamten 
with 
placebo on Participant-Reported 
health status individually 
• 
Change from baseline to Week 30 in Kansas 
City Cardiomyopathy Questionnaire (KCCQ) 
Clinical Summary Score (CSS) 
To compare the effect of a 30-week 
course of mavacamten on cardiac 
biomarkers 
• 
Change from baseline to Week 30 in N-
terminal pro-B-type natriuretic peptide (NT-
proBNP) 
• 
Change from baseline to Week 30 in cardiac 
troponin 
To compare the effect of a 30-week 
course 
of 
mavacamten 
with 
placebo on left ventricular (LV) 
mass 
evaluated 
by 
cardiac 
magnetic 
resonance 
(CMR) 
imaging 
• 
Change from baseline to Week 30 in LV mass 
index 
• 
Exploratory Efficacy 
To assess the effect of a 30-week 
course of mavacamten on cardiac 
function and structure as evaluated 
by echocardiography 
• 
Proportion of participants achieving NYHA 
Class I and LVOT peak gradient < 30 mmHg 
for resting and Valsalva gradients at Week 30 
• 
Change from baseline to Week 30 in 
echocardiographic indices of cardiac structure 
and systolic and diastolic function 


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Page 3 
 
To assess the effect of a 30-week 
course of mavacamten on cardiac 
function and structure as evaluated 
by CMR imaging 
• 
Change from baseline to Week 30 in 
myocardial fibrosis 
• 
Change from baseline to Week 30 in cellular 
hypertrophy, cardiac structure, and function 
To assess the effect of a 30-week 
course of mavacamten on 
Participant-Reported health status 
• 
Change from baseline to Week 30 in Total 
Symptom Score and Overall Summary Score 
from KCCQ 
Safety 
To 
assess 
the 
safety 
of 
mavacamten during the 30-week 
double-blinded, 
placebo-
controlled treatment period 
• 
Incidence of left ventricular ejection fraction 
(LVEF) < 50% determined by transthoracic 
echocardiography (TTE) 
• 
Incidence and severity of treatment-emergent 
adverse events (TEAEs), and treatment-
emergent serious adverse events (SAEs) 
• 
Incidence of major adverse cardiac events 
(MACEs; cardiovascular [CV] death, non-fatal 
stroke, non-fatal myocardial infarction) 
• 
Incidence of hospitalizations (due to CV and 
non-CV events) 
• 
Incidence of heart failure (HF) events 
including 
hospitalizations 
and 
urgent 
emergency room/outpatient visits for HF 
• 
Incidence of atrial fibrillation/flutter (new 
from screening, and recurrent) 
• 
Incidence 
of 
implantable 
cardioverter-
defibrillator (ICD) therapy and resuscitated 
cardiac arrest 
• 
Incidence of ventricular tachyarrhythmias 
including ventricular tachycardia, ventricular 
fibrillation, and Torsades de Pointe 
• 
Incidence of adverse events of special interest 
(AESIs; symptomatic overdose, outcomes of 
pregnancy, LVEF ≤ 30%) 
Long-term Extension  


Protocol No.: LB2001-301 
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Page 4 
 
To 
assess 
the 
effects 
of 
mavacamten 
on 
clinical 
symptoms, cardiac biomarkers, 
health status, echocardiographic 
measures, and CMR measures 
over time  
• 
Change from baseline in NYHA class, 
echocardiographic and CMR parameters, 
cardiac biomarkers, and KCCQ results through 
End of Study (EOS) 
To 
assess 
the 
safety 
of 
mavacamten over time 
• 
Incidence of safety events, including: LVEF < 
50%; TEAEs and treatment-emergent SAEs; 
MACEs; hospitalizations; HF events; atrial 
fibrillation/flutter; 
ICD 
therapy 
and 
resuscitated 
cardiac 
arrest; 
ventricular 
tachyarrhythmias, or AESIs 
Pharmacokinetics 
To describe the PK characteristics 
of mavacamten 
• 
Mavacamten plasma concentration over time 
• 
PK parameters using a population PK approach 
Sample Size 
Approximately 81 participants will be randomized in this study with the 
ratio of 2:1, with 54 participants in mavacamten group and 27 
participants in placebo group (2:1 randomization). 
Background 
There are at least 1 million hypertrophic cardiomyopathy (HCM) 
patients in China, among whom, the obstructive hypertrophic 
cardiomyopathy (oHCM) accounts for approximately 70% with poorer 
prognosis (Zou et al., 2004; Maron et al., 2006). The current guideline-
recommended drugs can not alter the natural history of HCM and only 
have modest effect on LVOT gradient. Although the invasive septal 
reduction therapy, including surgical septal myectomy and alcohol septal 
ablation, can effectively improve the outflow obstruction and symptoms 
of oHCM, these procedures expose patients to the inherent risks and 
require expertise that is not universally available in China (Heart Failure 
Committee of Chinese Medical Doctor Association et al., 2017). 
Mavacamten is a novel, small molecule, selective allosteric inhibitor of 
cardiac-specific myosin, for the treatment of patients with symptomatic 
oHCM. The studies including PIONEER-HCM (Phase II) and 
EXPLORER-HCM (Phase III) have demonstrated the efficacy and 
safety of mavacamten in the symptomatic oHCM patients (Heitner et al., 
2019; Olivotto et al., 2020). 
This study will assess the efficacy and safety of mavacamten in Chinese 
adults with symptomatic oHCM.  
Study 
This is a randomized, double-blinded, placebo-controlled clinical study 
with a long-term extension to evaluate the efficacy and safety of 


Protocol No.: LB2001-301 
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Design 
mavacamten in Chinese adults with symptomatic oHCM.  
Approximately 81 eligible participants will be enrolled and randomized 
in a 2:1 ratio (mavacamten:placebo). Randomization will be stratified 
according to current treatment with beta-blocker (yes or no). Participants 
will receive mavacamten or matching placebo for 30 weeks in double-
blinded manner.  
After 30-week double-blinded placebo-controlled treatment, eligible 
participants will receive mavacamten for additional 48 weeks (placebo 
group: switch from placebo to mavacamten, mavacamten group: 
maintain on mavacamten). Treatment allocation and dose will remain 
blinded until all the participants complete 30-week double-blinded 
placebo-controlled treatment and 30-week treatment database is locked. 
Then, the participants will receive treatment in open-label manner. 
Inclusion 
Criteria 
Each participant must meet the following criteria to be included in this 
study: 
1） Is at least 18 years old at screening. 
2） Body weight is greater than 45 kg at screening. 
3） Has adequate acoustic windows to enable accurate TTEs (refer to 
echocardiography related manual). 
4） Diagnosed with oHCM consistent with current American College of 
Cardiology Foundation/American Heart Association, European 
Society of Cardiology, and Chinese Society of Cardiology 
guidelines, i.e., satisfy 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 (e.g., hypertension, aortic 
stenosis) or systemic disease and with maximal LV wall thickness ≥ 
15 mm (or ≥ 13 mm with positive family history of hypertrophic 
cardiomyopathy), as determined by core laboratory interpretation, 
and 
b) Has LVOT peak gradient ≥ 50 mmHg during screening as 
assessed by echocardiography at rest or after Valsalva maneuver 
(confirmed by echocardiography core laboratory interpretation).  
5） Has documented LVEF ≥ 55% by echocardiography core laboratory 
read of screening TTE at rest. 
6） Has a valid measurement of Valsalva LVOT peak gradient at 
screening as determined by echocardiography core laboratory. 
7） Has NYHA Class II or III symptoms at screening. 
8） Has documented oxygen saturation at rest ≥ 90% at screening. 
9） Female participants must not be pregnant or lactating and, if 
sexually active, must be using one of the following acceptable birth 
control methods from the screening visit through 5 months after the 
last dose of investigational medicinal product (IMP). 
a) Estrogen- and progestogen-containing hormonal contraception 


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Page 6 
 
associated with inhibition of ovulation or progestogen-only 
hormonal contraception associated with inhibition of ovulation by 
oral, implantable, or injectable route of administration. 
b) Intrauterine device (IUD). 
c) Intrauterine hormone-releasing system (IHS). 
d) Bilateral tubal occlusion. 
e) Female 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 ≥ 1 year after cessation of all exogenous hormonal 
treatments, and follicle-stimulating hormone levels are in the 
postmenopausal range. 
f) Male partners of female participants must also use a contraceptive 
(e.g., barrier, condom, or vasectomy) from screening through 5 
months after the last dose of study drug. 
10） 
Able to understand and comply with the study procedures, 
understand the risks involved in the study, and provide written 
informed consent according to national, local, and institutional 
guidelines before the first study specific procedure. 
LTE inclusion criteria: 
1) Successful completion of 30-week double-blinded, placebo-
controlled treatment period (still on the study drug).  
2) In the judgment of investigator, participants have no active safety 
concerns. 
Exclusion 
Criteria 
A participant who meets any of the following exclusion criteria will be 
excluded from this study: 
1) 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 (if known), whichever is longer. 
2) Known infiltrative or storage disorder causing cardiac hypertrophy 
that mimics oHCM, such as Fabry disease, amyloidosis, or Noonan 
syndrome with LV hypertrophy. 
3) Has a history of syncope within 6 months prior to screening or 
sustained ventricular tachyarrhythmia with exercise within 6 months 
prior to screening. 
4) Has a history of resuscitated sudden cardiac arrest (at any time) or 
known history of appropriate ICD discharge for life-threatening 
ventricular arrhythmia within 6 months prior to screening. 


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5) Has paroxysmal, intermittent atrial fibrillation with atrial fibrillation 
present per the investigator’s evaluation of the participant’s ECG at 
the time of screening. 
6) 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: participants 
with persistent or permanent atrial fibrillation who are 
anticoagulated and adequately rate-controlled are allowed). 
7) Previously participated in a clinical study with mavacamten. 
8) Hypersensitivity to any of the components of the mavacamten 
formulation. 
9) Current treatment (within 14 days prior to screening) or planned 
treatment during the study with disopyramide, cibenzoline, or 
ranolazine. 
10) Current treatment (within 14 days prior to screening) or planned 
treatment during the double-blinded treatment with a combination 
of beta-blockers and verapamil or a combination of beta-blockers 
and diltiazem. 
11) For individuals on beta-blockers, verapamil, or diltiazem, any dose 
adjustment of that medication within 14 days prior to screening or 
any anticipated change in treatment regimen using these 
medications during the double-blinded treatment. 
12) 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 an unsuccessful 
myectomy or percutaneous ASA procedure performed > 6 months 
prior to screening may be enrolled if study eligibility criteria for 
LVOT gradient criteria are met). 
13) ICD placement within 2 months prior to screening or planned ICD 
placement during the study. 
14) Has QT interval with Fridericia correction (QTcF) > 500 msec when 
QRS interval < 120 msec or QTcF > 520 msec when QRS ≥ 120 
msec or any other ECG abnormality considered by the investigator 
to pose a risk to participant safety (e.g., second-degree 
atrioventricular block type II). 
15) Has documented obstructive coronary artery disease (> 70% 
stenosis in one or more epicardial coronary arteries) or history of 
myocardial infarction. 
16) Has known moderate or severe (as per investigator’s judgment) 
aortic valve stenosis, constrictive pericarditis, or clinically 
significant congenital heart disease at screening. 
17) Has any acute or serious comorbid condition (e.g., 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. 
18) History of malignant disease within 10 years of screening: 


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a) 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. 
b) Participants with other malignancies who are cancer-free for more 
than 10 years before screening can be included in the study. 
19) Has safety laboratory parameters (chemistry, hematology, 
coagulation, and urinalysis) outside normal limits (according to the 
local laboratory reference range) at screening as assessed by the 
local laboratory; however, a participant with safety laboratory 
parameters outside normal limits may be included if he or she meets 
all of the following criteria: 
a) The safety laboratory parameter outside normal limits is 
considered by the investigator to be clinically not significant. 
b) If 
there 
is 
an 
alanine 
aminotransferase 
or 
aspartate 
aminotransferase result, the value must be < 3 × the upper limit of 
the laboratory reference range. 
c) The body size–adjusted estimated glomerular filtration rate is ≥ 30 
mL/min/1.73 m2. 
20) Has a positive serologic test at screening for infection with human 
immunodeficiency virus, hepatitis C virus, or hepatitis B virus 
surface antigen. 
21) Known uncured COVID-19 (coronavirus disease 2019)  infection or 
with severe complication before screening.  
22) 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. 
23) Is currently taking, or has taken within 14 days prior to screening, a 
prohibited medication, such as a cytochrome P450 (CYP) 2C19 
inhibitor (e.g., omeprazole or esomeprazole), a strong CYP3A4 
inhibitor, or St. John’s Wort. Alternatives, such as pantoprazole are 
allowed and may be discussed with the medical monitor. 
24) Prior treatment with cardio toxic agents such as doxorubicin or 
similar. 
25) Unable to comply with the study requirements, including the 
number of required visits to the clinical site. 
26) Is a first degree relative of personnel directly affiliated with the 
study at the clinical study site, any study vendor, or the study 
sponsor. 
27) Is currently taking, or has taken within 14 days prior to screening, 
biotin supplements (multivitamins that contain < 1000 mg biotin are 
allowed during the study but must be stopped 24 hours prior to each 
study visit). 
28) Identified as alcohol addicts.  


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CMR exclusion criteria: 
A participant will be excluded from the CMR assessments if he or she 
has any of the following: 
1) An ICD or pacemaker, or another contraindication or condition not 
suitable for CMR in the judgment of the investigator. 
2) Atrial fibrillation at the time of screening (participants who are in 
atrial fibrillation at the time of imaging will be asked to return at a 
later time within the screening period, and if the participant is still 
in atrial fibrillation, the participant will be disqualified from the 
CMR assessments). 
3) Allergy or contraindication to contrast medium. 
Study 
Procedure 
In this study, participants will go through 4 periods as follow: 
• 
Screening period (up to 4 weeks): 
Participants who sign the informed consent form (ICF) will undergo a 
variety of general, cardiac and laboratory examinations to assess 
eligibility. Screening echocardiogram and electrocardiogram (ECG) 
results as reported by core laboratories will be used to confirm eligibility 
for randomization.  
• 
Double-blinded, placebo-controlled treatment period (30 
weeks): 
Participants who meet all eligibility criteria will be randomized via 
interactive response system to receive mavacamten or matching placebo. 
Pharmacodynamics (PD)/PK based dose titration scheme will be 
designed to achieve safe and effective dosing for each participant.  
During this period, the assessments including TTE, ECG, Holter, and 
CMR (if participant is eligible) will be performed at study visits and read 
by core laboratories. Cardiac biomarkers and PK sample will be 
collected at study visits and tested by central laboratories. This period 
will last 30 weeks.  
The primary endpoint will be evaluated at Week 30 by completing the 
TTE with Valsalva maneuver.  
• 
LTE period (48 weeks): 
Participants who complete the 30-week double-blinded placebo-
controlled treatment period and, in the judgment of the investigator, have 
no active safety concerns will roll directly into the LTE. All participants 
will receive active mavacamten in double-blinded manner until all the 
participants complete 30-week placebo-controlled treatment, database of 
the 30-week treatment is locked. Then the study is unblinded, and 
participants will receive study treatment in open-label manner. For 
participants who were in mavacamten group, they will continue on the 
dose received at the end of Week 30. For participants who were in 


Protocol No.: LB2001-301 
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placebo group, they will receive the 2.5 mg starting dose of mavacamten. 
The dose will be adjusted via PD-based dose titration scheme. 
During the double-blinded LTE phase, TTE will be read by core 
laboratory (data will be blinded to investigator). After study unblinded, 
TTE will be read by sites (data will be unblinded to investigator) and 
also be sent to core laboratories for data analysis. Cardiac biomarkers 
and PK sample will be tested by central laboratories. The LTE period 
will last 48 weeks. 
• 
Post treatment follow-up period (8 weeks/20 weeks if CYP2C19 
poor metabolizer): 
Once participants complete the LTE treatment, they will enter the post 
treatment follow-up period. The participants will receive a phone call 
visit 4 weeks later and onsite visit 8 weeks later. For CYP2C19 poor 
metabolizer, an additional onsite visit will perform 20 weeks later. PK 
sample will be collected at onsite visits and tested by central laboratory. 
Dose 
Regimen 
and 
Administrat
ion 
• 
Dose regimen:  
Double-blinded, placebo-controlled treatment period 
• 
Mavacamten group: mavacamten 2.5 mg starting dose once daily 
(QD). At designated time points, the dose of mavacamten will be 
adjusted (increase, decrease, or remain unchanged) via a 
prespecified dose titration scheme based on core laboratory read of 
echocardiography and pre-dose plasma drug concentration. The 
permissible doses are 1 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg. 
• 
Placebo group: matching placebo QD. 
LTE period 
• 
Mavacamten group: remain on dose of mavacamten at the end of 
Week 30. 
• 
Placebo group: mavacamten 2.5 mg starting dose QD. The dose will 
be adjusted (increase, decrease, or remain unchanged) via a 
prespecified dose titration scheme based on core laboratory read of 
echocardiography during double-blinded LTE phase and based on 
site-read echocardiography during open-label LTE phase. The 
permissible doses are 1 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg.  
• 
The dose may be adjusted after discussion between investigator and 
Sponsor or Sponsor assigned medical monitor after study is unblinded. 
• 
Temporary treatment discontinuation criteria: 
Double-blinded, placebo-controlled treatment period 
The treatment should be temporarily discontinued if a participant meets 
at least one of following criteria:  
1) Resting LVEF < 50% (determined by TTE). 
2) Pre-dose plasma drug concentration ≥ 1000 ng/mL. 
Once the participant meets the temporary treatment discontinuation 
criteria, the investigator will contact the participant by telephone and 


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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 be a 
scheduled or unscheduled visit. 
At the follow-up visit (T+2 to 4 weeks), plasma drug concentration and 
TTE assessments will be repeated and another unscheduled visit will be 
planned for 2 weeks later (T+4 to 6 weeks). If the plasma drug 
concentration is < 700 ng/mL and resting LVEF is ≥ 50% at T+2 to 4 
weeks, participants will restart the treatment at a lower dose at T+4 to 6 
weeks. Otherwise, study drug will be switched to placebo.  
LTE period 
The treatment should be temporarily discontinued when participants 
meet the following criterion:  
1) Resting LVEF < 50% (determined by TTE). 
Once the participant meets the temporary treatment discontinuation 
criterion, the investigator will contact the participant 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. 
At the first follow-up visit (T+2 to 4 weeks), TTE will be repeated to 
confirm whether resting LVEF is ≥ 50%. If resting LVEF is ≥ 50% at this 
visit, then study drug will be restarted at a lower dose. If resting LVEF 
is < 50%, then mavacamten will be discontinued.   
• 
Administration:  
Participants should be instructed to take mavacamten/placebo at 
approximately the same time every day (±8 hours). If the dosing window 
is missed, the participant should not take mavacamten /placebo that day. 
Participants should never receive 2 doses of study drug within an 8-hour 
period. 
Concomitan
t Therapy 
Background cardiomyopathy therapy (e.g., beta-blockers, verapamil, or 
diltiazem) is allowed. Participants should be on optimal medical therapy 
as determined by the primary physician and informed by HCM treatment 
guidelines. The treatment should be well tolerated for at least 2 weeks 
prior to screening, and the site investigator should maintain this 
treatment unchanged (i.e., at a stable dose) during the double-blinded 
treatment, unless safety or tolerability concerns arise and agreed by both 
investigator and Sponsor or Sponsor assigned medical monitor. During 
open-label treatment, investigators should manage background HCM 
medicines as clinically appropriate. The treatment may be adjusted or 
stopped as determined by the investigator in conjunction with the 
Sponsor or Sponsor assigned medical monitor.  
Any change in HCM medicines must be entered into the electronic case 
report form (eCRF) with the rationale for the change. 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 12 
 
PK 
Evaluation 
3mL whole blood will be collected at designated time points for 
mavacamten plasma concentration pre-specified times in enrolled 
participants. 
Safety 
Evaluation 
Safety monitoring will be ongoing during the study. Safety assessments 
include but are not limited to adverse events (AEs), vital signs, physical 
examinations, ECG, TTE, clinical laboratory tests (hematology, 
chemistry, urinalysis and coagulation test), pregnancy test and clinical 
evaluation, etc. 
Safety 
evaluation 
will 
be 
performed 
from 
first 
dose 
of 
mavacamten/placebo administration until EOS visits. 
Statistical 
Methods 
Approximately 81 participants will be randomized with a ratio of 2:1. 
The sample size should provide adequate power to determine the 
superiority of mavacamten in improving Valsalva LVOT gradient 
relative to placebo. The power calculation assumes a true difference of 
30 with a standard deviation of 35 in change from baseline of Valsalva 
LVOT gradient at 30 weeks between the active treatment arm and the 
placebo arm. The proposed sample size will provide > 90% power with 
a 1-sided 2.5% alpha level. Considering the estimated 10% dropout rate, 
the final sample size is 81 patients (54 mavacamten: 27 placebo). 
• 
Efficacy Analysis: 
Primary Endpoint Analysis 
The primary endpoint of Valsalva LVOT peak gradient change from 
baseline to Week 30 will be summarized using descriptive statistics and 
compared between treatment groups using Mixed-Effect Model for 
Repeated Measures (MMRM). The models will include baseline LVOT 
gradient value and stratification factor as a covariate (current treatment 
with beta-blocker or not), and treatment, visit and treatment-by-visit 
interaction as fixed effects, and participants as random effects. More 
detailed statistical analysis strategies will be documented in the 
statistical analysis plan (SAP). 
Secondary Endpoints Analysis 
The general analytical approach for the secondary efficacy endpoints is 
the following (The p-values generated for secondary endpoints will be 
considered as descriptive purpose and thus no multiplicity adjustment 
will be applied): 
• 
Continuous variables will be summarized with descriptive statistics, 
including mean, standard deviation, minimum, median, and 
maximum, and the comparison of the means between treatment 
groups will be analyzed by analysis of covariance that adjusts for 
the baseline value and stratification factor, or MMRM if appropriate. 
• 
Categorical variables will be summarized with number and 
percentage within each category, and the relationship with treatment 
will be analyzed by Cochran-Mantel-Haenszel test that takes into 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 13 
 
account of the stratification factor. Point estimate and 2-sided 95% 
CI for proportion difference between the treatment groups will be 
computed based on the “stratified Miettinen-Nurminen” method. 
Exploratory Endpoints Analysis 
The exploratory endpoints will be summarized using descriptive 
statistics. 
• 
Safety Analysis: 
Safety data will be analyzed using descriptive statistics without formal 
statistical testing. The safety analysis will focus on the treatment- 
emergent adverse event period. All other safety data (vital signs, physical 
examinations, ECG and clinical laboratory tests, etc.) will be 
summarized at each protocol scheduled time point. 
• 
Long-term Extension Analysis: 
The long-term extension endpoints will be summarized using descriptive 
statistics.  
• 
Pharmacokinetics Analysis: 
Plasma concentration will be summarized using descriptive statistics.  
Study 
Committees  
Clinical Event Adjudication Committee (CEAC) 
The 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 MACEs (e.g., CV death, stroke, 
myocardial infarction). The committee will be composed of experienced 
cardiovascular specialists and experts who will review all pertinent 
clinical, and diagnostic source documentation and independently 
adjudicate any CV events. The processes to identify coded events for 
submission to the committee members for adjudication will be described 
in a separate CEAC charter. The CEAC full committee will meet on a 
pre-defined frequency or as needed to review discordant cases. The 
CEAC charter 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. 
Independent Data Monitoring Committee 
An IDMC will meet at regular intervals to safeguard the interest of study 
participants by assessing unblinded safety data from the ongoing study 
and to advise the Sponsor on important emerging study conduct issues. 
The IDMC may provide recommendations regarding the procedures and 
methodologies by surveying and detecting potential safety signals. 
Meeting frequency, membership, and conduct will be described in the 
IDMC charter. 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 14  
Figure 1 Study Schema<1>: Screening to Week 30 
 
CMR = cardiac magnetic resonance; ECG = electrocardiogram; LTE = long-term extension; PK = pharmacokinetics; QD = once daily; TTE = transthoracic 
echocardiogram. 
a  Resting and Valsalva TTE. 
 
 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 15  
Figure 2 Study Schema<2>: LTE Period and Post Treatment Follow-up Period  
 
CMR = cardiac magnetic resonance; ECG = electrocardiogram; LTE = long-term extension; PK = pharmacokinetics; QD = once daily; TTE = transthoracic 
echocardiogram. 
Doses listed in the blue boxes refer to possible doses for prior placebo participants. Participants prior on mavacamten can be on any of the 5 doses throughout 
the LTE period. 
a    Resting and Valsalva TTE. 
 
#  After the study unblinded (during the open-label LTE phase), Week 52 and Week 64 visits could be removed for prior placebo participants. 
√  The required visits for prior mavacamten participants during open-label LTE phase: Week 34, Week 40, Week 46, Week 54, Week 62, Week 70, 
Week 78. 
*  For CYP2C19 poor metabolizer, an additional onsite visit will perform at Week 98 (20 weeks later after Week 78). 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 16 
 Table 1 Schedule of Study Procedures<1>: Screening to Week 30 
 
Screeninga 
Double-blinded, Placebo-controlled Treatment Period 
ETb 
Post-treatment Visitsc 
Visit 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
/ 
4 
weeks 
from 
ET/W 
30 
8 
weeks 
from 
ET/W 
30 
20 
weeks 
from 
ET/W 
30 
Day/Week 
Day -28 to 
Day -1 
Day 1d 
W 4 
W 6 
W 8 
W 12 
W 14 
W 18 
W 20 
W24 
W 26 
W 30 
/ 
Phone 
visit 
Site 
visit 
Site 
visit 
Window (days) 
/ 
/ 
±7 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±3 
±7 
/ 
±7 
±7 
±15 
Assessment: 
General procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Roll into LTE 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Body height, weight 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Prior/concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ICD download2 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Cardiac Assessments 
12-lead ECG4 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
Holter 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 17 
 
Screeninga 
Double-blinded, Placebo-controlled Treatment Period 
ETb 
Post-treatment Visitsc 
Visit 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
/ 
4 
weeks 
from 
ET/W 
30 
8 
weeks 
from 
ET/W 
30 
20 
weeks 
from 
ET/W 
30 
Day/Week 
Day -28 to 
Day -1 
Day 1d 
W 4 
W 6 
W 8 
W 12 
W 14 
W 18 
W 20 
W24 
W 26 
W 30 
/ 
Phone 
visit 
Site 
visit 
Site 
visit 
Window (days) 
/ 
/ 
±7 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±3 
±7 
/ 
±7 
±7 
±15 
Resting and Valsalva TTE5 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
CMR6 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Laboratory Assessments 
Hepatitis panel and HIV 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling (pre-dose)7 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
PK sampling (post-dose)8 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Coagulation test9 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
Chemistry10 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
Hematology11 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Urinalysis12 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Cardiac troponin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
NT-proBNP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
FSH13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (β-hCG)14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pharmacogenetics15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom Assessments 
NYHA functional 
classification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 18 
 
Screeninga 
Double-blinded, Placebo-controlled Treatment Period 
ETb 
Post-treatment Visitsc 
Visit 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
/ 
4 
weeks 
from 
ET/W 
30 
8 
weeks 
from 
ET/W 
30 
20 
weeks 
from 
ET/W 
30 
Day/Week 
Day -28 to 
Day -1 
Day 1d 
W 4 
W 6 
W 8 
W 12 
W 14 
W 18 
W 20 
W24 
W 26 
W 30 
/ 
Phone 
visit 
Site 
visit 
Site 
visit 
Window (days) 
/ 
/ 
±7 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±3 
±7 
/ 
±7 
±7 
±15 
KCCQ 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
Investigational Medical Product 
IMP QD 
 
 
 
 
 
 
IMP administered at site16  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
IMP compliance17 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BP = blood pressure; CK = creatine kinase; CMR = cardiac magnetic resonance; CYP = cytochrome P450; ECG = electrocardiogram; eGFR = 
estimated glomerular filtration rate; ET = early termination; FIB = fibrinogen; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; HR = heart rate; 
ICD = implantable cardioverter-defibrillator; IMP = investigational medicinal product; INR = international normalized ratio; KCCQ = Kansas City Cardiomyopathy 
Questionnaire; LTE = long term extension; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro B-type natriuretic 
peptide; NYHA = New York Heart Association; PK = pharmacokinetic; PT = prothrombin time; QD = once daily; RBC = red blood cell; SAE = serious AE; TT = thrombin 
time; TTE = transthoracic echocardiography; WBC = white blood cell; β-hCG = beta human chorionic gonadotropin. 
Note: Preferred order of assessments is ECG, vital signs, pre-dose PK, and TTE (TTE might be prior to pre-dose PK) if these assessments are to be conducted at the same visit, 
all prior to study drug dosing unless otherwise described below. 
a 
Screening: Participants who sign the ICF could receive examinations in screening. Screening may require more than 1 visit to accommodate all of the study procedures. 
b 
ET: Participants who prematurely discontinue the study drug will attend an ET visit as soon as possible. After ET visit, participant will participate the post-treatment visits 
and Week 30 visit. Week 30 visit could be earlier (if ET occurs after Week 22) or later (if ET occurs before Week 22) than 8-week post-treatment onsite visit. If the interval 
between Week 30 visit and 8-week post-treatment onsite visit within 2 weeks, only 1 visit is needed. Attempt will be made to obtain assessments at Week 30, if possible. 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 19 
c 
Post-treatment visits: If a participant does not proceed to the LTE period or ET occurs, the participants will be contacted by phone 4 weeks later and return to the site 8 
weeks later for an onsite visit after ET or Week 30 visit. For CYP2C19 poor metabolizer, an additional onsite visit will perform 20 weeks after ET or Week 30 visit. 
d 
Day 1: If the latest laboratory tests (hematology, chemistry, urinalysis, coagulation test) is more than 14 days, these examinations need to be repeated on Day 1. Otherwise, 
these tests don’t need to be repeated on Day 1. Pregnancy test is required to be repeated on Day 1 if applicable. 
1 
Physical examination: At screening, ET and Week 30, a complete physical examination will be conducted, including neurological examinations. At all other visits, an 
abbreviated cardiopulmonary physical examination will be conducted. 
2 
ICD download: For participants who have ICDs, information including rhythm strips and events will be downloaded from the ICDs at screening, Week 12, ET and Week 
30, or as clinically indicated after any ICD discharge interrogation occurring during the placebo-controlled treatment period. 
3 
Vital signs: At screening, ET and Week 30, 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. 
4 
12-lead ECG: 12-lead ECGs will be performed after 10 minutes of rest at screening and prior to examination of vital signs and PK sample collection at onsite study visits.  
5 
Resting and Valsalva TTE: Resting TTE images and views will be acquired at each onsite visit prior to dosing as detailed in the echocardiogram related manual. 
Instantaneous LVOT peak gradient (resting) and provoked LVOT peak gradient (Valsalva maneuver) will be assessed by the core laboratory. 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 blinded 
study site personnel, except in case of locally measured LVEF ≤ 30%. 
6 
CMR: The CMR assessments can be completed up to 5 days before the Week 30 visit. CMR should also be performed as close as possible to ET if it occurs. If CMR is 
performed at ET visit, CMR is not required for Week 30 visit. 
7 
Pre-dose PK sampling: Participants should not take study drug on day of visit prior to blood draw for pre-dose PK. PK sample will be collected within 2 hours before 
dosing. 
8 
Post-dose PK sampling: post-dose PK sample will be collected within 0.5 to 3 hours post dose. 
9 
Coagulation test: PT, INR, APTT, FIB, TT.  
10 Chemistry: ALP, ALT, AST, creatinine, eGFR, potassium, sodium, chloride, magnesium, calcium, direct bilirubin, total bilirubin, total protein, albumin, CK, uric acid, 
glucose. 
11 Hematology: hematocrit, hemoglobin, RBC counts, WBC counts including differentials, platelets. 
12 Urinalysis: glucose, ketones, pH, protein, specific gravity, RBC, WBC. 


Protocol No.: LB2001-301 
Confidential 
V3.0/Dec 25, 2023 
Page 20 
13 FSH: FSH test will be performed at screening for postmenopausal women to confirm postmenopausal status. If the FSH test result shows the participant is not in 
postmenopausal status, serum pregnancy test needs to be done during screening to ensure the participant has no pregnancy.  
14 Pregnancy test (β-hCG): For all females of childbearing potential, serum pregnancy test will be performed at screening, and urine pregnancy tests will be performed at all 
other onsite visits shown and serum test will be performed if any urine test is positive.  
15 Pharmacogenetics: Pharmacogenetic screening for CYP2C19 genotyping preferably will occur on Day 1.  
16 IMP administered at site: At all onsite visits, study drug will be administered at the investigational site to facilitate collection of PK samples within 2 hours prior to dosing. 
Note: There is no pre-dose PK sample at Day 1, Week 14 and Week 20. Study drug will be administered at the end of the visit when other assessments have been done, 
including drawing of blood for safety laboratory tests and cardiac biomarkers (except post-dose PK sampling, drawing of blood for post-dose PK will be done after study 
drug administration). 
17 IMP compliance: All participants will return their study drug dosing containers to the site pharmacy for capsule counts. Refer to the related Pharmacy manual for details.  
 
 


Protocol No.: LB2001-301 
Confidential 
V3.0/ Dec 25, 2023 
Page 21 
Table 2 Schedule of Study Procedures<2>: LTE and Post Treatment Follow-up Period 
 
LTE Period 
ETa 
Post-treatment Visitsb 
Week 
34d 
36 
40d 
42 
46d 
50 
52c 
54d 
58 
62d 
64c 
66 
70d 
74 
78d 
/ 
4 
weeks 
from 
ET/W 
78 
Phone 
visit 
8 
weeks 
from 
ET/W 
78 
Site 
visit 
20 
weeks 
from 
ET/W 
78 
Site 
visit 
Window (days)e 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
±3 
±7 
±7 
±3 
±3 
±7 
±7 
±7 
/ 
±7 
±7 
±15 
Assessment 
General Procedures 
Physical examination1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Body height, weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ICD download2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Cardiac Assessments 
12-lead ECG4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Holter 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Resting and Valsalva TTE5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
CMR6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Laboratory Assessments 
PK sampling7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Hematology8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Coagulation test9 
X 
 
X  
 
X  
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
Chemistry10 
X 
 
X  
 
X  
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
Urinalysis11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Pregnancy test (β-hCG)12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
NT-proBNP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Cardiac troponin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 


Protocol No.: LB2001-301 
Confidential 
V3.0/ Dec 25, 2023 
Page 22 
 
LTE Period 
ETa 
Post-treatment Visitsb 
Week 
34d 
36 
40d 
42 
46d 
50 
52c 
54d 
58 
62d 
64c 
66 
70d 
74 
78d 
/ 
4 
weeks 
from 
ET/W 
78 
Phone 
visit 
8 
weeks 
from 
ET/W 
78 
Site 
visit 
20 
weeks 
from 
ET/W 
78 
Site 
visit 
Window (days)e 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
±3 
±7 
±7 
±3 
±3 
±7 
±7 
±7 
/ 
±7 
±7 
±15 
Symptom Assessment 
NYHA functional classification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
KCCQ 
X 
 
X  
 
X  
 
 
X 
 
X 
 
 
X  
 
X 
X 
 
X 
X 
Investigational Medical Product 
Dose titration13 
 
X 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
 
 
 
 
IMP QD 
 
 
 
 
 
IMP administered at site14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
IMP compliance15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BP = blood pressure; CK = creatine kinase; CMR = cardiac magnetic resonance; CYP = cytochrome P450; ECG = electrocardiogram; eGFR = 
estimated glomerular filtration rate;  ET = early termination; FIB = fibrinogen; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; HR = heart rate; 
ICD = implantable cardioverter-defibrillator; IMP = investigational medicinal product; INR = international normalized ratio; KCCQ = Kansas City Cardiomyopathy 
Questionnaire; LTE = long term extension; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro B-type natriuretic 
peptide; NYHA = New York Heart Association; PK = pharmacokinetic; PT = prothrombin time; QD = once daily; RBC = red blood cell; SAE = serious AE; TT = thrombin 
time; TTE = transthoracic echocardiography; WBC = white blood cell; β hCG = beta human chorionic gonadotropin. 
Note: LTE period include a double-blinded phase and an open-label phase. Preferred order of assessments is ECG, vital signs, pre-dose PK, and TTE if these assessments are 
to be conducted at the same visit (TTE might be prior to pre-dose PK), all prior to study drug dosing unless otherwise described below. 
a 
ET: Participants who prematurely discontinue the study will attend an early termination visit as soon as possible.  
b 
Post-treatment visits: If participants are prematurely discontinue the study, or complete the Week 78 visit, the participants will be contacted by phone 4 weeks later and 
onsite visit 8 weeks later. For CYP2C19 poor metabolizer, an additional onsite visit will perform 20 weeks later. 
c 
Week 52 and Week 64: Week 52 and Week 64 visits could be removed for prior placebo participants during the open-label LTE phase. 


Protocol No.: LB2001-301 
Confidential 
V3.0/ Dec 25, 2023 
Page 23 
d 
Week 34, 40, 46, 54, 62, 70, 78: During open-label LTE phase, only these visits are required for prior mavacamten participants. 
e 
Window: Window for Week 54 and Week 66 visits could be ±7 if Week 52 and Week 64 visits are removed during the open-label LTE phase. 
1 
Physical examination: At Week 78/ET, a complete physical examination will be conducted, including neurological examinations. At all other visits, an abbreviated 
cardiopulmonary physical examination will be conducted, with other systems assessed as directed by interval history. 
2 
ICD download: For participants who have ICDs, information including rhythm strips and events will be downloaded from the ICDs at Week 78/ET, or as clinically 
indicated after any ICD discharge interrogation occurring. 
3 
Vital signs: At Week 78/ET, 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 sample 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.  
4 
12-lead ECG: 12-lead ECGs will be performed after 10 minutes of rest and prior to examination of vital signs at onsite study visits.  
5 
Resting and Valsalva TTE: Resting TTE images and views will be acquired at each onsite visit prior to dosing as detailed in the echocardiogram related manual. During 
double-blinded LTE phase, the TTE results will be kept blinded from the investigator and other blinded study site personnel, except in case of locally measured LVEF ≤ 
30%. During the open-label phase, TTE results will be read by site and not blinded to investigators. 
6 
CMR: The CMR assessments can be completed up to 5 days before the Week 78 visit. CMR should also be performed as close as possible to ET if it occurs. 
7 
PK sampling: pre-dose PK sampling will be collected at Week 78/ET. Participants should not take study drug on day of visit prior to blood draw for pre-dose PK. Pre-
dose PK sample will be collected within 2 hours before dosing. Post-dose PK sample will be collected within 0.5 to 3 hours post dose at Week 78 (last dose). PK samples 
will be collected at post-treatment onsite visits. 
8 
Hematology: hematocrit, hemoglobin, RBC counts, WBC counts, including differentials, platelets. 
9 
Coagulation test: PT, INR, APTT, FIB, TT. 
10 
Chemistry: ALP, ALT, AST, creatinine, eGFR, chloride, potassium, sodium, calcium, magnesium, direct bilirubin, total bilirubin, total protein, albumin, CK, uric acid, 
glucose. 
11 
Urinalysis: glucose, ketones, pH, protein, specific gravity, RBC, WBC. 
12 
Pregnancy test (β-hCG): For all females of childbearing potential, urine pregnancy tests will be performed at all onsite visits shown and serum test will be performed if 
any urine test is positive.  
13 
Dose titration: For prior placebo participants. During open-label LTE period, dose titration at Week 36, Week 42, Week 54 and Week 66 is based on site-read TTE on the 
day of visit. No scheduled dose titration for prior mavacamten participants. 


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14 
IMP administered at site: At all onsite visits, study drug will be administered at the investigational site. Study drug will be administered at the end of the visit when other 
assessments have been done (except post-dose PK sampling). 
15 
IMP compliance: All participants will return their study drug dosing containers to the site pharmacy for capsule counts. Refer to the Pharmacy Manual for details.  


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Table of Contents 
1.1 
Background ..................................................... 34 
1.2 
Clinical experience with mavacamten ................................ 35 
1.3 
Known and potential benefits and risks ............................... 39 
2.1 
Rationale for the study ............................................ 42 
2.2 
Rationale for dosing .............................................. 43 
4.1 
Study design ..................................................... 47 
4.2 
Study period .................................................... 47 
4.3 
Study procedure ................................................. 47 
 
Screening period (Day – 28 to Day -1) ........................................................... 47 
 
Double-blinded, placebo-controlled treatment period (Day 1 to Week 30) .... 47 
 
LTE period (48 weeks) .................................................................................... 49 
 
Post treatment follow-up period (8 weeks/ CYP2C19 poor metabolizer, 20 
weeks) 
50 
 
Description of other procedures and assessments ........................................... 50 
4.4 
Study committees ................................................ 51 
 
Clinical event adjudication committee ............................................................ 51 
 
Independent data monitoring committee ......................................................... 51 
5.1 
Inclusion criteria ................................................. 52 
5.2 
Exclusion criteria ................................................ 53 
5.3 
Screening and enrollment .......................................... 55 
6.1 
Randomization .................................................. 57 
6.2 
Study blinding ................................................... 57 
6.3 
Methods for unblinding ........................................... 58 
7.1 
Study treatment administered ...................................... 59 
7.2 
Study drug preparation, handling, storage, and accountability ............ 60 
 
Formulation, packaging, and labeling of study drug ....................................... 60 
7.3 
Study drug administration and schedule .............................. 60 
 
Treatment compliance ..................................................................................... 60 


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7.4 
Dose adjustments ................................................. 60 
 
Blinded dose adjustments during double-blinded placebo-controlled treatment 
period 
61 
 
Dose adjustments during LTE period .............................................................. 63 
 
Dose adjustments leading to temporary discontinuation ................................. 66 
 
Management in the specific case ..................................................................... 67 
7.5 
Hepatotoxicity stopping and re-challenge rules ......................... 68 
 
Criteria for permanent withholding of study drug due to potential hepatotoxicity
 
68 
 
Criteria for conditional withholding of study drug due to potential 
hepatotoxicity .................................................................................................................. 69 
 
Criteria for re-challenge of study drug after potential hepatotoxicity ............. 70 
7.6 
Overdose ....................................................... 70 
 
Reporting and follow-up of overdose .............................................................. 70 
7.7 
Prior and concomitant therapy ..................................... 71 
 
Prior therapy .................................................................................................... 71 
 
Background HCM therapy .............................................................................. 71 
 
Concomitant therapy ....................................................................................... 71 
 
Prohibited therapy ........................................................................................... 71 
8.1 
Treatment discontinuation ......................................... 72 
 
Temporary treatment discontinuation .............................................................. 72 
 
Permanent treatment discontinuation .............................................................. 72 
 
Permanent treatment discontinuation criteria .................................................. 73 
 
Management of participants after permanent treatment discontinuation ........ 73 
8.2 
Withdrawal from study ............................................ 73 
 
Withdrawal of consent for ongoing study participation .................................. 73 
 
Replacement of participants who withdraw from the study ............................ 74 
9.1 
Efficacy assessment ............................................... 75 
 
Echocardiography ........................................................................................... 75 
 
New York heart association functional classification ...................................... 76 
 
Kansas City Cardiomyopathy Questionnaire (23-item version)...................... 76 
 
Cardiac magnetic resonance imaging .............................................................. 76 
 
Pharmacokinetic assessments .......................................................................... 77 
 
Pharmacogenetic assessment ........................................................................... 77 
 
Cardiac biomarkers ......................................................................................... 77 
9.2 
Safety assessments ................................................ 77 
 
Medical history................................................................................................ 77 
 
Physical examination ...................................................................................... 78 
 
12-lead ECG .................................................................................................... 78 
 
Holter monitor ................................................................................................. 78 
 
Vital signs ........................................................................................................ 78 
 
Other safety assessments ................................................................................. 78 


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9.3 
Participant restrictions during this study ............................. 79 
9.4 
Study procedures by visit .......................................... 79 
9.5 
Visit scheduling .................................................. 79 
10.1 
Definitions ...................................................... 80 
 
Adverse event .................................................................................................. 80 
 
Serious adverse event ...................................................................................... 82 
10.2 
Collection and reporting of adverse event ............................. 82 
 
Collection periods ........................................................................................... 82 
 
Description ...................................................................................................... 83 
 
Start date/time and stop date/time ................................................................... 83 
 
Relationship to study treatment (suspected adverse reactions) ....................... 83 
 
Intensity ........................................................................................................... 84 
 
Seriousness ...................................................................................................... 84 
 
Outcome .......................................................................................................... 84 
10.3 
Reporting and evaluation of serious adverse events ..................... 84 
10.4 
Reporting adverse events of special interest ........................... 85 
10.5 
Follow-Up of adverse events and serious adverse events ................. 85 
10.6 
Reporting and follow-up of pregnancies .............................. 85 
10.7 
Safety reporting to investigators, institutional review boards, independent ethics 
committees, and regulatory authorities ...................................... 86 
12.1 
General considerations ............................................ 89 
12.2 
Sample size determination ......................................... 89 
12.3 
Study endpoints .................................................. 89 
12.4 
Definitions of analysis sets ......................................... 91 
 
Intention-to-treat population ........................................................................... 91 
 
Per-protocol population ................................................................................... 91 
 
Safety analysis population ............................................................................... 91 
 
PK analysis population .................................................................................... 91 
12.5 
Method of analysis................................................ 91 
12.6 
Disposition of participants ......................................... 92 
12.7 
Demographics, baseline characteristics ............................... 92 
12.8 
Extent of study treatment exposure and compliance .................... 92 
12.9 
Efficacy analyses ................................................. 92 
 
Primary endpoint analysis ............................................................................... 92 
 
Secondary endpoints analysis .......................................................................... 92 
 
Exploratory endpoints analysis ....................................................................... 93 
12.10 
Safety analysis ................................................... 93 
 
Adverse events ............................................................................................... 94 
 
12-lead electrocardiogram .............................................................................. 95 
 
Laboratory data .............................................................................................. 96 
 
Vital signs data ............................................................................................... 96 


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Concomitant medications ............................................................................... 96 
 
Other safety analyses ...................................................................................... 97 
12.11 
Long-term extension analysis ....................................... 97 
12.12 
Pharmacokinetics analysis ......................................... 97 
13.1 
Data confidentiality ............................................... 98 
13.2 
Study center monitoring ........................................... 98 
13.3 
Data collection ................................................... 99 
13.4 
Database quality assurance ........................................ 99 
13.5 
Study documentation, record keeping and retention of documents ......... 99 
15.1 
Sponsor’s responsibilities ......................................... 103 
 
Participant confidentiality ............................................................................. 103 
 
Investigator training ...................................................................................... 103 
 
Ongoing communication of safety information during the study.................. 104 
 
Study monitoring ........................................................................................... 104 
 
Study auditing and inspecting ....................................................................... 104 
15.2 
Investigator’s responsibilities ...................................... 104 
 
Screening log ................................................................................................. 104 
 
Mavacamten accountability ........................................................................... 104 
 
Reporting and recording of study data .......................................................... 105 
 
Source data and source documents ................................................................ 105 
 
Participant identification information ........................................................... 106 
 
Records retention .......................................................................................... 106 
 
Protocol deviations ........................................................................................ 106 
 
Blood sample collection/storage ................................................................... 107 
15.3 
Clinical trial insurance ........................................... 107 
15.4 
Protocol amendments and study administrative letters ................. 107 
15.5 
Administrative consideration ...................................... 107 
 
 


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List of Tables 
Table 1 Schedule of Study Procedures<1>: Screening to Week 30 ........................ 16 
Table 2 Schedule of Study Procedures<2>: LTE and Post Treatment Follow-up 
Period ................................................................................................................... 21 
Table 3 Objectives and Endpoints ............................................................................ 44 
Table 4 Study Treatments .......................................................................................... 59 
Table 5 PK/PD Criteria for Down-Titration during Double-Blinded Placebo-
Controlled Treatment Period ........................................................................ 62 
Table 6 Dose Titration during Double-Blinded Placebo-Controlled Treatment 
Period ................................................................................................................... 63 
Table 7 Dose Titration for Participants Previously on Placebo during LTE 
Period ................................................................................................................... 64 
Table 8 NYHA Functional Classification of HF ...................................................... 76 
 
 


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List of Figures 
Figure 1 Study Schema<1>: Screening to Week 30 ................................................ 14 
Figure 2 Study Schema<2>: LTE Period and Post Treatment Follow-up Period 15 


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List of Abbreviations 
Abbreviations 
Definitions 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AF 
Atrial Fibrillation  
AHA 
American Heart Association 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
ASA 
Alcohol Septal Ablation  
AST 
Aspartate Aminotransferase 
APTT 
Activated Partial Thromboplastin Time 
AUC 
Area under the Curve 
BIL 
Bilirubin 
BP 
Blood Pressure 
β-hCG 
beta Human Chorionic Gonadotropin 
CEAC 
Clinical Event Adjudication Committee  
CHF 
Congestive Heart Failure 
cGMP 
Current Good Manufacturing Practices 
Cmax 
maximum concentration 
CMR 
Cardiac Magnetic Resonance  
CPET 
Cardiopulmonary exercise test  
CK 
Creatine Kinase 
CRF 
Case report form 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization 
CSP 
Clinical Study Protocol  
CSS 
Clinical Summary Score 
CV 
Cardiovascular  
CYP 
Cytochrome P450  
DCIS 
Ductal Carcinoma in Situ 
DDI 
Drug-drug Interaction 
DILI 
Drug-induced Liver Injury 
EC 
Ethics Committee; refers to an IRB or IEC or equivalent 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECVF 
Extracellular Volume Fraction 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EMs 
Extensive Metabolizers 
EOS 
End of Study 
EOT 
End of Treatment 
ESC 
European Society of Cardiology 
ET 
Early Termination 


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Abbreviations 
Definitions 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIB 
Fibrinogen  
FPI 
First Patient in 
FSH 
Follicle-stimulating Hormone 
GCP 
Good Clinical Practice 
HB 
Hemoglobin 
HBV 
Hepatitis B Virus 
HCM 
Hypertrophic Cardiomyopathy 
HCV 
Hepatitis C Virus 
hERG 
Human Ether-à-go-go-Related Gene 
HF 
Heart Failure 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICD 
Implantable Cardioverter-Defibrillator  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHS 
Intrauterine Hormone-releasing System 
IME 
Important Medical Events  
IMP 
Investigational Medicinal Product  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-releasing System 
IV 
Intravenous 
IxRS 
Interactive Response System 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LAVI 
Left Atrial Volume Index 
LFT 
Liver Function Test 
LGE 
Late Gadolinium Enhancement 
LLN 
Low Limit of Normal 
LTE 
Long-term Extension  
LV 
Left Ventricular  
LVEF 
Left Ventricular Ejection Fraction 
LVH 
Left Ventricular Hypertrophy  
LVOT 
Left Ventricular Outflow Tract 
LVOTO 
Left Ventricular Outflow Track Obstruction  
MACE 
Major Adverse Cardiac Events 
MAD 
Multiple Ascending-dose  
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviations 
Definitions 
MET 
Metabolic Equivalents 
MMRM 
Mixed-Effect Model for Repeated Measures 
MR 
Mitral Regurgitation 
NASH 
Nonalcoholic Steatohepatitis 
nHCM 
Non-hypertrophic Cardiomyopathy 
NIMP 
Non-investigational Medicinal Product 
NT-proBNP 
N-terminal pro B-type Natriuretic Peptide  
NYHA 
New York Heart Association  
oHCM 
obstructive Hypertrophic Cardiomyopathy 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PKS 
Pharmacokinetics Set 
PLT 
Platelet 
PMs 
Poor Metabolizers 
PT 
Preferred Term 
PT 
Prothrombin Time 
PPS 
Per-Protocol Set 
pVO2 
Peak O2 Consumption 
QD 
Once Daily 
QTc  
Corrected QT interval  
QTcF 
QT Interval Corrected by Heart Rate using Fridericia's Formula 
RBC 
Red Blood Cell 
SAD 
Single-ascending Dose  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SBP 
Systolic Blood Pressure 
SCD 
Sudden Cardiac Death 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
SRT 
Septal Reduction Therapy 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life  
TBL 
Total Bilirubin 
TEAE 
Treatment-emergent Adverse Events  
tmax 
Time to Reach Maximum Concentration 
TT 
Thrombin Time 
TTE 
Transthoracic Echocardiography 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WOCBP 
Women of Child Bearing Potential 
 
 
 


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 Introduction 
1.1 
Background 
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder defined by left 
ventricular (LV) hypertrophy that cannot be explained by another cardiac or systemic 
disease. HCM is a chronic, progressive disease of the cardiomyocyte, and largely of the 
cardiac sarcomere, with a diverse clinical presentation and course. Over time, HCM 
results in tissue remodeling characterized histologically by myocyte hypertrophy and 
disarray, microvascular remodeling, and fibrosis (Frey et al., 2011). Approximately 40% 
of affected individuals overall and 60% of those with a family history of clinical disease 
have a mutation in one or more sarcomeric structural genes (Hershberger et al., 2009; 
Gersh et al., 2011; Maron et al., 2012; Alfares et al., 2015). Mutations in cardiac myosin 
and other sarcomeric proteins appear to increase net power generation by the sarcomere 
(Chuan et al., 2012; Sommese et al., 2013; Sung J. 2012), which is consistent with the 
generally hypercontractile state and impaired compliance of the myocardium observed 
clinically in HCM. Recent estimates of the prevalence of HCM using information from 
large administrative databases indicate that the prevalence of clinically diagnosed HCM 
ranges from 3 to 7 per 10,000 (Maron et al., 2016; Husser et al., 2018; Pujades-
Rodriguez et al., 2018; Moon et al., 2020). In China, it is estimated that there are more 
than 1 million adults affected by HCM (Zou et al., 2004). 
Two HCM phenotypes are recognized based on the presence or absence of obstruction 
of the LV outflow tract (LVOT), obstructive HCM (oHCM, also known as HOCM) and 
non-obstructive HCM (nHCM), where obstruction is defined as a peak LVOT gradient 
≥ 30 mmHg at rest or with provocation (Gersh et al., 2011). Approximately 70% of 
individuals diagnosed with HCM have oHCM (Maron et al., 2006). Based on this, the 
prevalence rate of oHCM is likely between 2 and 5 per 10,000, based on the recent 
estimates of HCM. The combination of the abnormal ventricular geometry caused by 
septal hypertrophy, reduced ventricular cavity size, and the pathologic elongation of the 
mitral valve are considered contributing factors (Sherrid et al., 2000), but the precise 
mechanism of LVOT obstruction is unknown. Ventricular obstruction produces 
increased LV systolic pressure and an array of subsequent abnormalities, including 
prolongation of ventricular relaxation, elevation of LV diastolic pressure, mitral 
regurgitation (MR), atrial fibrillation (AF), myocardial ischemia, and decreased 
forward cardiac output (Maron et al., 2003). The presence of LVOT obstruction is an 
important prognostic factor in HCM, and is associated with an increased risk of disease 
progression, congestive heart failure (CHF), stroke, and death (Elliott et al., 2006; 


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Autore et al., 2005). The risk of sudden cardiac death (SCD), which is one of the most 
common nontraumatic causes of death in young adults and sometimes the first 
manifestation of HCM, is also increased in the presence of LVOT obstruction (Ho et 
al., 2002; Gersh et al., 2011; Ho et al., 2018). 
Current guidelines for the pharmacologic management of HCM rely on empirical use 
of established cardiovascular (CV) medications (including beta-blockers, verapamil, 
diltiazem, and disopyramide) (Ommen SR et al., 2020; Elliott et al., 2014; Heart Failure 
Committee of Chinese Medical Doctor Association et al., 2017) that cannot alter the 
natural history of HCM and only have modest effect on LVOT gradient. In oHCM, 
septal reduction therapy (SRT) may reduce obstruction and improve LV outflow, and 
an implantable cardioverter-defibrillator (ICD) may prevent SCD, but both involve 
invasive procedures, require specialized operators and clinic settings, and may not be 
available to all patients (Kim et al., 2016). Cardiac transplant is the only option when 
treatment fail to adequately manage oHCM. None of these treatment options address 
the underlying etiology of HCM. 
Mavacamten is a small-molecule allosteric inhibitor of cardiac myosin that reversibly 
inhibits its binding to actin, thereby relieving systolic hypercontractility and improving 
ventricular compliance. Sponsor is developing mavacamten for the treatment of adults 
with symptomatic oHCM in China. 
1.2 
Clinical experience with mavacamten 
To date, 18 clinical studies have been initiated to investigate the safety and tolerability 
of mavacamten. 15 studies have been completed as follows: 
• 
Study MYK-461-001, a single-ascending dose (SAD) study in 15 participants 
with HCM. 
• 
Study MYK-461-002, a SAD study in 48 healthy participants. 
• 
Study MYK-461-003, a multiple ascending-dose (MAD) study in 60 healthy 
participants. 
• 
Study MYK-461-004 (PIONEER-HCM), a Phase II study in 21 participants with 
oHCM. 
• 
Study MYK-461-005 (EXPLORER-HCM), a Phase III, multinational, 
randomized, double-blind, placebo-controlled study in 251 participants with 
symptomatic oHCM. 
• 
Study MYK-461-006 (MAVERICK-HCM), a Phase II randomized, double-
blind, placebo-controlled, concentration-guided exploratory study in 59 
participants with symptomatic nHCM. 
• 
Study MYK-461-009, a drug-interaction study with verapamil in 25 healthy 
participants. 


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• 
Study MYK-461-010, a drug-interaction study with an oral contraceptive in 
13 healthy women. 
• 
Study MYK-461-011, an ethnobridging pharmacokinetic (PK) study in 20 
Japanese and 8 Caucasian participants. 
• 
Study MYK-461-012, an intrinsic factor PK study in 16 healthy participants who 
are CYP2C19 poor metabolizers (PMs) (8 participants) or CYP2C19 normal 
metabolizers (8 participants). 
• 
Study MYK-461-013, a single-dose, mass-balance study in 6 healthy 
participants. 
• 
Study MYK-461-014, a 3-period cross-over study in 24 healthy participants to 
assess the relative bioavailability of the initial capsule formulation and the final 
commercial formulation of mavacamten, and the effect of food on the final 
commercial formulation.  
• 
Study MYK-461-015, an intrinsic factor study in 27 participants to assess the 
effect of mild and moderate hepatic impairment on the PK of mavacamten. 
• 
MYK-461-016, a drug-interaction study with midazolam in 13 healthy 
participants with CYP2C19 genotype *1/*1, *1/*17, or *17/*17. 
• 
MYK-461-018, a drug-interaction study with omeprazole in 29 healthy 
participants with CYP2C19 genotype *1/*1 or *1/*17. 
Ongoing studies includes: 
• 
Study MYK-461-007 (MAVA-LTE), an ongoing, open-label extension study in 
267 participants with HCM who were previously enrolled in Studies MYK-461-
006 (MAVERICK-HCM) or MYK-461-005 (EXPLORER-HCM) studies 
• 
Study MYK-461-008 (PIONEER-OLE), an ongoing, open-label extension study 
in 13 participants with symptomatic oHCM who were previously enrolled in 
Study MYK-461-004 PIONEER-HCM study 
• 
Study MYK-461-017 (VALOR-HCM), an ongoing, randomized, double-blind, 
placebo-controlled study to evaluate mavacamten in adults with symptomatic 
oHCM who are eligible for septal reduction therapy. 
In total, 647 participants with HCM or healthy participants have been enrolled across 
the completed studies, 590 of whom were exposed to at least 1 dose of mavacamten 
(date of data cut: 30-Oct-2020). Key points regarding dosing, preliminary efficacy, 
preliminary safety, PK profile, and drug interactions are summarized below. 
In the MYK-461-001 and MYK-461-003 studies, oral doses of mavacamten up to 96 
mg (single doses administered in 8 even aliquots every 15 minutes) and 18.5 mg once 
daily (QD) (28-day course) were well tolerated, respectively. The predefined stopping 
criterion for dose escalation (reduction in left ventricular ejection fraction [LVEF] by 
≥ 20%) was satisfied in both of these studies, at 144 mg in the single-dose study (MYK-


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461-001) and at 25 mg daily up to 25 days in the 28-day multidose study (MYK-461-
003). 
Preliminary efficacy was demonstrated in a 21-participant study, in which participants 
with symptomatic oHCM received open-label mavacamten at doses ranging from 2 to 
20 mg for 12 weeks (Study MYK-461-004; PIONEER-HCM). This 2-part study 
demonstrated a marked reduction in LVOT gradient to levels considered clinically 
insignificant at plasma mavacamten concentrations ≥ 350 ng/mL with LVEF remaining 
essentially within normal range at concentrations of up to 1000 ng/mL. The gradient 
reduction was accompanied by the resolution of systolic anterior motion of the mitral 
valve (SAM) in all but 2 participants (9 of 11 [82%]) in the high-dose portion of the 
study. The study also demonstrated an improvement in New York Heart Association 
(NYHA) class and dyspnea score, a decrease in N-terminal pro-B-type natriuretic 
peptide (NT-proBNP) levels and a trend toward improved exercise tolerance as 
measured by peak oxygen consumption (pVO2) on cardiopulmonary exercise testing 
(CPET). Lastly, there were improvements in diastolic function as measured by 
echocardiographic criteria. Overall, mavacamten was well tolerated; there was 1 serious 
adverse event (SAE) of AF in a participant with a history of AF. 
In the EXPLORER-HCM (MYK-461-005) Phase III, randomized, double-blinded, 
placebo-controlled study, patients with oHCM were assigned (1:1) to receive 
mavacamten (starting at 5 mg) or placebo for 30 weeks (Ho et al., 2020). Treatment 
with mavacamten was superior to placebo across the primary endpoint and all 
secondary endpoints in a study population with 92% of participants on either beta-
blocker or non-dihydropyridine calcium channel blocker therapy. Participants treated 
with mavacamten demonstrated twice the response rate of those in the placebo group 
on the composite functional primary endpoint (36.6% vs 17.2%), with a highly 
statistically significant between-group difference (19.4% [95% CI: 8.67, 30.13], p = 
0.0005). Additionally, 20.3% of participants treated with mavacamten met the criteria 
of ≥ 3.0 mL/kg/min increase in pVO2 and ≥ 1 NYHA class improvement compared 
with 7.8% of participants on placebo. Mavacamten treatment was also effective in 
reducing LVOT gradients and improving symptoms, exercise performance, and health 
status, as shown by significant improvement in all secondary endpoints (Olivotto et al., 
2020).  
MAVERICK-HCM (MYK-461-006) was the first therapeutic study to demonstrate a 
substantial reduction of NT-proBNP in nHCM patients. Although this dose-ranging, 
exploratory study was underpowered to detect clinical benefit as reflected by pVO2 or 
NYHA class, the rapid and sustained dose-dependent reduction in NT-proBNP with 
mavacamten treatment suggests physiological benefit (Ho et al., 2020). 
The preliminary safety of mavacamten has been evaluated for single and multiple doses 
in healthy participants and participants with HCM. Overall, mavacamten appears to be 
generally well tolerated with little evidence for off-target toxicity.  
Treatment with mavacamten was well tolerated in the EXPLORER-HCM (MYK-461-
005) study through 30 weeks of treatment. Overall, treatment-emergent adverse events 


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(TEAEs) were higher in the mavacamten group compared with the placebo group 
during the on-treatment (Day 1 to Week 30) period (87.8% vs 78.9%) and treatment-
emergent (Day 1 to Week 38) period (87.8% and 81.3%). It is notable that the TEAE 
rate did not increase in the mavacamten group with 8 weeks of additional observation 
during study drug washout. The proportion of participants in the mavacamten group 
with treatment discontinuations due to TEAEs was 1.6% (2 of 123 participants). No 
participants in the placebo group discontinued treatment due to TEAEs. SAEs were 
balanced between treatment groups; on-treatment rates of SAEs were 8.1% in the 
mavacamten group versus 8.6% in the placebo group, and rates of treatment-emergent 
SAEs were 11.4% and 9.4%, respectively (Olivotto et al., 2020). 
Treatment with mavacamten was well tolerated in the MAVERICK-HCM (MYK-461-
006) study (Ho et al., 2020). The majority of TEAEs were mild or moderate in severity, 
with few severe TEAEs and no fatal adverse events (AEs). The types of TEAEs 
reported were similar for the mavacamten and placebo groups and were representative 
of the underlying disease. The incidence of SAEs was low, and the only SAE reported 
for > 1 participant was AF. No life-threatening or fatal TEAEs were reported. Five 
participants (2 participants in the 200 ng/mL group and 3 participants in the 500 ng/mL 
group) discontinued treatment due to meeting the protocol-specified stopping criteria 
of LVEF ≤ 45% and/or heart failure (HF) with systolic dysfunction. In all cases, LVEF 
increased and mavacamten concentrations decreased upon discontinuation of study 
drug. 
The PK profile of mavacamten is characterized by a biphasic profile with a rapid 
absorption (time to reach maximum concentration [tmax] generally between 1 and 2 h) 
and a long terminal half-life (t1/2) with a mean of 6 to 9 days in CYP2C19 extensive 
metabolizers (EMs). In CYP2C19 PMs, t1/2 is approximately 24 days and the area under 
the curve (AUC) is increased up to approximately 3-fold and maximum concentration 
(Cmax) by 50% compared to EM (i.e., *1/*1 genotype). The exposure is slightly greater 
than dose proportional starting at doses of 12.5 mg. At steady state, the peak-to-trough 
plasma concentration ratio with QD dosing is very low (1.5 to 1). Clearance and volume 
of distribution have not been determined in humans as they require intravenous (IV) 
administration; however, data are consistent with a low clearance and high volume of 
distribution, as shown in nonclinical studies. Four metabolites have been detected in 
human plasma from the MAD clinical trial (MYK-461-003). The exposure of the most 
abundant metabolite in human plasma was less than 5% of the exposure of mavacamten, 
and the other metabolites had exposure less than 1% of the exposure of mavacamten. 
This was confirmed in a human 14C absorption, distribution, metabolism, and excretion 
(ADME) study where all plasma metabolites were < 10% of the parent. The available 
data thus far indicate that approximately 75% of the metabolism occurs through 
CYP2C19, 16% through 3A4/5 and the rest through CYP2C19. Approximately 2% of 
the administered drug is found unchanged in the urine. Pilot data indicate a food effect 
of less than 15% reduction in exposure when mavacamten was administered after a high 
fat meal vs the fasted state. In most cases, the between-participant variability 
(coefficient of variation) for exposure is moderate (in the 30 to 50% range). 


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A drug-interaction study with the moderate CYP3A4 inhibitor, verapamil, which is 
frequently used in oHCM, revealed no changes in AUC and a 50% increase in Cmax 
after a single dose of mavacamten. These changes are not considered clinically 
significant, especially when using a dosing strategy of starting every participant on a 
low dose of mavacamten and increasing the dose as needed. An ethnobridging study 
indicated no important PK differences between Japanese and Caucasian CYP2C19 
EMs. 
Because of the potential for mavacamten to cause induction of CYP3A4, a drug-drug 
interaction (DDI) study was conducted with a typical oral contraceptive consisting of 
ethinyl estradiol and norethindrone (Ortho-Novum®), which was administered before 
and after a 17-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg 
daily for 15 days). Mavacamten did not decrease the exposure to either ethinyl estradiol 
or norethindrone, thus ruling out a drug interaction with oral contraceptives. 
A drug-drug interaction study with omeprazole (MYK-461-018), assessed the effect of 
omeprazole, a moderate CYP2C19 inhibitor, on the PK of mavacamten 15 mg 
administered as a single dose to healthy participants. When coadministered with a 31-
day course of omeprazole 20 mg daily, a single 15 mg dose of mavacamten resulted in 
a 58% higher AUC0-inf and AUC0-last than the same mavacamten dose administered 
alone. Other PK parameters including Cmax, tmax, and t1/2 were not affected appreciably. 
In this study, omeprazole and esomeprazole are prohibited.  
1.3 
Known and potential benefits and risks  
The potential clinical benefit of mavacamten in this study is to provide therapeutic 
effect in participants with symptomatic oHCM. 
Based on nonclinical data and the available clinical data, four important risks have been 
described in the latest Development Safety Update Report with data lock point of 30-
Oct-2020: heart failure due to systolic dysfunction defined as symptomatic LVEF < 
50%, teratogenicity, QT prolongation, and increased risk of heart failure due to 
interaction with CYP2C19 and potent CYP3A4 inhibitors.  
• 
Heart failure due to systolic dysfunction （defined as symptomatic LVEF < 
50%  
In the mavacamten program, systolic dysfunction associated with mavacamten was 
observed as episodes of reversible LVEF reduction below the normal range. This 
systolic dysfunction ranged from drops in LVEF (either symptomatic or 
asymptomatic), and contrasted with LVEF reductions in the setting of clinical events 
of cardiac failure observed in complex clinical scenarios with other acute conditions 
such as stress cardiomyopathy, AF, anaphylactic shock, or other intercurrent acute 
conditions that confounded the causality assessment for mavacamten. Systolic 
dysfunction with mavacamten has been reversible and has not resulted in a picture of 
progressive cardiac failure (recurrent hospitalizations and progressive LVEF reduction) 
as described in the literature associated with progression of underlying HCM. However, 
the serious risk of cardiac failure due to systolic dysfunction (defined as symptomatic 


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LVEF < 50%) is an important identified risk, and cardiac failure and systolic 
dysfunction are considered as adverse drug reactions for mavacamten. 
• 
Teratogenicity 
Oral administration of mavacamten in reproductive toxicity studies in 2 species (rats, 
rabbits) resulted in developmental toxicity in preclinical studies (post-implantation loss, 
decrease in fetal body weight, and skeletal malformations in rats; visceral and skeletal 
malformations in rabbits), suggestive of a teratogenic potential of the compound. There 
are no clinical data on the safety of mavacamten during pregnancy, and highly effective 
contraception is required in the ongoing clinical studies. 
• 
QT Prolongation 
In healthy hearts, modest dose-dependent and concentration-dependent QTc 
prolongation has been observed. However, nonclinical data demonstrated that QTc 
prolongation in healthy hearts is not torsadogenic and did not result from an off-target 
direct effect of mavacamten; instead, the findings are attributed to an adaptive response 
to myosin inhibition in hearts with normal LV contractility. No torsadogenic clinical 
events (e.g., malignant ventricular arrhythmias, seizures, or sudden death) have been 
observed to date in the mavacamten clinical program other than 1 event of sudden death 
(study MYK-005) observed on placebo treatment. In participants p with oHCM, 
centrally read ECG results were consistent with a regression analysis demonstrating a 
negative correlation between mavacamten plasma concentrations and changes in QTcF. 
Based on the findings in healthy hearts, and due to abnormalities of QTcF in HCM 
patients in clinical practice (e.g., interventricular conduction delay, bundle branch 
block, or repolarization changes due to underlying disease, use of implantable 
cardioverter-defibrillators/pacemakers, or concomitant use of proarrhythmic drugs), as 
well as the limited experience of concomitant use of mavacamten with known QT-
prolonging drugs commonly used in the HCM population, QTc interval change remains 
an important potential risk for mavacamten.  
• 
Increased risk of heart failure due to interaction with CYP2C19 and potent 
CYP3A4 inhibitors 
Mavacamten is primarily metabolized by CYP2C19 and CYP3A4. Starting or 
increasing the dose of any CYP2C19 or potent CYP3A4 inhibitors may increase the 
risk of systolic dysfunction. Stopping or decreasing dose of a CYP2C19 or potent 
CYP3A4 inhibitor may lead to a loss of therapeutic response to mavacamten. The 
potential for drug interactions with a CYP2C19 inhibitor, including over-the-counter 
medications (such as omeprazole or esomeprazole), must be considered prior to and 
during mavacamten therapy. A list of prohibited medications for participants in 
mavacamten clinical trials are utilized for screening and monitoring of participants in 
the program. 
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 


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definition and management of overdose, see Section 7.6.  
Notably, clinical studies for mavacamten are ongoing. New safety information could 
emerge from ongoing clinical studies, which would be reflected in the Investigator's 
Brochure and Developmental Safety Update Report. 


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Rationale for the Study and Dosing 
2.1 
Rationale for the study  
Mavacamten is a novel, small molecule, allosteric inhibitor of cardiac-specific myosin, 
for the treatment of patients with symptomatic oHCM, a condition with significant 
unmet medical need, with the goals of eliminating LVOT gradient, improving exercise 
capacity, functional capacity, and symptoms including fatigue and dyspnea. This Phase 
III study is designed to evaluate the safety and efficacy of a 30-week course of 
mavacamten compared with placebo and the long-term effects of mavacamten in 
Chinese participants with symptomatic oHCM. 
In preclinical and early clinical studies, treatment with mavacamten successfully 
relieved LVOT gradients and improved parameters of left ventricular filling. In the 
Phase II, open-label PIONEER-HCM study, mavacamten was well tolerated and 
significantly reduced LVOT gradients in oHCM. The EXPLORER-HCM study 
demonstrated a mean change in Valsalva LVOT gradient of -49 (standard deviation 
[SD] 34.4) mmHg at Week 30 in the mavacamten group vs -12 (SD 31.0) mmHg in the 
placebo group (Olivotto et al., 2020). 
The proposed primary endpoint in this study is the change from baseline to Week 30 in 
Valsalva LVOT peak gradient. The sample size of 81 (2:1 ratio) would provide 
approximately > 90% power to detect a treatment difference of 30 with a SD of 35 in 
change from baseline of LVOT gradient at 30 weeks between the active treatment arm 
and the placebo arm with a 1-sided 2.5% alpha level and assuming dropout rate at 10%. 
NYHA functional class, other resting and Valsalva transthoracic echocardiography 
(TTE) parameters, Kansas City Cardiomyopathy Questionnaire (KCCQ), and safety of 
mavacamten will be assessed to determine 30 week’s outcomes of participants 
receiving mavacamten. 
Cardiac magnetic resonance (CMR) imaging is an important tool for the diagnosis and 
management of HCM and has an added value over other imaging modalities. CMR can 
provide three-dimensional tomographic cardiac imaging and help diagnosis by 
characterizing the HCM phenotype (Quarta et al., 2018). CMR is considered a standard 
of reference for the assessment of ventricular volumes and function. Additionally, the 
evaluation of fibrosis by late gadolinium enhancement (LGE) has been extensively 
investigated and associated with clinical outcomes (Maron et al., 2012; Moravsky et 
al., 2012). The results of the EXPLORER-HCM CMR sub-study primary endpoint 
showed a decrease in LV mass index after 30 weeks of mavacamten treatment 
compared with placebo, with a between-group difference in the change from baseline 
of -16 g/m2 (95% CI: -22.6, -9.0046). Importantly, left atrial volume, a predictor of 
adverse cardiac events and AF in HCM decreased from baseline to Week 30 in the 
mavacamten group (between-group differences at Week 30 were -10 mL/m2 [95% CI: 
-16.0, -4.6] for maximum left atrial volume index [LAVI] and -8.8 mL/m2 [95% CI: -
15.1, -2.5] for minimum LAVI compared with no changes in the placebo group. Finally, 


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there were no notable between-group differences on measures of fibrosis by LGE or 
extracellular volume fraction (ECVF; a reflection of the total interstitial space) 
(Olivotto et al., 2020). This study will evaluate the effect of mavacamten on cardiac 
function and structure, and fibrosis assessed by CMR.  
After 30 weeks of placebo-controlled treatment period, participants will be rolled into 
the long-term extension (LTE) period if eligible. The participants from placebo group 
will have the opportunity to receive mavacamten for additional 48 weeks during the 
LTE period. During this LTE period, efficacy and safety of mavacamten will be 
assessed to determine long-term outcomes of participants receiving mavacamten. 
2.2 
Rationale for dosing 
The rationale for dosing in this study is to ensure safety by titrating to the lowest 
effective dose in each individual participant based on their own PK/ pharmacodynamic 
(PD) response parameters and avoiding excessive pharmacologic effects. In the Phase 
II PIONEER-HCM study, significant reductions in LVOT gradient to levels below 
30 mmHg were achieved while maintaining normal LVEF (50% to 70%) at plasma 
concentrations of mavacamten between 350 ng/mL and 700 ng/mL. Improvements in 
exercise capacity and symptoms were also seen in this range.  
Clinical, nonclinical, PK modeling studies, and Exposure-Response Modeling study 
using Chinese participants’ body weight and CYP2C19 genotype parameters have 
shown that mavacamten 2.5 mg QD is expected to be a safe starting dose, even in 
participants with reduced clearance due to CYP2C19 PMs or other factors. 
During double-blinded, placebo-controlled treatment period, the dose will be adjusted 
with an up-titration scheme to a maximum of 15 mg QD, designed to achieve safe and 
effective dosing for each participant based on their own PK/PD response parameters. 
PD response parameters evaluated by TTE are read by core laboratories. 
During the LTE period, dose titration is designed be step-wise based on PD response 
parameters (evaluated by TTE) and are not allowed to skip dose levels. 


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Objectives and Endpoints 
The efficacy, safety, and PK objectives and endpoints of the study are as follows: 
Table 3 Objectives and Endpoints 
Objectives 
Endpoints 
Efficacy 
• 
Primary Efficacy 
To compare the effect of a 30-week 
course of mavacamten with placebo on 
Valsalva LVOT gradient peak as 
determined 
by 
Doppler 
echocardiography 
• 
Change from baseline to Week 30 in Valsalva 
LVOT peak gradient 
• 
Secondary Efficacy 
To compare the effect of a 30-week 
course of mavacamten with placebo on 
LVOT obstruction 
• 
Change from baseline to Week 30 in resting 
LVOT peak gradient 
• 
Proportion of participants achieving a Valsalva 
LVOT peak gradient < 30 mmHg at Week 30 
• 
Proportion of participants achieving a Valsalva 
LVOT peak gradient < 50 mmHg at Week 30 
To compare the effect of a 30-week 
course of mavacamten with placebo on 
clinical symptoms 
• 
Proportion of participants with at least 1 class 
improvement 
in 
NYHA 
functional 
classification from baseline to Week 30 
To compare the effect of a 30-week 
course of mavacamten with placebo on 
Participant-Reported 
health 
status 
individually 
• 
Change from baseline to Week 30 in KCCQ 
Clinical Summary Score (CSS) 
To compare the effect of a 30-week 
course of mavacamten on cardiac 
biomarkers 
• 
Change from baseline to Week 30 in NT-
proBNP 
• 
Change from baseline to Week 30 in cardiac 
troponin 
To compare the effect of a 30-week 
course of mavacamten with placebo on 
LV mass evaluated by CMR imaging 
• 
Change from baseline to Week 30 in LV mass 
index 
• 
Exploratory Efficacy 


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To assess the effect of a 30-week course 
of mavacamten on cardiac function and 
structure 
as 
evaluated 
by 
echocardiography 
• 
Proportion of participants achieving NYHA 
Class I and resting and Valsalva LVOT peak 
gradient < 30 mmHg at Week 30 
• 
Change from baseline to Week 30 in 
echocardiographic indices of cardiac structure 
and systolic and diastolic function 
To assess the effect of a 30-week course 
of mavacamten on Cardiac function 
and structure as evaluated by CMR 
imaging 
• 
Change from baseline to Week 30 in 
myocardial fibrosis  
• 
Change from baseline to Week 30 in cellular 
hypertrophy, cardiac structure, and function 
To assess the effect of a 30-week course 
of 
mavacamten 
on 
Participant-
Reported health status 
• 
Change from baseline to Week 30 in Total 
Symptom Score and Overall Summary Score 
from KCCQ 
Safety 
To assess the safety of mavacamten 
during the 30-week double-blinded, 
placebo-controlled treatment period 
• 
Incidence of LVEF < 50% determined by TTE 
• 
Incidence and severity of TEAEs, and 
treatment-emergent SAEs 
• 
Incidence of major adverse cardiac events 
(MACEs; CV death, non-fatal stroke, non-fatal 
myocardial infarction) 
• 
Incidence of hospitalizations (due to CV and 
non-CV events) 
• 
Incidence 
of 
HF 
events, 
including 
hospitalizations 
and 
urgent 
emergency 
room/outpatient visits for HF 
• 
Incidence of atrial fibrillation/flutter (new 
from screening, and recurrent) 
• 
Incidence of ICD therapy and resuscitated 
cardiac arrest 
• 
Incidence of ventricular tachyarrhythmias 
including ventricular tachycardia, ventricular 
fibrillation, and Torsades de Pointe 
• 
Incidence of adverse events of special interest 
(AESIs; symptomatic overdose, outcomes of 
pregnancy, LVEF ≤ 30%) 
Long-term Extension 
To assess the effects of mavacamten on 
Clinical 
symptoms, 
cardiac 
• 
Change 
from 
baseline 
in 
NYHA, 
echocardiographic and CMR parameters, 


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biomarkers, 
health 
status, 
echocardiographic measures, and CMR 
measures over time 
cardiac biomarkers, and KCCQ results through 
end of study (EOS) 
To assess the safety of mavacamten 
over time  
• 
Incidence of safety events, including: LVEF < 
50%, TEAEs and treatment-emergent SAEs, 
MACEs, hospitalizations, HF events, atrial 
fibrillation/flutter, 
ICD 
therapy 
and 
resuscitated 
cardiac 
arrest, 
ventricular 
tachyarrhythmias, or AESIs 
Pharmacokinetics 
To describe the PK characteristics of 
mavacamten 
• 
Mavacamten plasma concentration over time 
• 
PK parameters using a population PK 
approach  


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Overall Study Design 
4.1 
Study design 
This is a Phase III, randomized, double-blinded, placebo-controlled, multicenter, 
parallel-group clinical study with a long-term extension to evaluate the efficacy, safety, 
and PK of mavacamten in Chinese adults with symptomatic oHCM. Approximately 81 
eligible participants will be enrolled and randomized (2:1). Randomization will be 
stratified according to current treatment with beta-blocker (yes or no).  
4.2 
Study period 
The study will be composed of 4 periods as below: 
• 
Screening period: up to 4 weeks 
• 
Double-blinded, placebo-controlled treatment period: 30 weeks 
• 
LTE period: 48 weeks, including a double-blinded LTE phase and an open-
label LTE phase 
• 
Post treatment follow-up period: 8 weeks (or 20 weeks for poor CYP2C19 
metabolizer) 
4.3 
Study procedure  
 Screening period (Day – 28 to Day -1) 
Participants who sign the informed consent form (ICF) will undergo a variety of 
general, cardiac and laboratory assessments to assess eligibility (see Table 1). A goal 
of at least 25% of the participants will be NYHA functional class III. Key screening 
tests include electrocardiogram (ECG) and TTE conducted at rest, with Valsalva 
maneuver. Screening ECG and TTE test results as reported by core laboratories will be 
used to confirm eligibility for randomization. In other assessments, CMR (if participant 
is eligible) will be read by core laboratory; Cardiac biomarkers will be tested by central 
laboratory; Safety laboratory tests will be tested by local laboratories. 
The screening assessments may be repeated, as long as they are within the 28-day 
screening window. Repeat assessments are allowed if central/core laboratories require 
a repeat submission due to quality, or investigator considers to be necessary.  
Participants who screen fail may be considered for rescreening based on the 
investigator’s discretion and discussion with sponsor or sponsor assigned medical 
monitor, taking into consideration the reason(s) for screening fail. One attempt at 
rescreening will be allowed, and all procedures must be repeated.  
 Double-blinded, placebo-controlled treatment period (Day 1 to Week 30) 
Participants who meet all eligibility criteria will first be randomized via an interactive 
response system (IxRS) in a 2:1 ratio (mavacamten: placebo) to receive mavacamten 
2.5 mg starting dose or matching placebo QD. Dose titration scheme was designed to 
achieve safe and effective dosing for each participant (please see Table 5-6 for more 


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details). The permissible doses during the study are 1 mg, 2.5 mg, 5 mg, 10 mg, and 15 
mg. 
All clinic visits will include but are not limited to clinical evaluation (symptoms, KCCQ 
results), AE/SAE assessments, concomitant medications, laboratory tests. PK (plasma 
concentrations), cardiac biomarkers, TTE, CMR (if participant is eligible), Holter, and 
ECG will be collected/performed at study visits and read by core/central laboratories 
(see Table 1). Results of TTEs performed at each scheduled visit following 
randomization should be kept blinded to the participants, investigator and other blinded 
study site personnel. An exception may occur if LVEF ≤ 30% is measured at the site, 
then the investigator will be notified at the first moment by site TTE reporter and study 
drug will be permanently discontinued (see Section 8.1). 
After randomization, participants will first be seen at Week 4 for an initial evaluation 
of clinical tolerability and safety. Pre-dose PK sample collection will be performed at 
this visit. In the event that the results from Week 4 meet pre-dose PK criteria for down-
titration (700 ng/mL < pre-dose plasma concentration < 1000 ng/mL), the dose will be 
decreased at Week 6 to 1 mg via the IxRS (see Table 5). 
Participants will subsequently be seen at Week 6, Week 12, and Week 18 for repeat 
evaluation. Blinded assessments including pre-dose PK, and TTE measures of LVEF 
and LVOT gradient with Valsalva will be performed to guide dose adjustment via the 
IxRS. At Week 8, Week 14, and Week 20, the dose will be adjusted (increase, decrease, 
remain unchanged) based upon results of Week 6, Week 12 and Week 18 assessments, 
respectively, as specified in Table 6 and Section 7.4.1. For added safety, blinded 
assessments at Week 8 can inform dose reduction or temporary discontinuation of study 
drug based on predefined criteria detailed in Section 7.4.1 and Section 7.4.3. If criteria 
met, an unscheduled visit (a drug dispensing visit only) will be arranged 2 weeks later 
to reduce dose as specified in Section 7.4.1 and Section 7.4.3.  
After Week 20, there are no additional scheduled dose titrations. Blinded assessments 
at Weeks 24, and 26 can inform dose reduction or temporary discontinuation of study 
drug based on predefined criteria detailed in Section 7.4.1 and Section 7.4.3.  
At any time if pre-dose plasma concentration ≥ 1000 ng/mL or LVEF < 50%, then the 
study will be temporarily discontinued (see Section 7.4.3). 
The primary endpoint will be evaluated at Week 30. Participants will complete at rest, 
with Valsalva maneuver TTE, and CMR (if participant is eligible) for endpoints 
evaluation. Attempt will be made to obtain these assessments at Week 30, if possible.  
For any participant permanently discontinuing treatment prior to Week 30, an early 
termination (ET) visit should be conducted as soon as possible, including resting and 
Valsalva TTE, and CMR (if participant is eligible) assessments. After ET visit, the 
participant will participate post-treatment visits (as outlined in Table 1) and Week 30 
visit. Week 30 visit could be earlier (if ET occurs after Week 22) or later (If ET occurs 
before Week 22) than 8-week onsite post-treatment visit. If the interval between Week 
30 and 8-week onsite post-treatment visit within 2 weeks, only 1 visit is needed. 
Attempt will be made to obtain assessments at Week 30, if possible. 


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 LTE period (48 weeks) 
Participants who complete the 30-week double-blinded, placebo-controlled treatment 
period and, in the judgment of the investigator, have no active safety concerns will roll 
directly into the LTE period. All participants will receive active mavacamten in blinded 
manner (double-blinded LTE phase, prior treatment allocation and study drug dosage 
remain blinded) until all the participants complete 30-week placebo-controlled 
treatment, database of the 30-week treatment is locked. Once the study is unblinded, 
participants will receive study treatment in open-label manner (Open-label LTE phase). 
All participants will receive active study drug (mavacamten) QD for a duration of 48 
weeks during the LTE period (an exception will occur if participants who were 
randomized to mavacamten group but already switched to placebo, they will continue 
on placebo during the double-blinded LTE period).  
During LTE period, clinic visits will include but are not limited to clinical evaluation 
(symptoms, KCCQ results), AE/SAE assessments, concomitant medications, 
laboratory tests (see Table 2). During the double-blinded phase, TTE will be read by 
core laboratory. Results of TTEs performed at each scheduled visit during double-
blinded LTE period should remain to be blinded to the participants and investigator. An 
exception may occur if LVEF ≤ 30% is measured at the site. During the open-label LTE 
phase, TEE will be read by site. Results of TTE will be unblinded to participants and 
investigator. TTE will also be sent to core laboratories for data analysis. PK (plasma 
concentrations), cardiac biomarkers, CMR (if participant is eligible), Holter, and ECG 
will be collected/performed at study visits and read by core/central laboratories (see 
Table 2).  
Participants who were previously in mavacamten group will continue to receive dose 
received at Week 30, unless any of dose discontinuation criteria is met (detailed in 
Section 7.4.3). After study is unblinded, visits are required at Week 34, 40, 46, 54, 62, 
70 and 78. During the open-label LTE phase, increases in dosage are permitted after 
discussion between investigator and Sponsor or Sponsor assigned medical monitor 
(maximum dose 15 mg QD, see Section 7.4.2). For participants who were randomized 
to mavacamten group but already switched to placebo, a retrial of mavacamten 1 mg 
might be considered after discussion between investigator and Sponsor or Sponsor 
assigned medical monitor. If LVEF again falls to <50%, mavacamten will be 
permanently discontinued. 
Participants who were previously in placebo group will receive mavacamten (2.5 mg, 
QD). During the double-blinded phase, the dose will be adjusted at Week 36, Week 42, 
Week 54, and Week 66 based on TTE measures of LVEF and LVOT gradient with 
Valsalva at Week 34, Week 40, Week 52, and Week 64 (read by core laboratory) via 
the IxRS (see Table 7, see Section 7.4.2). After study unblinded, the dose will be 
adjusted at Week 36, Week 42, Week 54, and Week 66 based on TTE assessment on 
the day of visit (read by site). Week 52 and Week 64 visit could be removed during the 
open-label phase. After Week 66, there are no additional scheduled dose titrations. The 


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dose may be reduced or discontinued at any time based on the predefined criteria (see 
Section 7.4.3) during the LTE period. 
At Week 78 (end of treatment, EOT), participants will complete at rest, with Valsalva 
maneuver TTE, and CMR (if participant is eligible). 
For any participant who is not rolled into LTE period, post-treatment visits (phone call-
visit and onsite visits) will be conducted (see Table 1). For any participant permanently 
discontinuing treatment prior to Week 78, an ET visit should be conducted as soon as 
possible, including resting and Valsalva TTE, and CMR (if participant is eligible) 
assessments. Participants who prematurely discontinue the study will attend an ET visit, 
post-treatment visits (phone call-visit and onsite visits) as outlined in Table 2. 
 Post treatment follow-up period (8 weeks/ CYP2C19 poor metabolizer, 20 
weeks) 
Once a participant has completed the treatment at Week 78, the participant will be 
contacted by phone 4 weeks (Week 82) later and return to the site 8 weeks (Week 86) 
later for an onsite visit. For CYP2C19 poor metabolizer, an additional onsite visit will 
perform 20 weeks later (Week 98). 
Telephone assessments will include AEs, and concomitant medications. Onsite visit 
will include but not be limited to symptoms, AE/SAE assessments, ECG, TTE, KCCQ 
results, laboratory tests, PK, NT-proBNP and cardiac troponin. 
In the context of COVID-19 or other pandemics, natural disasters, or major disruptions, 
provisions may be made to accommodate participants who are unable to attend onsite 
study visits for scheduled assessments and dispensation of mavacamten. Guidance on 
participants management in these situations is outlined in Appendix 4. 
 Description of other procedures and assessments  
Participant with ICDs will have their data downloaded at screening, Week 12, ET and 
Week 30 in the placebo-controlled treatment period, and at Week 78/ET in the LTE 
period, or as clinically indicated whenever device discharge is interrogated and/or prior 
to any device reset (see Table 1-2).  
Eligible participants will undergo CMR during screening, ET and Week 30 (If ET 
occurs and CMR is performed at ET visit, CMR is not required at Week 30 visit) in the 
placebo-controlled treatment period, Week 78/ET in the LTE period to evaluate changes 
in LV mass, myocardial fibrosis, cellular hypertrophy, and cardiac structure and 
function (see Table 1-2). 
The KCCQ assessment will be completed at the visits of D1, Week 6, Week 12, Week 
18, ET and Week 30 in the placebo-controlled treatment period; Week 34, Week 40, 
Week 46, Week 54, Week 62, Week 70, Week 78/ET in the LTE period and post-
treatment onsite visits (see Table 1-2).  
Blood samples will be collected for analysis of CYP2C19 polymorphism. 


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4.4 
 Study committees 
 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 (e.g., CV death, 
stroke, myocardial infarction). 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 CV events. The 
processes to identify coded events for submission to the committee members for 
adjudication will be described in a related CEAC charter. The CEAC full committee 
will meet on a pre-defined frequency or as needed to review discordant cases and 
conduct their responsibilities as outlined in the related CEAC charter. The related 
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. 
  Independent data monitoring committee 
An IDMC will meet at regular intervals to safeguard the interest of study participants 
by assessing unblinded safety data from the ongoing study and to advise the Sponsor 
on important emerging study conduct issues. The IDMC may provide recommendations 
regarding the procedures and methodologies by surveying and detecting potential safety 
signals. Meeting frequency, membership, and conduct will be described in the related 
IDMC charter. 
 
 


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Study Population 
Approximately 81 participants with symptomatic oHCM are expected to enroll in this 
study from approximately 15 clinical sites in China. 
5.1 
Inclusion criteria 
Each participant must meet the following criteria to be included in this study: 
1) Is at least 18 years old at screening. 
2) Body weight is greater than 45 kg at screening. 
3) Has adequate acoustic windows to enable accurate TTEs (refer to 
echocardiography related manual). 
4) Diagnosed with oHCM consistent with current American College of Cardiology 
Foundation/American Heart Association, European Society of Cardiology, and 
Chinese Society of Cardiology guidelines, i.e., satisfy 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 (e.g., hypertension, aortic stenosis) or systemic disease 
and with maximal LV wall thickness ≥ 15 mm (or ≥ 13 mm with positive family 
history of hypertrophic cardiomyopathy), as determined by core laboratory 
interpretation, and 
B. Has LVOT peak gradient ≥ 50 mmHg during screening as assessed by 
echocardiography at rest or after Valsalva maneuver (confirmed by 
echocardiography core laboratory interpretation). 
5) Has documented LVEF ≥ 55% by echocardiography core laboratory read of 
screening TTE at rest. 
6) Has a valid measurement of Valsalva LVOT peak gradient at screening as 
determined by echocardiography core laboratory. 
7) Has NYHA Class II or III symptoms at screening. 
8) Has documented oxygen saturation at rest ≥ 90% at screening. 
9) Female participants must not be pregnant or lactating and, if sexually active, must 
be using one of the following acceptable birth control methods from the screening 
visit through 5 months after the last dose of investigational medicinal product 
(IMP). 
a) 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. 
b) Intrauterine device (IUD). 
c) Intrauterine hormone-releasing system (IHS). 
d) Bilateral tubal occlusion. 


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e) Female 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 ≥1 year after cessation of all exogenous hormonal treatments, and 
follicle-stimulating hormone levels are in the postmenopausal range. 
f) Male partners of female participants must also use a contraceptive (e.g., barrier, 
condom, or vasectomy) from screening through 5 months after the last dose of 
study drug. 
10) Able to understand and comply with the study procedures, understand the risks 
involved in the study, and provide written informed consent according to national, 
local, and institutional guidelines before the first study specific procedure. 
LTE inclusion criteria: 
1) Successful completion of 30-week double-blinded, placebo-controlled treatment 
period (still on the study drug).  
2) In the judgment of the investigator, participants have no active safety concerns. 
5.2 
Exclusion criteria  
A participant who meets any of the following exclusion criteria will be excluded from 
this study: 
1) 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 (if known), 
whichever is longer. 
2) Known infiltrative or storage disorder causing cardiac hypertrophy that mimics 
oHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV 
hypertrophy. 
3) Has a history of syncope within 6 months prior to screening or sustained ventricular 
tachyarrhythmia with exercise within 6 months prior to screening. 
4) Has a history of resuscitated sudden cardiac arrest (at any time) or known history 
of appropriate ICD discharge for life-threatening ventricular arrhythmia within 6 
months prior to screening. 
5) Has paroxysmal, intermittent atrial fibrillation with atrial fibrillation present per 
the investigator’s evaluation of the participant’s ECG at the time of screening. 
6) 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: participants with persistent or permanent atrial fibrillation 
who are anticoagulated and adequately rate-controlled are allowed). 
7) Previously participated in a clinical study with mavacamten. 
8) Hypersensitivity to any of the components of the mavacamten formulation. 
9) Current treatment (within 14 days prior to screening) or planned treatment during 
the study with disopyramide, cibenzoline, or ranolazine. 


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10) Current treatment (within 14 days prior to screening) or planned treatment during 
the double-blinded treatment with a combination of beta-blockers and verapamil 
or a combination of beta blockers and diltiazem. 
11) For individuals on beta-blockers, verapamil, or diltiazem, any dose adjustment of 
that medication within14 days prior to screening or any anticipated change in 
treatment regimen using these medications during the double-blinded treatment. 
12) 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 
an unsuccessful myectomy or percutaneous ASA procedure performed > 6 months 
prior to screening may be enrolled if study eligibility criteria for LVOT gradient 
criteria are met). 
13) ICD placement within 2 months prior to screening or planned ICD placement 
during the study. 
14) Has QTcF > 500 msec when QRS interval < 120 msec or QTcF > 520 msec when 
QRS ≥ 120 msec or any other ECG abnormality considered by the investigator to 
pose a risk to participant safety (e.g., second-degree atrioventricular block type II). 
15) Has documented obstructive coronary artery disease (> 70% stenosis in one or 
more epicardial coronary arteries) or history of myocardial infarction. 
16) Has known moderate or severe (as per investigator’s judgment) aortic valve 
stenosis, constrictive pericarditis, or clinically significant congenital heart disease 
at screening. 
17) Has any acute or serious comorbid condition (e.g., 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. 
18) History of malignant disease within 10 years of screening: 
a) 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. 
b) Participants with other malignancies who are cancer free for more than 10 years 
before screening can be included in the study. 
19) Has safety laboratory parameters (chemistry, hematology, coagulation, and 
urinalysis) outside normal limits (according to the local laboratory reference range) 
at screening as assessed by the local laboratory; however, a participant with safety 
laboratory parameters outside normal limits may be included if he or she meets all 
of the following criteria: 
a) The safety laboratory parameter outside normal limits is considered by the 
investigator to be clinically not significant. 
b) If there is an alanine aminotransferase or aspartate aminotransferase result, the 


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value must be < 3 × the upper limit of the laboratory reference range. 
c) The body size–adjusted estimated glomerular filtration rate is ≥30 mL/min/1.73 
m2. 
20) Has a positive serologic test at screening for infection with human 
immunodeficiency virus, hepatitis C virus, or hepatitis B virus surface antigen. 
21) Known uncured COVID-19 (coronavirus disease 2019) infection or with severe 
complication before screening. 
22) 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. 
23) Is currently taking, or has taken within 14 days prior to screening, a prohibited 
medication, such as a cytochrome CYP2C19 inhibitor (e.g., omeprazole or 
esomeprazole), a strong CYP3A4 inhibitor, or St. John’s Wort. Alternatives, such 
as pantoprazole are allowed and may be discussed with the medical monitor. 
24) Prior treatment with cardio toxic agents such as doxorubicin or similar. 
25) Unable to comply with the study requirements, including the number of required 
visits to the clinical site. 
26) Is a first degree relative of personnel directly affiliated with the study at the clinical 
study site, any study vendor, or the study sponsor. 
27) Is currently taking, or has taken within 14 days prior to screening, biotin 
supplements (multivitamins that contain < 1000 mg biotin are allowed during the 
study but must be stopped 24 hours prior to each study visit). 
28) Identified as alcohol addicts. 
CMR exclusion criteria: 
A participant will be excluded from the CMR assessments if he or she has any of the 
following: 
1) An ICD or pacemaker, or another contraindication for CMR or conditions not 
suitable for CMR in the judgment of the investigator. 
2) Atrial fibrillation at the time of screening (participants who are in atrial fibrillation 
at the time of imaging will be asked to return at a later time within the screening 
period, and if the participant is still in atrial fibrillation, the participant will be 
disqualified from the CMR assessments). 
3) Allergy or contraindication to contrast medium. 
5.3 
Screening and enrollment 
An ICF must be signed and dated by the participant before any study-specific tests or 
procedures may be performed. 
If possible, each participant should keep his or her unique identification number that 
was assigned upon entry into the study. Numbers do not include identifiable 
information. The identification number will be used to identify the participant 
throughout the study. 


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Once a participant signs the ICF, the screening window opens, and participants shall 
finish all screening tests and evaluations within 28 days. 
Participants who fail to meet all enrollment criteria may be re-screened. Sponsor or 
Sponsor assigned medical monitor should be contacted to discuss the specific situation. 
 


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Randomization and Blinding Procedures 
6.1 
Randomization 
A stratified block randomization scheme will be used in this study. Randomization will 
be stratified according to current treatment with beta-blocker or not. A computer-
generated stratified block randomization schedule will be prepared by an unblinded 
statistician prior to the start of the study. 
After signing the ICF, each participant will be given a screening number according to 
the screening order. Following the screening, participants who meet the inclusion 
criteria and none of the exclusion criteria are to be randomly assigned to receive either 
mavacamten or placebo (2: 1), in accordance with the randomization schedule. At the 
time of randomization, the participant will be assigned a unique randomization number, 
which will be allocated sequentially based on the predetermined stratified block 
randomization schedule and according to the chronological order of enrollment in the 
study. The allocation of participants to treatment will be performed via an IxRS. 
Confirmation of the treatment number allocated will be documented in the drug 
accountability records and recorded in the eCRF. 
6.2 
Study blinding  
During double-blinded, placebo-controlled treatment period and double-blinded LTE 
phase, the investigator, site staff, Sponsor, the central/core laboratories, relevant 
contract research organization (CRO) staff, and participants are all blinded to treatment 
assignment. No individual-participant information that can potentially unblind the 
investigator or participants will be reported until the 30-week treatment database is 
locked and the unblinding is informed by the Sponsor. 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 
and assigned to participants through the IxRS. 
During double-blinded, placebo-controlled treatment period and double-blinded LTE 
phase, results of titration required parameters (i.e., echocardiography results and plasma 
drug concentration data) will be transferred to the IxRS by the respective core/central 
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 (unblinded 
site personnel, e.g., sonographer or unblinded clinician/cardiologist) may be unblinded 
to these parameters, but still blinded to the treatment allocation. In the case of LVEF ≤ 
30%, the investigator will be notified as described in Section 7.4.4. During blinded 
treatment, the pharmacovigilance (PV) operation team or designee will be unblinded 
for suspected unexpected serious adverse reaction (SUSAR) for health authority 
reporting purpose. The IDMC may also be unblinded to treatment allocation and all 


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safety and efficacy data. During open-label LTE period, results of TTE assessments are 
not blinded to the participants and investigators. 
6.3 
Methods for unblinding 
All efforts should be made to keep participants blinded to treatment assignment before 
study unblinded. However, participants may be unblinded to treatment assignment upon 
request from the investigator and agreement by the Sponsor by following reasons: 
1) A serious, unexpected, treatment-related events for reasons of participant safety, 
2) An urgent safety measure taken by the investigator or Sponsor to protect 
participants against immediate hazard to health, 
3) A potential life-threatening drug interaction, 
4) Ethical consideration such as medical emergency where understanding the 
treatment assignment will impact future treatments or clinical care of the 
participants.  
Unblinding by the investigator independently of the Sponsor also may occur if an SAE 
or other medical emergency where identification of the medication for the welfare of 
the participants.  
The unblinding for emergency purposes will be performed via the IxRS. The date and 
reason for unblinding must be clearly documented. 
The final unblinding will be performed after the database of 30-week treatment is 
locked and the unblinding is informed by the Sponsor. 


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Study Treatment  
7.1 
Study treatment administered 
The study treatments administered in this study are mavacamten and matching placebo. 
Mavacamten is supplied as 1 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg capsules. 
Mavacamten capsules of all strengths are identical in appearance. Matching placebo is 
supplied as a single capsule to match all mavacamten strengths and is identical in 
appearance to mavacamten capsules. 
Participants will receive mavacamten (1 mg, 2.5 mg, 5 mg, 10 mg, or 15 mg) or 
matching placebo QD for 30 weeks (Day 1 to Week 30) in a double-blind manner. 
Beginning LTE period, all participants (i.e., mavacamten group and placebo-to-active 
group) will receive mavacamten QD through Week 78. During the study, there are 
opportunities for mavacamten dose titration as described in Section 7.4  
Study drug will be supplied to participants via the IxRS in 30 count high-density 
polyethylene bottles that are appropriately labeled. Refer to Table 1-2 for the complete 
schedule of study drug administration. The participants will be instructed to store the 
study drug capsules and bottles in a cool, dry place.  
Participants will take study drug as directed by the study investigator. Participants 
should be instructed to take the study drug at approximately the same time every day 
(± 8 hours). Study drug should be taken with approximately 8 ounces (~240 mL) of 
water. If the dosing window is missed, the participant should not take study drug that 
day. In the event of vomiting, dose should not be repeated, but taken again the next day. 
Participants should never take 2 doses of study drug within an 8-hour period. 
Table 4 provides an overview of the study treatments during double-blinded, placebo-
controlled period. 
 
Table 4 Study Treatments 
 
Treatment Group 
 
Mavacamten 
Placebo 
Name of Study Treatment  
Mavacamten 
Placebo 
Type  
Study drug 
Placebo 
Dose Formulation  
Capsules 
Capsules 
Unit Dose Strength  
1 mg, 2.5 mg, 5 mg, 10 mg, and 
15 mg 
Placebo capsule matching all 
mavacamten strengths 
Dosage Level  
1 mg, 2.5 mg, 5 mg, 10 mg, or 15 
mg QD 
Placebo QD 
Route of Administration  
Oral 
Sourcing  
Sponsor 
Packaging and Labeling  
see Section 7.2 
Current/Former Name  
Mavacamten/MYK-461 
Not applicable 
 Abbreviations: QD = once daily.  


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7.2 
Study drug preparation, handling, storage, and accountability 
The investigator or designee must confirm appropriate temperature conditions were 
maintained during transit for all study drug received and that any discrepancies are 
reported and resolved before use of the study drug. 
Only participants randomized into the study may receive study drug, and only 
authorized study staff may supply or administer study drug. All study drug must be 
stored in a secure and monitored area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff. 
The investigator/designee is responsible for study drug accountability, reconciliation, 
and record maintenance (i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study drug are 
provided in the related pharmacy manual. 
 Formulation, packaging, and labeling of study drug 
Mavacamten capsules are provided as size 2, blue opaque capsules printed with a 
yellow band on the body and a black band on the cap. Each capsule contains white to 
off-white powder. 
Mavacamten capsules are supplied in 1 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg strengths. 
Mavacamten capsules of all strengths are identical in appearance. Matching placebo 
capsules are identical in appearance to mavacamten capsules. 
Mavacamten and matching placebo capsules are manufactured according to current 
Good Manufacturing Practice (cGMP) regulations. They are supplied in high-density 
polyethylene bottles with induction seals and child-resistant caps with 30 capsules in 
each bottle. All bottles are labeled according to applicable local regulatory guidelines. 
Mavacamten and placebo capsules must be stored at 2℃ to 25℃ (36℉ to 77℉) in the 
packaging supplied by sponsor. 
7.3 
Study drug administration and schedule 
  Treatment compliance  
Compliance with study drug will be monitored by capsule count at all study visits. Refer 
to the related pharmacy manual for details.  
On study visit days, participants should wait to do examinations before taking study 
drug as indicated in the schedule of study procedures. 
7.4 
Dose adjustments  
Dose adjustments will be made by the investigator using the IxRS which will dispense 
IMP in a double-blind manner during 30-week double-blinded treatment period and 
double-blinded LTE phase. During open-label LTE phase, the dose adjustments will be 
made by investigator using the IxRS in an open-label manner. The Tables 5-7 outline 
how the dose may be adjusted and the IxRS will be programmed accordingly, but the 


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investigator and the participant will not know the dose during the double-blinded 
treatment. 
 Blinded dose adjustments during double-blinded placebo-controlled 
treatment period 
The double-blinded placebo-controlled treatment period will include a three-step dose 
titration scheme at Weeks 8, 14 and Week 20 designed to achieve safe and effective 
dosing for each participant based on their own PK/PD response parameters (see Table 
5-6). 
In this study, the starting dose of study drug is mavacamten 2.5 mg or matching placebo 
QD and each participant will receive this dose of study drug from Day 1 through Week 
8 unless the PK/PD criteria for down-titration is met at Week 4, in which case the dose 
will be reduced at Week 6 (see Table 5). 
At Weeks 8, 14 and 20, participants will undergo dose titration (increase or remain 
unchanged) based on their results of pre-dose plasma concentration, resting LVEF and 
Valsalva gradient determined by TTE at Week 6, 12 and 18, respectively (see Table 6). 
After the dose titration at Week 20, there are no further dose up-titrations. The intent is 
for dose to remain unchanged unless for safety or other reasons for premature 
discontinuation. 
If the PK/PD criteria for down-titration is met at Week 6, Week 8, Week 12, Week 18, 
Week 24, or Week 26, then a scheduled or unscheduled visit 2 weeks later will be 
arranged to reduce dose (see Table 5). To avoid potential bias, the IxRS will randomly 
select participants from the placebo arm to undergo unscheduled visits (see 
Section 6.2). 
At each visit, AEs, concomitant medications, and symptoms will be assessed. ECG, 
pre-dose PK, and TTE will be performed for ongoing safety monitoring. Compliance 
with study drug will also be monitored by capsule count at each visit. 
The dose titration scheme is provided for IxRS programming. Sites and investigators 
are not allowed to actively adjust doses during the placebo-controlled treatment period. 
All dose adjustments will occur in a double-blinded manner via the IxRS, and all 
participants, whether receiving mavacamten or matching placebo, will undergo 
assessments that could lead to a blinded dose adjustment. However, the participants 
who are on placebo will remain on placebo (in blinded fashion) unless the participant 
meets the criteria of temporary discontinuation as described in Section 7.4.3 or 
permanent treatment discontinuation as described in Section 7.4.4 and 8.1.3. 
If the dose of mavacamten is decreased at any time, then the participant will continue 
on the reduced dose during the double-blinded treatment unless safety concerns or 
intolerability arise requiring further dose reduction or dose discontinuation. 


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Table 5 PK/PD Criteria for Down-Titration during Double-Blinded Placebo-
Controlled Treatment Period 
Requires resting LVEF ≥ 50% regardless of Valsalva gradienta 
Time of Assessment 
Pre-dose 
Mavacamten 
Plasma 
Concentration 
(ng/mL)a 
Time and Doseb 
Week 4 
700 < Plasma concentration < 
1000 
Week 6:  
· 
Dose reduces from 2.5 mg to 1 mg 
Week 6 
700 < Plasma concentration < 
1000 
Week 8:  
· 
Dose reduces from 2.5 mg to 1 mg (If dose is reduced at 
Week 6, it should remain unchanged at Week 8) 
Week 8c 
700 < Plasma concentration < 
1000 
2 weeks later:  
· 
Dose reduces from 5 mg to 2.5 mg or 
· 
Dose reduces from 2.5 mg to 1 mg or 
· 
Dose reduces from 1 mg to placebo (If dose is reduced at 
Week 8, it should remain unchanged 2 weeks later) 
Week 12 
700 < Plasma concentration < 
1000 
Week 14:  
· 
Dose reduces from 5 mg to 2.5 mg or 
· 
Dose reduces from 2.5 mg to 1 mg or 
· 
Dose reduces from 1 mg to placebo 
Week 18 
700 < Plasma concentration < 
1000 
Week 20:  
· 
Dose reduces from 10 mg to 5 mg or  
· 
Dose reduces from 5 mg to 2.5 mg or 
· 
Dose reduces from 2.5 mg to 1 mg or 
· 
Dose reduces from 1 mg to placebo 
Weeks 24 
700 < Plasma concentration < 
1000 
Week 26:  
· 
Dose reduces from 15 mg to 10 mg or  
· 
Dose reduces from 10 mg to 5 mg or 
· 
Dose reduces from 5 mg to 2.5 mg or 
· 
Dose reduces from 2.5 mg to 1 mg or 
· 
Dose reduces from 1 mg to placebo 
Weeks 26 
700 < Plasma concentration < 
1000 
2 weeks later:  
· 
Dose reduces from 15 mg to 10 mg or  
· 
Dose reduces from 10 mg to 5 mg or 
· 
Dose reduces from 5 mg to 2.5 mg or 
· 
Dose reduces from 2.5 mg to 1 mg or 
· 
Dose reduces from 1 mg to placebo (If dose is reduced at 
Week 26, it should remain unchanged 2 weeks later) 
Abbreviations: IxRS = interactive response system; LVEF = left ventricular ejection fraction; PD = 
pharmacodynamics; PK = pharmacokinetics; TTE = transthoracic echocardiography.  
a LVEF and pre-dose mavacamten plasma concentration will be communicated directly to the IxRS from 
the core/central laboratories based on assessments so that it is blinded to the investigator, study site 
personnel, and the Sponsor. If LVEF < 50%, see Section Treatment Discontinuation. Note: LVEF will 
not be performed at Week 8 (see also footnote c).  
b Dose reduction applies if pre-dose PK criterion is met.  
c Week 8 assessment for dose reduction will be based solely on pre-dose mavacamten plasma 
concentration value, there will be no TTE performed at Week 8, and therefore, no LVEF result. 


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Table 6 Dose Titration during Double-Blinded Placebo-Controlled Treatment 
Period 
Requires resting LVEF ≥ 50% and pre-dose mavacamten plasma concentration ≤ 700 ng/mL 
Time 
of 
Assessment 
Dose Titration Criteria 
(based on the LVEF, Valsalva gradient and pre-dose 
mavacamten plasma concentration) 
Dose 
Titrationa 
Time and Doseb 
Week 6 
LVEF ≥ 55%  
Valsalva gradient ≥ 30 mmHg AND 
plasma concentration < 350 ng/mL  
Increase 
Week 8:  
· 
Dose increases from 
2.5 mg to 5 mg 
LVEF ≥ 55% 
Valsalva gradient < 30 mmHg and 
plasma concentration < 350 ng/mL OR 
350 ≤ plasma concentration ≤ 700 
ng/mL 
(regardless 
of 
Valsalva 
gradient) 
No change 
Week 8:  
· 
Dose remains at 2.5 
mg or 1 mg  
50% ≤ LVEF < 
55% 
Regardless of Valsalva gradient and 
plasma concentration 
Week 12 
LVEF ≥ 55%  
Valsalva gradient ≥ 30 mmHg AND 
plasma concentration < 350 ng/mL 
Increase 
Week 14:  
· 
Dose increases from 
5 mg to 10 mg or  
· 
Dose increases from 
2.5 mg to 5 mg  
LVEF ≥ 55% 
Valsalva gradient < 30 mmHg and 
plasma concentration < 350 ng/mL OR 
350 ≤ plasma concentration ≤ 700 
ng/mL 
(regardless 
of 
Valsalva 
gradient) 
No change 
Week 14:  
· 
Dose remains at 5 
mg or 2.5 mg or 1 
mg 
50% ≤ LVEF < 
55% 
Regardless of Valsalva gradient and 
plasma concentration 
Week 18 
LVEF ≥ 55% 
Valsalva gradient ≥ 30 mmHg AND 
plasma concentration < 350 ng/mL 
Increase 
Week 20:  
· 
Dose increases from 
10 mg to 15 mg or 
· 
Dose increases from 
5 mg to 10 mg or  
· 
Dose increases from 
2.5 mg to 5 mg 
LVEF ≥ 55% 
Valsalva gradient < 30 mmHg and 
plasma concentration < 350 ng/mL OR 
350 ≤ plasma concentration ≤ 700 
ng/mL 
(regardless 
of 
Valsalva 
gradient) 
No change 
Week 20: 
· 
Dose 
remains 
at 
10mg, 5 mg or 2.5 
mg or 1 mg 
50% ≤ LVEF < 
55% 
Regardless of Valsalva gradient and 
plasma concentration 
Abbreviations: IxRS = interactive response system; LVEF = left ventricular ejection fraction.  
a Titration adjustments will also be communicated directly to the IxRS based on Week 6, 12 and 16 
including measures of peak Valsalva gradient reported by the core laboratory so that blinding is 
maintained.  
b If the mavacamten dose is decreased at any time during the study, then the participant will continue on 
the reduced dose to the Week 30 unless safety concerns or intolerability arise requiring further dose 
reduction or dose discontinuation. 
 
 Dose adjustments during LTE period 
During the double-blinded LTE phase: 


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• 
Participants who were previously on placebo will start 2.5 mg mavacamten at the 
end of Week 30, and the dose will be adjusted per a dose titration schedule (see 
Table 7). Scheduled dose decrease may occur at Week 36 if down-titration is met 
at Week 34 and with opportunities to dose increase at Weeks 42, Week 54 and 
Week 66 based on their results of resting LVEF and Valsalva gradient determined 
by TTE at Week 40, Week 52 and Week 64, respectively (see Table 7). After Week 
66, no dose up-titration will be allowed. The dose titration scheme is provided for 
IxRS programming. Sites and investigators are not allowed to actively adjust doses 
during the double-blinded LTE period. All dose adjustments will occur in a double-
blind manner via the IxRS.  
• 
Participants previously on mavacamten will continue on the dose received at Week 
30 unless the participant meets the criteria of temporary discontinuation as 
described in Section 7.4.3 or permanent treatment discontinuation as described in 
Section 7.4.4 and 8.1.3. 
During the open-label LTE phase, dose adjustments will base on site-read resting LVEF 
and LVOT gradient with Valsalva maneuver evaluated by TTE on the day of the visit:  
• 
For participants who were previously on placebo, dose adjustments will occur in 
an open-label manner via the IxRS guiding by the dose titration schedule (Table 
7). If safety concern raised, sites and investigators might allow to actively adjust 
doses (decrease, temporarily discontinue, or remain unchanged even up-titration 
criteria is met) in conjunction with Sponsor or Sponsor assigned medical monitor. 
If dose actively adjusted, participants should return to the clinical site 4 weeks later 
(±7 days) visit with resting and Valsalva TTE assessment, to confirm safety. Based 
on results and clinical symptoms at follow-up visits, subsequent dose adjustments 
will be discussed with Sponsor or Sponsor assigned medical monitor.  
• 
For participants previously on mavacamten, dose increase may be considered (if 
LVEF ≥ 55% and Valsalva gradient ≥ 30 mmHg) during the open-label LTE period 
(maximum dose 15 mg QD. Skipping dose levels is not allowed.) after discussion 
with Sponsor or Sponsor assigned medical monitor. For participants who were 
randomized to mavacamten group but already switched to placebo, a retrial of 
mavacamten 1 mg might be considered after discussion between investigator and 
Sponsor or Sponsor assigned medical monitor. If LVEF again falls to <50%, 
mavacamten will be permanently discontinued. The investigator, in conjunction 
with Sponsor or Sponsor assigned medical monitor, may also reduce or temporarily 
discontinue participant’s mavacamten dose if safety concern raised. Participants 
who have had a dose adjustment should return to the clinical site 4 weeks later (±7 
days) visit with resting and Valsalva TTE assessment, to confirm safety. Based on 
results and clinical symptoms at follow-up visits, subsequent dose adjustments will 
be discussed with Sponsor or Sponsor assigned medical monitor. 
 
Table 7 Dose Titration for Participants Previously on Placebo during LTE 


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Period 
Requires resting LVEF ≥ 50% 
Time of Dose 
Adjustment 
Dose Titration Criteria 
(based on the LVEF and Valsalva 
gradient)a 
Dose 
Titration 
Doseb 
Week 36 
LVEF ≥ 50% 
Valsalva gradient ≥ 20 
mmHg 
No change 
· 
Remains at 2.5 mg 
LVEF ≥ 50% 
Valsalva gradient < 20 
mmHg 
Decrease 
· 
Reduces from 2.5 mg to 1 mg 
Week 42 
LVEF ≥ 55% 
Valsalva gradient ≥ 30 
mmHg 
Increase 
· 
Increases from 2.5 mg to 5 mg or 
1 mg to 2.5 mg 
LVEF ≥ 55% 
Valsalva gradient < 30 
mmHg 
No change 
· 
Remains at 2.5 mg or 1 mg 
50% ≤ LVEF < 
55% 
Regardless of Valsalva 
gradient 
Week 54 
LVEF ≥ 55% 
Valsalva gradient ≥ 30 
mmHg  
Increase 
· 
Increases from 5 mg to 10 mg or  
· 
Increases from 2.5 mg to 5 mg or 
· 
Increases from 1 mg to 2.5 mg 
LVEF ≥ 55% 
Valsalva gradient < 30 
mmHg 
No change 
· 
Remains at 5 mg or 2.5 mg or 1 mg 
50% ≤ LVEF < 
55% 
Regardless of Valsalva 
gradient 
Week 66 
LVEF ≥ 55% 
Valsalva gradient ≥ 30 
mmHg  
Increase 
· 
Dose increases from 10 mg to 15 
mg or 
· 
Dose increases from 5 mg to 10 
mg or 
· 
Dose increases from 2.5 mg to 5 
mg or  
· 
Dose increases from 1 mg to 2.5 
mg 
LVEF ≥ 55% 
Valsalva gradient < 30 
mmHg 
No change 
· 
Remains at 10 mg or 5 mg or 2.5 
mg or 1 mg 
50% ≤ LVEF < 
55% 
Regardless of Valsalva 
gradient 
Abbreviations:  LTE = long-term extension; LVEF = left ventricular ejection fraction.  
a During the double-blinded LTE phase, dose titration will be based on LVEF and Valsalva gradient 
measured 2 weeks before, i.e., Week 34, 40, 52, 64, respectively. During open-label LTE phase, dose 
titration will be based on LVEF and Valsalva gradient measured on the date of dose adjustment, i.e., 
Week 36, 42, 54, 66, respectively. 
b 15 mg once daily is the maximum allowable dose of mavacamten. If dose is planned to increase to 15mg 
during open-label LTE phase, investigator is encouraged to discuss with medical monitor. 
* If the mavacamten dose is decreased at any time during the double-blinded LTE due to LVEF < 50%, 
then the participant will continue on the reduced dose to the end of double-blinded treatment unless safety 
concerns or intolerability arise requiring further dose reduction or dose discontinuation. 
 


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 Dose adjustments leading to temporary discontinuation 
In addition to the dose adjustments described above at any time (T) during the treatment 
period, dosing may be temporarily discontinued in the case of systolic dysfunction 
(LVEF < 50%) or higher than expected plasma concentration. 
• 
Double-blinded, placebo-controlled treatment period 
The treatment should be temporarily discontinued if a participant meets at least one of 
following criteria:  
1) Resting LVEF < 50% (determined by TTE) by core laboratory 
2) Pre-dose plasma drug concentration ≥ 1000 ng/mL by central laboratory 
It will be communicated to the investigator and Sponsor that a criterion for temporary 
discontinuation has been met. Upon receipt of this information, once the participant 
meets the temporary treatment discontinuation criteria, the 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. 
At the follow-up visit (T+ 2 to 4 weeks), plasma drug concentration and TTE 
assessments will be repeated and another unscheduled visit will be planned for 2 weeks 
later (T+4 to 6 weeks; drug dispensing visit only if performing as unscheduled visit). If 
the plasma drug concentration is < 700 ng/mL and resting LVEF ≥ 50%, participants 
shall restart the treatment at a lower dose (If follow-up visit [T+2 to 4 weeks] occurs 
beyond Week 30, only TTE will be repeated. In this situation, only LVEF ≥ 50% is 
required for restarting the treatment at a lower dose). 
If plasma drug concentration and/or resting LVEF are still out of range at the follow-up 
visit, then study drug will be switched to placebo.  
• 
Double-blinded LTE phase 
The treatment should be temporarily discontinued if a participant meets the following 
criterion:  
1) Resting LVEF < 50% (determined by TTE) by core laboratory 
It will be communicated to the investigator and Sponsor that the criterion for temporary 
discontinuation has been met. Upon receipt of this information, once the participant 
meets the temporary treatment discontinuation criterion, the 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. 
At the follow-up visit (T+2 to 4 weeks), TTE assessments will be repeated and another 
unscheduled visit will be planned for 2 weeks later (T+4 to 6 weeks). If the resting 
LVEF ≥ 50%, participants shall restart the treatment at a lower dose. If follow-up visit 
(T+2 to 4 weeks) occurs during open-label LTE period, additional visit 2 weeks later 


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(T+4 to 6 weeks; drug dispensing visit only if performing as unscheduled visit) is not 
required. Dose will be adjusted at follow-up visit (T+2 to 4 weeks). 
If resting LVEF are still out of range (< 50%) at the follow-up visit, then study drug 
will be switched to placebo. 
If the mavacamten dose is decreased at any time due to LVEF < 50% during the double-
blinded LTE period, then the participant will continue on the reduced dose to the end 
of double-blinded treatment unless safety concerns or intolerability arise requiring 
further dose reduction or dose discontinuation. 
• 
Open-label LTE phase 
The treatment should be temporarily discontinued when participates meet the following 
criterion:  
1) Resting LVEF < 50% (site-read TTE). 
Upon receipt of this information, once the participant meets the temporary treatment 
discontinuation criterion, the investigator will instruct the participant to discontinue 
study drug on the day of visit 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. 
At the follow-up visit (T+2 to 4 weeks), TTE will be repeated to confirm if resting 
LVEF is ≥ 50%. If resting LVEF is ≥ 50% at this visit, then study drug may be restarted 
at a lower dose.  
If at the follow up visit (T+2 to 4 weeks), resting LVEF is < 50%, the participants will 
be permanently discontinued. Participants will be followed until LVEF ≥ 50%, 
stabilization, or the participant is considered lost to follow-up. 
At any time during the treatment period, dosing would be permanent discontinued in 
the case of LVEF ≤ 30% and new or worsening heart failure (see Section 7.4.4).  
 Management in the specific case 
• 
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 blinded study site 
personnel during placebo-controlled and double-blinded LTE phase. 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 
professional (other qualified sonographer or unblinded clinician/cardiologist) who is 
not the blinded investigator (i.e., primary investigator and sub-primary investigator). If 
the result is confirmed (LVEF ≤ 30%), then the blinded 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. It should be subsequently managed as described in Section 


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8.1.4. Participants will be followed until LVEF ≥ 50%, stabilization, or the participant 
is considered lost to follow-up. 
• 
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 (e.g., 5 to 10 μg/kg/min dobutamine infusion) should be considered. Additional 
supportive measures, e.g., 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 and should be subsequently managed as 
described in Section 8.1.4. 
7.5 
Hepatotoxicity stopping and re-challenge rules 
Participants with abnormal hepatic laboratory values (e.g., 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. 
 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:  
1) TBL > 2 × upper limit of normal (ULN) or international normalized ratio > 1.5.  
2) AND increased AST or ALT, if the baseline value was < ULN and AST or ALT 
elevation is > 3 × ULN.  
3) 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 (e.g., hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella).  
• Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 


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significant right sided heart failure.  
• Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (e.g., indinavir, atazanavir, irinotecan) or herbal or 
dietary supplements.  
• Heritable disorders causing impaired glucuronidation (e.g., 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. 
 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:  
1) Elevation of either AST or ALT, regardless of baseline AST or ALT value, if:  
1. > 8 × ULN at any time.  
2. > 5 × ULN and < 8 × ULN for ≥ 2 weeks.  
3. > 5 × ULN and < 8 × ULN and unable to adhere to enhanced monitoring 
schedule.  
2) 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.  
3) 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. Re-challenge may be considered 
if an alternative cause, such as acute hepatitis B infection, is discovered and the 


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laboratory abnormalities resolve to normal or baseline. 
 Criteria for re-challenge of study drug after potential hepatotoxicity 
The decision to re-challenge the participant should be discussed and unanimously 
agreed by the investigator and Sponsor and Sponsor assigned medical monitor.  
If signs or symptoms recur with re-challenge, then study drug will be permanently 
discontinued. Participants who clearly meet the criteria for permanent discontinuation 
should never be re-challenged. 
7.6 
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 and may reflect 
enhanced on-target PD effects of mavacamten. Only symptomatic overdoses should be 
reported as AEs.  
In the event of symptomatic overdose or in the presence of significant symptoms and/or 
clinical compromise, including depressed cardiac contractility or asystole, the 
investigator should promptly contact the medical monitor. No further treatment should 
be administered until the cause for the event is fully understood, the participant has 
returned to a stable clinical state and the medical monitor of Sponsor has approved the 
restart of study drug.  
The participant should be closely monitored clinically for AEs/SAEs, with supportive 
measures undertaken as clinically indicated. There is no specific antidote for 
mavacamten. In acute overdose or toxic ingestion, gastrointestinal decontamination 
should be considered. If necessary, corrective measures, as described in the 2013 
American College of Cardiology Foundation/American Heart Association Guideline 
for the Management of Heart Failure (Yancy et al., 2013) , in the 2016 European Society 
of Cardiology Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart 
Failure (Ponikowski et al., 2016) and in the 2018 Guidelines for Diagnosis and 
Treatment of Chinese Adult Patients with Heart Failure (Chinese Society of Cardiology, 
2018) should be implemented. 
Based on its almost exclusive hepatic metabolism through the CYP2C19 and CYP3A4 
enzymes, avoidance of inhibitors of these enzymes (e.g., omeprazole) is important and 
administration of inducers of CYP2C19 and CYP3A4 may be helpful. The efficacy of 
other measures of elimination has not been established.  
 Reporting and follow-up of overdose 
Symptomatic overdose is an AESI. If a participant should experience symptomatic 
overdose, the investigator will report the symptomatic overdose to the medical monitor 
and complete the required information in the Overdose Reporting Form/SAE form 
within 24 hours of study staff becoming aware of the overdose. Follow-up on the 
participant’s condition will be conducted by the investigator and study staff. 


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7.7 
Prior and concomitant therapy 
 Prior therapy 
At the time of signing the ICF, participants will be asked about their medication history 
over the previous 28 days, including prescription and nonprescription medications, 
herbal medications, vitamins, and minerals. Prior medications were those with a stop 
date within 28 days prior to the first dose of study drug of analysis interest. 
If participants have not taken any prohibited medications in the past 14 days prior to 
signing the ICF, they may proceed to screening. Participants taking prohibited 
medications must discontinue treatment for 14 days before proceeding to the screening 
assessments. 
 Background HCM therapy 
Background cardiomyopathy therapy (e.g., beta-blocker, verapamil, or diltiazem) is 
allowed. Participants should be on optimal medical therapy as determined by the 
primary physician and informed by HCM treatment guidelines. The treatment should 
be well tolerated for at least 2 weeks prior to screening, and the site investigator should 
maintain this treatment unchanged (i.e., at a stable dose) until the end of the double-
blinded treatment unless safety or tolerability concerns arise and agreed by both 
investigator and Sponsor or Sponsor assigned medical monitor.  
In open-label LTE phase, investigators should manage background HCM medicines as 
clinically appropriate. The treatment may be adjusted or stopped as determined by the 
investigator in conjunction with the Sponsor or Sponsor assigned medical monitor. 
Any change in HCM medications must be entered into the eCRF with the rationale for 
the change. 
 Concomitant therapy 
Concomitant medications are those with a stop date on or after the first dose of study 
drug of analysis interest or were ongoing at the end of the analysis period. 
Concomitant therapy will be collected at all clinic visits from the first dose until the end 
of the study. Document all concomitant therapies on the appropriate eCRF, whether 
prescription or over-the-counter, vitamin and/or mineral supplements, herbs, and 
medications taken for an event or procedure (e.g., biopsy). Include start/stop dates, 
dose, route, and indication. 
 Prohibited therapy  
Prior or concomitant treatment with cardiotoxic agents such as doxorubicin or similar 
is prohibited. Use of disopyramide, cibenzoline or ranolazine is prohibited from 14 days 
before screening to the EOS. 
Additional prohibited medications are listed in APPENDIX 2. 
 
 


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Treatment Discontinuation and Withdrawal from Study 
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. 
8.1 
Treatment discontinuation 
 Temporary treatment discontinuation 
Temporary treatment discontinuation 
• Will be implemented when a predefined safety threshold has been met (see 
Section 7.4.3) 
• 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 8.1.3). 
If a temporary treatment discontinuation was caused by a safety threshold being met, 
treatment will be resumed approximately 2 to 6 weeks later, either at a lower dose or 
with switch to placebo or discontinuation, transmitted via IxRS (see Section 7.4.3). 
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 (i.e., 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. 
 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. 
All permanent treatment discontinuation should be recorded in the eCRF. 


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 Permanent treatment discontinuation criteria 
The following reasons will lead to permanent treatment discontinuation or withdraw 
from study: 
1) If all the criteria are met for possible DILI. 
2) Pregnancy. 
3) LVEF ≤ 30% as determined by site laboratory. 
4) New or worsening HF associated with systolic dysfunction. 
5) Any breaking of the study blind requested by the investigator. 
6) Continued administration of study drug is considered by the investigator to be 
detrimental to the participant’s safety or well-being. 
7) The participant requests to discontinue study drug. 
8) The Sponsor requests that the participant permanently discontinues study drug. 
 Management of participants after permanent treatment discontinuation 
There may be situations in which it is necessary for a participant to permanently 
discontinue study drug. In all cases, participants should be encouraged to discuss 
stopping study drug with the investigator/designee so that questions can be addressed, 
and concomitant therapy can be adjusted if needed. Investigators should contact the 
Sponsor or Sponsor assigned medical monitor prior to permanent study drug 
discontinuation to discuss the situation. 
If a participant permanently discontinues treatment prior to Week 30, the participants 
will be asked to undergo an ET visit as soon as possible after stopping study drug and 
be encouraged to participate post-treatment visits (phone visit and the onsite visits, 
using the procedure outlined in Table 1) and Week 30 visit.  
If permanent treatment discontinuation occurs during LTE period. The participants will 
be asked to undergo an ET visit, phone visit and the onsite post-treatment visits, using 
the procedure outlined in Table 2.  
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 
(e.g., 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 
(e.g., number of attempts and dates of attempted telephone contact or receipt for 
sending a registered letter). 
8.2 
Withdrawal from study 
 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. Permanent treatment discontinuation described 
above should be distinguished from withdrawal of consent for ongoing study 
participation.  


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Participant who withdraws 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 endpoint. 
Participants who have withdrawn from the study cannot be re-randomized (treated) in 
the study. Their inclusion and treatment numbers must not be reused. 
 Replacement of participants who withdraw from the study 
Participants who withdraw from the study after randomization will not be replaced.  
 
 


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Study Assessment  
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, 2. When several assessments are to be 
conducted at the same time point, the preferred order of assessments is ECG, vital signs, 
pre-dose PK, and then TTE all prior to study drug dosing. The order of assessments 
may vary slightly at specific time points to facilitate the most contemporaneous 
performance of the required assessments (e.g., TTE might be prior to pre-dose PK). 
Unscheduled or additional safety assessments may be performed if necessary, in the 
opinion of the investigator. Whenever possible discussion with the Sponsor or Sponsor 
assigned 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. 
9.1 
 Efficacy assessment 
  Echocardiography 
In the double-blinded, placebo-controlled treatment period and double-blinded LTE 
phase, all echocardiography data will be sent to a central imaging; pre-specified 
echocardiography results from multiple visits will be transmitted to the IxRS to confirm 
eligibility and to maintain blinding.  
In the open-label LTE treatment phase, echocardiograms will be site-read and not 
blinded to the investigator or the site. Echocardiography data used for dose titration will 
be sent to the IxRS. Echocardiograms will also be sent to a core laboratory for data 
analysis.  
Echocardiography assessments will take place as described in Table 1, 2. 
• 
Resting transthoracic echocardiography 
Resting TTE will be assessed prior to dosing during onsite visits as described in Table 
1, 2. Instantaneous peak LVOT gradient at rest and provoked peak LVOT gradient 
(Valsalva maneuver) will be assessed. The investigator should confirm during 
screening that participant can adequately perform the Valsalva maneuver. Care should 
be taken to select the best window and angle when obtaining Doppler signal to assess 
the LVOT gradient and to avoid contamination by MR jet if present. Left ventricular 
ejection fraction (2-dimensional LVEF) and left ventricular fractional shortening will 
also be analyzed along with a variety of other echocardiographic measures.  
TTE results (at least, the LVEF and peak LVOT gradient value) performed at each 
scheduled visit following randomization during the placebo-controlled period and 


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double-blinded LTE phase should be kept blinded to the investigators, except the 
unblinded site personnel (sonographer and unblinded clinician/cardiologist). During the 
open-label LTE phase, resting TTE will be assessed at clinical site study visits and also 
read by core laboratory.  
  New York heart association functional classification 
The NYHA Functional Classification of HF assigns participants to 1 of 4 categories 
based on the participants’ symptoms. HF classification will be assessed by the 
investigator at every study visit and recorded as indicated in the clinical database. 
Table 8 NYHA Functional Classification of HF 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less-than 
ordinary-activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of 
heart failure at rest. If any physical activity is undertaken, discomfort 
increases. 
  Kansas City Cardiomyopathy Questionnaire (23-item version) 
The KCCQ (23-item version) is a patient-reported questionnaire that measures the 
impact of patients’ CV disease or its treatment on 6 distinct domains using a 2-week 
recall: symptoms/signs, physical limitations, quality of life, social limitations, self-
efficacy, and symptom stability (Green et al., 2000). In addition to the individual 
domains, 2 summary scores can be calculated from the KCCQ: the overall summary 
score (includes the total symptom, physical limitation, social limitations and quality of 
life scores) and the clinical summary score (combines the total symptom and physical 
limitation scales). Scores range from 0 to 100, with higher scores reflecting better health 
status. The KCCQ will be administered to participants as indicated. The KCCQ, 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. 
  Cardiac magnetic resonance imaging  
Qualified participants will participate in the cardiac CMR assessments. Participants will 
undergo CMR at baseline (during screening period), Week 30, ET, Week 78 to evaluate 
changes in LV mass, myocardial fibrosis, cellular hypertrophy, and cardiac structure 
and function. Refer to the CMR related manual for additional details. 


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  Pharmacokinetic assessments 
Blood samples will be collected for pre-dose mavacamten plasma concentration 
assessments prior to dosing at post-Day 1 most onsite visits during the placebo-
controlled treatment period, and at the visits of Week 78/ET. In additional, a PK sample 
will be collected 0.5 to 3 hours post-dose at selected visits (See Table 1-2). PK sample 
will also be collected at post-treatment onsite visits. Unscheduled or additional PK 
samples may be collected if appropriate in the opinion of the investigator and/or 
Sponsor (also see Section 7.4.3). 
At all visits from Day 1 through Week 78, study drug will be administered at the 
investigational site to facilitate collection of pre-dose PK samples. The date and time 
of dosing will be documented. All PK samples will be sent to a central laboratory for 
processing and pre-dose PK results will be transmitted to the IxRS. 
  Pharmacogenetic assessment 
Blood will be drawn preferably on Day 1 for CYP2C19 genotyping.  
  Cardiac biomarkers 
9.1.7.1 NT-proBNP and cardiac troponin 
Blood samples will be collected for NT-proBNP and cardiac troponin concentrations at 
screening and most post-screening onsite visits (Table 1-2). Serum concentrations of 
NT-proBNP and cardiac troponin will be included in the data package provided for the 
periodic IDMC meetings. Unscheduled or additional blood samples may be collected 
if appropriate in the opinion of the investigator (e.g., for medical management of HF) 
and/or Sponsor. Whenever possible, discussion with the Sponsor or Sponsor assigned 
medical monitor is encouraged. 
9.2 
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.  
Safety data will be monitored on an ongoing basis by the study Sponsor, comprised of 
individuals with specialized expertise in Cardiology, Pharmacology and PV. 
  Medical history 
A complete medical history will be recorded at screening visit, which will include 
evaluation (past or present) of the following: general, head and neck, eyes, ears, nose, 
throat, chest/respiratory, heart/CV, 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). 


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  Physical examination 
At selected visits, a complete physical examination will be conducted including 
neurological examinations (gross motor and deep tendon reflexes), height and weight, 
and assessment of the following: general appearance, skin, head and neck, mouth, 
lymph nodes, thyroid, abdomen, musculoskeletal, CV, and respiratory systems. At all 
other visits, an abbreviated cardiopulmonary physical examination will be conducted. 
Height (cm) and body weight (kg) will be measured, 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. 
  12-lead ECG 
12-lead ECG evaluations will be performed after 10 minutes of rest at screening and at 
all onsite study visits. On visits during the treatment period ECGs will be taken prior to 
dosing. All ECG data will be sent to a core laboratory. 
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. 
  Holter monitor 
At 4 time points during the study, participants will wear a Holter monitor to collect 
continuous HR and rhythm data for approximately 24-48 hours (Table 1-2). The Holter 
monitor uses surface electrodes, internal electronics to capture a continuous ECG 
waveform, removable memory card to store data, 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. 
  Vital signs 
Vital signs are to be assessed at each onsite study visit. At selected visit, 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 participants 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 laboratory related manual for additional details. 
  Other safety assessments 
Refer to Section 10 for information on AE assessment and Section 7.7 for concomitant 
therapy. 


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Safety laboratory results will be assessed in an ongoing manner. Essential laboratory 
parameters are provided in Appendix 1. 
Serum pregnancy testing will be performed at screening, urine pregnancy at remaining 
visits throughout the whole study period for all females of childbearing potential. 
Confirmatory serum testing will be performed if any urine test is positive. 
9.3 
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 (e.g., 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 
• 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 
(e.g., tonic water) 
Contraception requirements are discussed in Section 11. 
9.4 
Study procedures by visit  
Study procedures are presented by visit in Table 1-2. 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 Sponsor or Sponsor assigned medical monitor before conducting an 
unblinded TTE if possible. And best effort should be made that unblinded 
clinician/cardiologist review the TTE prior to the investigator, to decide whether to 
report the TTE result to investigator or which data to report (e.g., based on unblinded 
clinician/cardiologist’s clinical judgement,not report LVEF or LVOT gradient to 
investigator is acceptable). All information collected from unscheduled visits will be 
recorded on the eCRF and included in the clinical database. 
9.5 
Visit scheduling 
All visits after Day 1 should occur within the visit window (see Table 1-2). If an 
evaluation is missed, reschedule and perform it as close as possible to the original date. 
 
 


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 Evaluation, Recording and Reporting of Adverse Events 
10.1 Definitions 
  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 (e.g., tachycardia, enlarged liver, clinically 
important or abnormal laboratory result), participant-reported symptom (e.g., 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 (e.g., invasive procedures such as biopsies). 
For Sponsor to collect additional information about clinically important laboratory 
results or diagnostic tests (e.g., 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 (e.g., >3× deviation from the upper or lower limit 
of the analyzing laboratory reference range, or as otherwise specified in the 
protocol) 
• 
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 


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therapy, close observation, more frequent follow-up assessment, or further 
diagnostic investigation  
The following additional points should be considered for AEs: 
• 
Preplanned medical or surgeries or procedures 
- 
Preplanned surgeries or procedures that were scheduled prior to signing 
of informed consent are not considered AEs. However, if a planned procedure 
is performed early (e.g., as an emergency) due to worsening of a preexisting 
condition, the worsening of the condition should be captured appropriately as 
an AE. 
• 
Hospitalization for elective surgeries or procedures 
- 
Elective procedures performed for which there is no change in the participant’s 
medical condition should not be recorded as AEs. 
- 
A hospitalization that was planned prior to the study or was scheduled during the 
study when the elective surgery or procedure became necessary because of the expected 
normal progression of the disease should not be recorded as AEs. 
• 
Insufficient clinical response (lack of efficacy) 
- 
Insufficient clinical response, efficacy, or pharmacologic action should not be 
recorded as an AE. The investigator must make the distinction 
• 
Overdose 
- 
Cases of overdose with any medication without manifested side effects are not 
considered AEs. 
The term AE is used generally to include any AE whether serious or nonserious. 
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 


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• 
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 (e.g., 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 
  Serious adverse event 
An SAE is an AE that fulfills one or more of the following criteria in the opinion of the 
investigator or Sponsor: 
• 
Results in death 
• 
Is immediately life-threatening (places the participant at immediate risk of death 
from the event as it occurred) 
• 
Requires participant hospitalization or prolongation of existing hospitalization 
• 
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. 
10.2 Collection and reporting of adverse event  
  Collection periods 
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 


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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. 
  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 (e.g., 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.  
  Start date/time and stop date/time 
The date (and time, if eligible) that the AE started and the date (and time, if eligible) 
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. 
  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?” 
The following factors can be used in consideration of causality assessment: 
• 
Dechallenge: Did the event abate after study medication was reduced or interrupted? 
• 
Rechallenge: Did the event reappear after study medication was reintroduced? 
• 
Temporal relationship and time to onset plausibility 
• 
Confounding risk factors 
• 
Amount and duration of study drug exposure 
• 
Concomitant medications 
For SAEs, causal relationship will also be assessed for other medications and study 
procedures. Note that, for SAEs that could be associated with any study procedure, the 


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causal relationship is implied as “yes.” 
  Intensity 
Record the intensity or severity of the AE 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 interventional indicated. 
• 
Fatal: event led to death. 
  Seriousness 
Record SAE criteria described in Section 10.1.2 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 (see Section 10.2.5), whereas seriousness is defined 
by the criteria in Section 10.1.2. 
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. 
  Outcome 
Record the outcome of the event based on the options provided on the eCRF. Outcome 
of the SAE should be recorded in SAE form. 
10.3 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 EOS regardless of causality will be reported by 
the investigator or designee to Sponsor/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 will be provided in separate materials for site reference.  
Medical records may be requested to support documentation of an SAE. The 
investigator is responsible for summarizing the pertinent aspects of the event (including 
discharge summaries, diagnostic procedures, laboratory data, interventions) and 


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updating the SAE form with this information.  
Sponsor retains the right to request additional information for any participant with any 
ongoing AEs/SAEs at the end of the study, if judged necessary. 
Prompt notification by the investigator to the sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities for the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
10.4 Reporting adverse events of special interest 
Symptomatic overdose, outcomes of a pregnancy, and LVEF ≤ 30% as determined by 
local site read echocardiogram are considered AESI.  
AESIs are required to be reported by the investigator to the Sponsor within 24 hours. 
10.5 Follow-Up of adverse events and serious adverse events 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and AESIs will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is 
considered lost to follow-up at the end of the study. 
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. 
The Sponsor 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. 
10.6 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 5 months after the last dose of study drug. The investigator is responsible for 
informing Sponsor within 24 hours of knowledge of the pregnancy even if no AE has 
occurred per the reporting guidelines. The participant will be asked to provide 
information on the outcome of the pregnancy through 6 months after birth or details of 
premature termination. Spontaneous miscarriage and congenital abnormalities will be 
reported as SAEs. Consent to report information regarding pregnancy and pregnancy 
outcomes should be obtained from the partner of the male participant.   
Pregnancy of a participant or partner of a male participant should be entered on the 
Pregnancy Notification CRF. Pregnancy follow-up should be documented on a follow-
up form and report to Sponsor or designee within 24 hours.  
Any SAE experienced by a participant during pregnancy must be reported on SAE form 
and be reported within 24 hours. 


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10.7 Safety reporting to investigators, institutional review boards, independent 
ethics committees, and regulatory authorities 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, institutional review boards 
(IRBs)/independent ethics committees (IECs), and investigators. 
SUSARs are SAEs that qualify for mandatory expedited reporting to regulatory 
authorities when the SAE is suspected to be caused by the study drug and is considered 
unexpected (i.e., not defined as expected in the current investigator’s brochure [IB], 
clinical study protocol, or approved labeling for marketed products). In this case, 
Sponsor/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 IRB/IEC of 
the SUSAR as required by local regulatory authorities and in accordance with their 
IRB/IEC policy. 
An investigator who receives an investigator safety report describing a SUSAR or other 
specific safety information (e.g., summary or listing of SUSARs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
 


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 Risks and Precautions 
11.1 General risks 
Based on nonclinical data and the available clinical data, four important risks have been 
described: heart failure due to systolic dysfunction defined as symptomatic LVEF < 
50%, teratogenicity, QT prolongation, and increased risk of heart failure due to 
interaction with CYP2C19 and potent CYP3A4 inhibitors. Refer to Section 1.3 for 
details of general risks.  
11.2 Pregnancy 
 Avoidance of pregnancy 
Women of childbearing potential must use appropriate methods of birth control. Women 
of non-childbearing 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 follicle 
stimulating hormone (FSH) levels are in the postmenopausal range. 
 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 5 months after the last dose of study drug, female participants should practice 
true abstinence or use effective means of contraception as follows: 
• 
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. 
• 
IUD. 
• 
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 FSH are in the 
postmenopausal range. 
In addition to the above contraceptive requirements for female participants, male 
partners must also use a contraceptive (e.g., barrier, condom or vasectomy). 


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   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 5 months after the last dose of study drug. The investigator is responsible for 
informing Sponsor within 24 hours of knowledge of the pregnancy even if no AE has 
occurred per the reporting guidelines. The participant will be asked to provide 
information on the outcome of the pregnancy through 6 months after birth or details of 
premature termination. Spontaneous miscarriage and congenital abnormalities will be 
reported as SAEs.  
 


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 Statistical Analyses 
12.1 General considerations 
A comprehensive SAP will be prepared and finalized before first patient in (FPI) and 
any subsequent amendments will be documented, with final amendments completed 
prior to database lock.  
12.2 Sample size determination 
Approximately 81 participants will be randomized with a ratio of 2:1. The sample size 
should provide adequate power to determine the superiority of mavacamten in 
improving Valsalva LVOT gradient relative to placebo. The power calculation assumes 
a true difference of 30 with a standard deviation of 35 in change from baseline of 
Valsalva LVOT gradient at 30 weeks between the active treatment arm and the placebo 
arm. The proposed sample size will provide > 90% power with a 1-sided 2.5% alpha 
level. Considering the estimated 10% dropout rate, the final sample size would be 81 
patients (54 mavacamten: 27 placebo). 
12.3 Study endpoints 
The analyses will be performed at the end of the 30-week placebo-controlled treatment 
period and the end of study. The 30-week placebo-controlled treatment period is 
randomized, two-arm double-blinded, and the conceptual analytical approach is to 
compare the mavacamten treatment arm with the placebo arm. The goal of the LTE 
analysis is to access extension follow-up efficacy and safety with all participants 
receiving mavacamten treatment, to summarize the data from the first administration of 
mavacamten in the study, by the randomized (treatment) group and, if appropriate, for 
overall.  
• 
Primary efficacy endpoint 
• Change from baseline to Week 30 in Vaslalva LVOT peak gradient. 
• 
Secondary efficacy endpoint 
• Change from baseline to Week 30 in resting LVOT peak gradient. 
• Proportion of participants achieving a Valsalva LVOT peak gradient < 30 mmHg 
at Week 30. 
• Proportion of participants achieving a Valsalva LVOT peak gradient < 50 mmHg 
at Week 30. 
• Proportion of participants with at least 1 class improvement in NYHA functional 
classification from baseline to Week 30. 


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• Change from baseline to Week 30 in KCCQ CSS. 
• Change from baseline to Week 30 in NT-proBNP.  
• Change from baseline to Week 30 in cardiac troponin. 
• Change from baseline to Week 30 in LV mass index assessed by CMR imaging. 
• 
Exploratory efficacy endpoints 
• Proportion of participants achieving NYHA Class I and LVOT peak gradient < 
30 mmHg for resting and Valsalva gradients at Week 30. 
• Change from baseline to Week 30 in echocardiographic indices of cardiac 
structure and systolic and diastolic function. 
• Change from baseline to Week 30 in myocardial fibrosis by CMR imaging.  
• Change from baseline to Week 30 in cellular hypertrophy, cardiac structure and 
function by CMR imaging. 
• Change from baseline to Week 30 in Total Symptom Score and Overall Summary 
Score from KCCQ. 
• 
Safety endpoints  
• Incidence of LVEF < 50% determined by transthoracic echocardiography TTE.  
• Incidence and severity of TEAEs, and treatment-emergent SAEs. 
• Incidence of MACEs (CV death, non-fatal stroke, non-fatal myocardial 
infarction). 
• Incidence of hospitalizations (due to CV and non-CV events). 
• Incidence of HF events including HF hospitalizations and urgent emergency 
room/outpatient visits for HF. 
• Incidence of atrial fibrillation/flutter (new from screening, and recurrent). 
• Incidence of ICD therapy and resuscitated cardiac arrest.  
• Incidence of ventricular tachyarrhythmias including ventricular tachycardia, 
ventricular fibrillation, and Torsades de Pointe. 


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• Incidence of AESIs (symptomatic overdose, outcomes of pregnancy, LVEF ≤ 
30%). 
• 
Long-term extension endpoints 
• Change from baseline in NYHA class, echocardiographic and CMR parameters, 
cardiac biomarkers, and KCCQ results through EOS. 
• Incidence of safety events, including: LVEF < 50%; TEAEs and treatment-
emergent SAEs; MACEs; hospitalizations; HF events; atrial fibrillation/flutter; 
ICD therapy and resuscitated cardiac arrest; ventricular tachyarrhythmias; or 
AESIs. 
• 
Pharmacokinetic endpoint 
• Mavacamten plasma concentration over time. 
• PK parameters using a population PK approach. 
12.4 Definitions of analysis sets 
  Intention-to-treat 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, completed all efficacy 
assessments and have no important protocol deviation affecting primary efficacy 
endpoint, 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 mavacamten and have at 
least 1 detectable mavacamten plasma drug concentration. 
12.5 Method of analysis 
Descriptive summary statistics for continuous variables will include the number of 
participants, mean, SD, median, first quartile, third quartile, minimum, and maximum. 
Categorical variables will be summarized using counts and percentages. 


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12.6 Disposition of participants 
The number and percentage of participants who complete and discontinue as well as 
reasons for early discontinuation will be presented.  
12.7 Demographics, baseline characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
12.8 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. 
The duration of study drug exposure is defined as last dose date – first dose date + 1 
day, regardless of intermittent discontinuations. Adjusted duration will also be derived 
by taking protocol-defined interruptions into account. 
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 exposure and compliance will be summarized descriptively (number [n], 
mean, SD, median, minimum, and maximum). The compliance of participants with 
compliance < 80%, 80%~120%, > 120% will be summarized.  
12.9 Efficacy analyses 
All efficacy analyses will be performed on the ITT population. Supplementary analysis 
of primary endpoint will also be performed on the Per Protocol population.  
  Primary endpoint analysis 
The primary endpoint of Valsalva LVOT peak gradient change from baseline at Week 
30 will be summarized using descriptive statistics and compared between treatment 
groups using Mixed-Effect Model for Repeated Measures (MMRM). The models will 
include baseline LVOT gradient value and stratification factor as a covariate (current 
treatment with beta-blocker or not), and treatment, visit and treatment-by-visit 
interaction as fixed effects, and participants as random effects. The within-participant 
covariance between visits will be estimated via an unstructured covariance matrix. In 
case of convergence problems, alternative covariance structures will be considered in 
the following order, with the first structure that converges being used in the analysis: 
heterogeneous Toeplitz, standard Toeplitz, and AR (1) with separate participant random 
effect. The normality assumption will be assessed graphically by a QQ plot of residuals 
versus the expected quantiles of the standard normal distribution. If normality 
assumption appears to be violated, other methods might be considered. More detailed 
statistical analysis strategies will be documented in SAP. 
  Secondary endpoints analysis 
The general analytical approaches of the secondary efficacy endpoints are the following 


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(The p-values generated for secondary endpoints will be considered as descriptive 
purpose and thus no multiplicity adjustment will be applied): 
• 
Continuous variables will be summarized with descriptive statistics, including 
mean, standard deviation, minimum, median, and maximum, and the comparison 
of the means between treatment groups will be analyzed using analysis of 
covariance that adjusts for the baseline value and stratification factor, or MMRM 
if appropriate. 
• 
Categorical variables will be summarized with number and percentage within each 
category, and the relationship with treatment will be analyzed by Cochran-Mantel-
Haenszel test that takes into account of the stratification factor. Point estimate and 
2-sided 95% CI for proportion difference between the treatment groups will be 
computed based on the “stratified Miettinen-Nurminen” method. 
  Exploratory endpoints analysis 
The exploratory endpoints will be summarized using descriptive statistics. Additional 
details will be specified in the SAP. 
12.10 Safety analysis 
All safety analyses will be performed on the safety population using the following 
common rules: 
• 
The safety analysis performed for the 30-week placebo-controlled period will focus 
on comparing the mavacamten and placebo, and data will be summarized by the 
treatment received.  
• 
The baseline value is defined as the last available value before the first 
administration of study drug of analysis interest (i.e., the first dose of randomized 
drug in the analysis for double blind period).  
• 
For quantitative safety parameters based on 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 and within first 30-week treatment. 


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 Adverse events 
AEs will be mapped to system organ classes (SOC) 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 SOC and PT in descending order for each treatment 
group. Multiple occurrences of the same event in the same 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, all TEAEs leading to permanent 
treatment discontinuation, and AESI. 
 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 
group. 
• Death in nonrandomized 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 and PT showing number and percent of 
participants sorted by descending order of count. 
 Pregnancy 
The following pregnancy summaries will be generated: 
• Number of participants or partners of participant 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 sorted by SOC and PT. 


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 Overdose 
The following summaries for reports of overdose will be generated: 
• Number of participants who experienced overdose summarized by treatment 
group 
• Analysis of the cause and occurrence of the overdose 
• TEAE experienced during the overdose by primary SOC and PT showing the 
number and percent of participants sorted by SOC and PT.  
 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 
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. 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 post dose QTcF values of 
> 450 msec, > 480 msec, > 500 msec, > 520 msec, and > 550 msec will be tabulated 
for all participants. Participants with QTcF values > 500 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 
ECG morphologies for each participant will be listed. 


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 Concentration-QTc analyses 
A concentration-QTc regression analysis, based on data collected from the ECG 
recordings after drug administration and pre-dose 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. 
 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 participant 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 number and percentage of participant 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). Potential Hy’s law cases 
will be investigated by summarizing the number of participants with elevated ALT or 
AST (> 3 × ULN) and with elevated TBL (> 2 × ULN) where transaminase elevation 
coincides with or precedes bilirubin elevation. 
 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. 
 Concomitant medications 
Concomitant medications will be summarized. 


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 Other safety analyses 
Abnormal physical examination results will be listed. 
12.11 Long-term extension analysis 
The efficacy and safety endpoints of long-term extension will be summarized using 
descriptive statistics. Additional details will be specified in the SAP. 
12.12 Pharmacokinetics analysis 
Plasma concentration will be summarized.  
In addition, a population PK analysis may be performed and will be reported in separate 
report. Data from previously conducted mavacamten studies might be added for the 
population PK model development, simulation PK/PD and/or exposure-response 
analysis. This analysis will only be done after related local regulatory approval. 
 
 


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 Data Collection and Management 
13.1 Data confidentiality 
All records identifying the participant will be kept confidential and, in accordance with 
the applicable laws and/or regulations, will not be made publicly available. Participant 
names will not be supplied to the Sponsor. Only the screening or randomization number 
will be recorded on the eCRF. If the participant’s name appears on any other document 
or trial materials, then that information must be redacted before a copy of the document 
is supplied to the Sponsor. Trial data stored on a computer will be stored in accordance 
with local data protection laws and regulations. Participants will be informed in writing 
that representatives of the Sponsor, IRB/IEC/REB, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws and regulations. 
If the results of the trial are published, the participants’ identity will remain confidential. 
The investigator will maintain a list to enable participants’ records to be identified in 
accordance with applicable laws and regulations. 
The data collection system for this study uses built-in security features to encrypt all 
data for transmission in both directions, preventing unauthorized access to confidential 
participant information. Access to the system will be controlled by a sequence of 
individually assigned user identification codes and passwords, made available only to 
authorized personnel who have completed prerequisite training. 
Either year of birth or exact date of birth (depending on local privacy regulations) will 
be recorded to establish that the participant satisfies protocol age requirements and to 
enable appropriate age-related normal ranges to be used in assessing laboratory test 
results. 
13.2 Study center monitoring 
Before study initiation, at a study center initiation visit or at an investigator’s meeting, 
Sponsor (or designated CRO) will review the protocol and eCRFs with the investigators 
and their staff. During the study, the field monitor will visit the study center regularly 
to check the completeness of participant records, the accuracy of entries on the eCRFs, 
the adherence to the protocol and to Good Clinical Practice (GCP), the progress of 
enrollment, and to ensure that study drug is being stored, dispensed, and counted 
appropriately according to specifications by site staff. Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain source documents for each participant in the study, 
consisting of case and visit notes (hospital or clinic medical records) containing 
demographic and medical information, laboratory data, ECGs, and the results of any 
other tests or assessments. All information recorded on eCRFs must be traceable to 
source documents in the participant's file. The investigator must also keep the original 


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signed ICF (a signed copy is given to the participant). 
The investigator must give the field monitor access to all relevant source documents to 
confirm their consistency with the eCRF entries. Sponsor’s monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria and documentation of SAEs. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study 
specific monitoring plan. 
13.3 Data collection 
The designated investigator staff will enter the data required by the protocol into the 
eCRFs. The eCRFs have been built using fully validated secure web-enabled software. 
The investigator and site staff will not be given access to the electronic data capture 
(EDC) system until they have been trained. Automatic validation programs check for 
data discrepancies in the eCRFs and allow modification or verification of the entered 
data by the investigator’s staff. 
The principal investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
PK and cardiac biomarker samples and imaging scans obtained during the course of the 
study will be collected from the study centers and analyzed by a Sponsor designated 
laboratory. Designated study center staff will enter the information required by the 
protocol into the appropriate eCRF and/or designated laboratory requisition forms. 
Field monitors will review the eCRFs and laboratory paper requisition forms for 
accuracy and completeness and instruct site personnel to make any required corrections 
or additions. One copy of the requisition form will be forwarded to each analytical 
laboratory with the respective sample(s) by the designated study center staff; and one 
copy will be retained at the study center. 
13.4 Database quality assurance 
Quality assurance and quality control systems will be implemented and maintained per 
Standard Operating Procedures (SOP) 
by Sponsor 
or 
Sponsor 
contracted 
CRO, as appropriate, to ensure that this clinical study is conducted and data are generate
d, documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) E6 GCP: Consolidated Guidance and the 
applicable regulatory requirement. 
13.5  Study documentation, record keeping and retention of documents 
Each participating study center will maintain appropriate medical and research records 
for this trial, in compliance with section 4.3 of the ICH E6 GCP, and regulatory and 
institutional requirements for the protection of confidentiality of participants. As part 
of participating in sponsored study, each study center will permit authorized 
representatives of the Sponsor(s) and regulatory agencies to examine (and when 
required by applicable law, to copy) clinical records for the purposes of quality 


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assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies).Examples of these source documents, 
data and records include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, participants’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, and participant files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved 
in the clinical trial. 


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 Study Compliance and Ethical Considerations 
14.1 Compliance statement 
This clinical study will be performed in accordance with ethical principles that have 
their origin in the Declaration of Helsinki and are consistent with ICH/ GCP, applicable 
regulatory requirements. 
14.2 Informed consent 
The ICFs used for the study must comply with the ICH GCP guidelines, and 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, to 
ensure 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 an impartial 
witness, must give informed consent in writing. 
Prior to participation in any study-related procedures, participants must sign and date 
an Ethics Committee (EC)-approved written ICF in a language the participant can 
understand. The informed consent 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. 
14.3 Ethics committee 
The term EC used in this document refers to an IRB or 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 (e.g., 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 


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The EC approval must be in writing, clearly identifying the study (by protocol date 
and/or version), including the documents reviewed, such as informed consent, and date 
of the review. The investigator has the responsibility to provide Sponsor 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 10.7) 
• 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 
Documentation of subsequent reviews of the study must also be forwarded to Sponsor. 
 
 
 


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 Administrative Procedure 
15.1 Sponsor’s responsibilities 
Sponsor reserves the right to terminate the study at any time. Sponsor and the 
investigators will assure that adequate consideration is given to the protection of the 
participants’ interests. Sponsor retains the right to terminate the study and remove 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 
 
 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 IMP used in this study. These 
data will be processed with adequate precautions to ensure confidentiality according to 
applicable laws. 
Sponsor 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 participant. 
Sponsor, 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. 
Participants will be entitled to request confirmation of the existence of personal data 
held by Sponsor and will have the right to rectify erroneous or inaccurate data up until 
database lock. 
 
 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 


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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. 
 
 Ongoing communication of safety information during the study 
Sponsor will provide the investigator(s) with documentation of SUSARs from this 
study and other studies. The investigator(s) must forward this documentation to the EC 
as per EC’s requirement or local regulation. 
Sponsor 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. 
 
 Study monitoring 
Sponsor 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 (e.g., pharmacy, diagnostic laboratories). 
 
 Study auditing and inspecting 
Sponsor 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 Sponsor, EC, government regulatory authority, and Sponsor’s quality 
assurance personnel or its designees by providing direct access to source 
data/documents after appropriate notification from Sponsor. 
15.2 Investigator’s responsibilities 
 
 Screening log 
The investigator must keep a record that lists all participants who signed an informed 
consent and the reason for non-inclusion if the potential participant does not ultimately 
enroll and receive IMP. 
 
 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 


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adequate records of distribution, dispensing, and return/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 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. 
 
 Reporting and recording of study data 
Data will be captured and compiled using procedures developed by Sponsor or 
designee. 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 delegation 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 (i.e., 
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. 
 
 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, 
phone) 
• Documentation verifying participant eligibility (i.e., medical history, physical 
examination) 


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• 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 
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. 
 
 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. 
 
 Records retention 
Sponsor 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 
Sponsor, the investigator agrees to keep records, including the identity of all 
participants (i.e., 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 Sponsor. 
 
 Protocol deviations 
Unless there is a safety concern, no protocol deviations will be allowed or waived 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 participant without prior EC approval. Immediately after the 
implemented deviation or change, the investigator must report and explain the reasons 


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for the protocol deviation to sponsor and EC as per EC’s requirement. The medical 
monitor will review the protocol deviation and notify the study monitor of the response. 
 
 Blood sample collection/storage 
Blood samples that are collected as part of protocol procedures will be stored and 
analyzed for PK, PD and CYP2C19 genotype analyses. 
15.3 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. 
15.4 Protocol amendments and study administrative letters 
Study procedures will not be changed without the approval of Sponsor. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment/addendum and, where required, in a new 
version of the study protocol. 
The amendment/addendum 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/addendum requires a change to the ICF, the EC will need to 
approve the revised ICF before the revised form is used. 
If there are non-substantial changes such as clarification of statement or corrections to 
obvious errors/typos/inconsistencies in the protocol, or change to logistical or 
administrative aspects, then Sponsor may issue an Administrative Letter. If local 
regulations require any administrative change, it will be communicated to or approved 
by the EC. 
15.5 Administrative consideration 
• 
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 into 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 collect ECG,  
echocardiographic, Holter and CMR data from digital equipment used by 
clinical site personnel  
• IxRS will be used to dispense IMP and transfer data in double-blinded manner 


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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. 
In addition, other central data management systems/databases and software may be 
used to collect and analyze study data: 
• Laboratory proprietary systems will be used by laboratories for storing and/or 
analyzing gene, bioanalytical and biomarker laboratory data collected 
throughout the study 
• Statistical software will be used for the statistical analysis of the study data as 
outlined in the SAP 
• 
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 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. 


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 Publication Policy  
The data and results of the study will be owned by Sponsor and shall be confidential 
information of Sponsor, participant to the investigator’s publication rights, all as 
outlined in the agreement between the investigator/institution and Sponsor regarding 
the conduct of the clinical study (the “Clinical Study Agreement”). It is understood by 
the investigator that Sponsor may use the information developed in this study in 
connection with the development of Sponsor 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 Sponsor. 
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 Sponsor’s intention to 
prevent publication of the data generated in the study; rather, Sponsor 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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Autore, CP, Bernabo P, Barilla CS, Bruzzi P, Spirito P. The prognostic importance of 
left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation 
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of the α-cardiac myosin Arg-403-Gln mutation in familial hypertrophic 
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Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, et al., Historical trends 
in reported survival rates in patients with hypertrophic cardiomyopathy. Heart. 
2006;92: 785-91.  
Elliott PM, Anastasakis A, Borger MA, et al., 2014 ESC Guidelines on diagnosis and 
management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35(39):2733-2779.  
Firoozi S, Elliott PM, Sharma S, et al., Septal myotomy-myectomy and transcoronary 
septal alcohol ablation in hypertrophic obstructive cardiomyopathy: a comparison of 
clinical, haemodynamic and exercise outcomes. Eur Heart J. 2002;23(20):1617-1624. 
Frey N, Luedde M, and Katus HA. Mechanisms of disease: hypertrophic cardiomyopa
thy, Nat Rev Cardiol. 2011;9: 91-100.  
Gersh BJ, Maron BJ, Bonow RO, et al., 2011 ACCF/AHA Guideline for the diagnosis 
and treatment of hypertrophic cardiomyopathy: a report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice 
Guidelines. J Am Coll Cardiol. 2011;58: e212-260. 
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart 
failure. J Am Coll Cardiol. 2000;35: 1245-1255. 
Heart Failure Committee of Chinese Medical Doctors Association, et al., Chinese 
guidelines for the management of hypertrophic cardiomyopathy. Chin J Heart Fail & 
Cardiomyopathy.2017; 1(2): 65-86. 


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Heart Failure Group of Chinese Society of Cardiology, et al., Chinese guidelines for 
the diagnosis and treatment of heart failure 2018. Zhonghua Xin Xue Guan Bing Za 
Zhi. 2018; 46(10): 760-789. 
Heitner SB, Jacoby D, Lester SJ, Owens A, et al., Mavacamten treatment for obstructive 
hypertrophic cardiomyopathy a clinical trial. Annals of internal medicine. 
2019;170(11):741-748. 
Hershberger RE, Cowan J, Morales A, Siegfried JD. Progress with genetic 
cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and 
arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Heart Fail. 2009;2: 
253-61.   
Hua TR, Zhang SY. Cardiomyopathies in China: A 2018-2019 state-of-the-art review, 
Chronic Dis Transl Med.2020; 6(4): 224-238. 
Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, et al., 
Assessment of diastolic function with Doppler tissue imaging to predict genotype in 
preclinical hypertrophic cardiomyopathy. Circulation. 2002;105: 2992-7. 
Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, et al., Genotype and 
Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the 
Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation.2018;138: 1387-
98.  
Kim LK, Swaminathan RV, Looser P, Minutello RM, Wong SC, Bergman G, et al., 
Hospital volume outcomes after septal myectomy and alcohol septal ablation for 
treatment of obstructive hypertrophic cardiomyopathy: US Nationwide Inpatient 
Database, 2003-2011. JAMA Cardiol. 2016;1: 324-32. 
Maron BJ, Rowin EJ, Casey SA, Link MS, Lesser JR, et al., Hypertrophic 
cardiomyopathy in adulthood associated with low cardiovascular mortality with 
contemporary management strategies. J Am Coll Cardiol. 2015;65(18):1915–1928. 
Maron MS. Clinical utility of cardiovascular magnetic resonance in hypertrophic 
cardiomyopathy. J Cardiovasc Magn Reson. 2012; 14:13. 
Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, et al., 
Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow 
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Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron 
BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in 
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Mckenna WJ, Maron BJ, Thiene G, et al., Classification, epidemiology, and global 
burden of cardiomyopathies. Circ Res. 2017;121(7): 722-730. 
McKenna WJ, Judge DP. Epidemiology of the inherited cardiomyopathies. Nat Rev 
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Wintersperger BJ, Crean A. Myocardial fibrosis in hypertrophic cardiomyopathy: 
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2013; 6: 587-596. 
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prevalence and incidence of hypertrophic cardiomyopathy in Korea: A nationwide 
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S, Lakdawala NK, et al, Mavacamten for treatment of symptomatic obstructive 
hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, 
placebo-controlled, phase 3 trial. Lancet.2020; 396(10253):759–769. 
Ommen SR, Mital S, Burke MA, Day SM, Deswal A, Elliott P, Evanovich LL, Hung 
J, Joglar JA, Kantor P, Kimmelstiel C, Kittleson M, Link MS, Maron MS, Martinez 
MW, Miyake CY, Schaff HV, Semsarian C, Paul S. 2020 AHA/ACC Guideline for the 
diagnosis and treatment of patients with hypertrophic cardiomyopathy: executive 
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treatment of acute and chronic heart failure. Eur Heart J. 2016 May 20;37(27):2129-
2200. 
Pujades-Rodriguez M, Guttmann OP, Gonzalez-Izquierdo A, Duyx B, O'Mahony C, 
Elliott P, et al., Identifying unmet clinical need in hypertrophic cardiomyopathy using 
national electronic health records. PLoS One. 2018;13: e0191214.  
Quarta G, Aquaro GD, Pedrotti P, Pontone G, Dellegrottaglie S, Iacovoni A, Brambilla 
P, Pradella S, et al., Cardiovascular magnetic resonance imaging in hypertrophic 
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2018;19: 601-610. 
Sedehi D, Finocchiaro G, Tibayan Y, et al., Long-term outcomes of septal reduction for 
obstructive hypertrophic cardiomyopathy. J Cardiol. 2015;66(1):57-62. 
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Sommese RF, Sung J, Nag S, et al., Molecular consequences of the R453C hypertrophic 
cardiomyopathy mutation on human beta-cardiac myosin motor function. Proc Natl 
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β-cardiac myosin to elucidate molecular mechanism of familial hypertrophic and 
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Teekakirikul P, Zhu W, Huang HC, Fung E. Hypertrophic Cardiomyopathy: an 
overview of genetics and management. Biomolecules. 2019;9(12):878. 
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Management of Heart Failure: a report of the American College of Cardiology 
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Zou Yubao, Song Lei, Wang Zhimin, Ma Aiqun, Liu Tangwei, Gu Huimin, et al., 
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echocardiographic analysis of 8080 adults. AM J Med. 2004;116(1):14-8. 


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Appendix 1: Laboratory Assessment 
The following safety laboratory parameters will be measured by the local laboratory: 
Hematology/Coagulation 
Biochemistry 
Urinalysisa 
•WBC count, including 
differential count 
• Platelet count 
• Hemoglobin 
• Hematocrit 
• RBC count 
• APTT 
• INR 
• FIB 
• PT 
• TT 
 
• Sodium 
• Potassium 
• Chloride 
• Calcium 
• Magnesium 
• Creatinine 
• eGFR 
• ALP 
• ALT 
• AST 
• CK 
• Glucose 
• Total protein 
• Albumin 
• Total bilirubin 
• Direct bilirubin 
• Uric acid 
• Specific gravity 
• pH 
• Protein 
• Glucose 
• Ketones  
• RBC 
• WBC 
 
ALT = alanine aminotransferase; ALP = alkaline phosphatase; APTT = activated partial thromboplastin 
time; AST = aspartate aminotransferase; CBC = complete blood count; CK = creatine kinase; eGFR = 
estimated glomerular filtration rate; FIB = fibrinogen; INR = international normalized ratio, RBC = red 
blood cells; TT = thrombin time; WBC = white blood cells.  
a Urine microscopy will be performed if there is a significant abnormality in the dipstick.  
 
In addition, NT-proBNP and cardiac troponin 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 (HBV and HCV)  
• HIV test  
• FSH (only for postmenopausal women) 
• Pregnancy test (β hCG) (for all females of childbearing potential) 
 
 


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Appendix 2: Prohibited Medications 
Cardiotoxic Agents 
Prior or concomitant treatment with cardiotoxic agents such as doxorubicin or similar 
is prohibited. 
Disopyramide, cibenzoline or ranolazine 
Use of disopyramide, cibenzoline or ranolazine is prohibited from 14 days before 
Screening to the EOS. 
Moderate and Potent CYP2C19 Inhibitors and Potent CYP3A4 Inhibitors 
Potent and moderate CYP2C19 inhibitors and potent CYP3A4 inhibitors are prohibited 
from 14 days before Screening through the EOS. Examples are listed below. For any 
medication in question, ask the medical monitor. 
CYP2C19 inhibitors 
• 
Efavirenz (antiviral) 
• 
Etravirine (antiviral) 
• 
Fluconazole (antifungal) 
• 
Fluvoxamine (selective serotonin reuptake inhibitor [SSRI] / antidepressant) 
• 
Fluoxetine (SSRI / antidepressant) 
• 
Moclobemide (monoamine oxidase [MAO] inhibitor / antidepressant) 
• 
Omeprazole (proton pump inhibitor) 
• 
Esomeprazole (proton pump inhibitor) 
• 
Ticlopidine (platelet inhibitor) 
• 
Voriconazole (antifungal) 
CYP3A4 inhibitors 
• 
Boceprevir (antivirals) 
• 
Ceritinib (kinase inhibitors) 
• 
Clarithromycin (antibiotics) 
• 
Cobicistat (GS-9350) 
• 
Conivaptan (diuretics) 
• 
Grapefruit juice (food products) 
• 
Idelalisib (kinase inhibitors) 
• 
Indinavir (protease inhibitors) 
• 
Itraconazole (antifungals) 
• 
Josamycin (antibiotics) 
• 
Ketoconazole (antifungals) 


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• 
LCL161 (cancer treatments) 
• 
Mibefradil (calcium channel blockers) 
• 
Mifepristone (antiprogestins) 
• 
Nefazodone (antidepressants) 
• 
Nelfinavir (protease inhibitors) 
• 
Posaconazole (antifungals) 
• 
Ribociclib (kinase inhibitors) 
• 
Ritonavir (protease inhibitors) 
• 
Saquinavir (protease inhibitors) 
• 
Telaprevir (antivirals) 
• 
Telithromycin (antibiotics) 
• 
Tipranavir (protease inhibitors) 
• 
Troleandomycin (antibiotics) 
• 
Tucatinib (kinase inhibitors) 
• 
Viekira Pak (antivirals) 
 
St. John’s Wort 
Use of St. John’s Wort is prohibited from 14 days before Screening to EOS. 
 
Biotin Supplements 
Biotin supplements are prohibited from 14 days prior to screening through the end of 
study visit. Multivitamins that contain <1000 mg QD of biotin are allowed during the 
study but must be stopped 24 hours prior to each study visit. 
 
 
 


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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 (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 sponsor as an SAE within 24 hours of discovery or 
notification of the event (ie, before additional etiologic investigations have been 
concluded). 
 
The appropriate CRF (e.g., AE CRF) that captures information necessary to facilitate 
the evaluation of treatment-emergent liver abnormalities are to be completed and sent 
to sponsor. 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they 
meet the criteria for an SAE. 
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, 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 


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• 
Obtain complete blood count with differential to assess for eosinophilia 
• 
Obtain appropriate blood sampling for 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: 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. 
• 
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 Management of Participants Who Are Unable to Attend 
Onsite Study Visits with Unavoidable Circumstances (e.g., COVID-19 
or other pandemics or natural disasters)  
If participants are not able to visit the study site due to unavoidable circumstances (e.g., 
COVID-19 or other pandemics or natural disasters), the following provisions may be 
made: 
• 
Study visits may be performed by phone/virtually. 
• 
Study visits may be performed in participants’ home residence by a visiting health 
care professional assigned by Primary Investigator and approved by sponsor.  
• 
Study assessments may be performed in a local hospital close to participants’ home 
residence with Sponsor’s approval. 
• 
Participants who are unable to “be safety monitored during maintaining the 
study drug” (see below) may be required to temporarily discontinue study drug 
(mavacamten or placebo). 
 
The visiting health care professional or local hospital must be confirmed as qualified 
and approved by the investigator and Sponsor before performing study assessments. 
If possible, training will be provided to ensure assessments’ quality and reduce 
discrepancy between on-site and remote assessments. 
 
Remote Health Assessment 
Protocol-specified assessments listed below may be conducted in the participant’s 
home by a visiting health care professional or via telemedicine:  
• 
NHYA classification may be assessed by the principal investigator via 
telemedicine 
• 
The KCCQ may be completed independently by the participant at home   
• 
ECG may be acquired by visiting health professional 
• 
Holter monitor may be applied and removed at participant's home by a visiting 
healthcare professional. 
• 
Blood sample collection may be done by a visiting health care professional 
All above also can be done in a local hospital close to participants’ home residence with 
Sponsor’s approval with similar method.  


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In addition, physical examination may be performed by the local hospital. TTE may be 
performed by a qualified sonographer who has been certified by the echocardiography 
core lab at a local hospital and submitted to the core lab for interpretation. If impossible, 
the TTE may be performed and interpreted by sonographer in the local hospital 
according to his/her routine clinical practice. The TTE will not be submitted to the core 
lab or used for data analysis. These TTE will only be used as safety monitoring to ensure 
the safety (i.e., LVEF not less than 50%) during maintaining the study drug (and the 
dose). Please refer to the study-related documents for details. 
 
Drug Dispensation 
In certain circumstances, it may be necessary to ship study drug directly to participants. 
When study drug is shipped directly to the participants, a qualified individual who is 
contracted by the Sponsor or CRO will open the package of study drug, review 
temperature monitoring data, and confirm receipt. Study sites should contact 
participants by telephone to confirm study drug delivery. The study drug bottle(s) from 
the previous study visit will be returned to the site by the designee. 
 
Temporary Discontinuation of Study Drug  
Participants in 30-week Placebo-controlled Period (Day 1 to Week 30)  
Under unusual circumstances such as a Pandemic or Natural Disaster, if participants in 
the placebo-controlled dosing period of the study, cannot “be safety monitored during 
maintaining the study drug” ( i.e., at a minimum, TTE to be performed for safety 
assessment) within 1 week over their scheduled study assessment window, as they 
cannot be seen at the site, local hospital or by a home healthcare provider, the participant 
will be contacted by the site at the end of the 1-week overdue period and instructed to 
temporarily discontinue study drug (mavacamten or placebo). Participants who 
discontinue study drug should be contacted by the site every 4 weeks from the time of 
discontinuing study drug to assess for AEs and to document concomitant medications.  
If participants can return to the study site for visit or “be safety monitored during 
maintaining the study drug” within 6 weeks of discontinuation of study drug and prior 
to the “Week 20” visit (including “Week 20” visit), the study drug could be resumed at 
the site or under the remote guidance of the site (i.e., resume the study drug and the 
dose received prior to discontinuation) at scheduled or unscheduled visit. For example, 
if participants cannot return to the study site for the “Week 8” visit, the site will instruct 
them to discontinue the study drug and conduct a remote visit during this period. If 
participants can return to the study site after 3 weeks, unscheduled visit (“Week 11”) 
will be performed and the study drug will be resumed, and subsequent scheduled visits 
will be completed according to the protocol. If participants can return to the study site 
after 6 weeks, the study drug will be resumed at the “Week 14” visit (scheduled visit).  
If the study drug is resumed at “Week 6”, “Week 12” or “Week 18” visit, the dose will 


Protocol No.: LB2001-301 
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not be up-titrated at “Week 8”, “Week 14” or “Week 20” regardless of TTE parameters 
and pre-dose PK results (dose remain unchanged). Dose adjustments at subsequent 
visits will comply with Table 5 and Table 6. If the study drug is resumed at “Week 8”, 
“Week 14” or “Week 20” visit, an unscheduled TTE should be performed to assess 
participants’ safety. 
If participants cannot return to the study site for visit or “be safety monitored during 
maintaining the study drug” within 6 weeks of discontinuation of study drug OR prior 
to the “Week 20” visit (including the “Week 20” visit), the "post-treatment visit" will 
be performed (remote visit; participants will be followed up to 8 weeks after the last 
dose, 20 weeks for poor CYP-2C19 metabolism). When the participant can return to 
the study site and the study is still in the participants’ enrollment, under sponsor’s 
approval, the participant may receive a new participant ID and undergo rescreening to 
re-enter the study (Prior to re-screening, the treatment should be discontinued for at 
least 8 weeks, 20 weeks for poor CYP-2C19 metabolism). All screening assessments 
need to be repeated. Participants must meet the inclusion and exclusion criteria (the 
exclusion criteria #7 is no longer applicable): 
• 
Participants will restart study drug (mavacamten 2.5 mg or placebo, consistent 
with the drug that the participant was randomized to at the beginning of the study, 
before temporary discontinuation) at Day 1 and resume study visits from Day 1.  
• 
Participants who do not qualify based on re-screening assessments may be 
scheduled for repeat screening at a later time.  
 
Participants in LTE Period 
Under unusual circumstances such as a Pandemic or Natural Disaster, if participants 
in the LTE period, cannot “be safety monitored during maintaining the study drug” 
( i.e., at a minimum, TTE to be performed for safety assessment) within 4 weeks over 
their scheduled study assessment window, as they cannot be seen at the site, local 
hospital or by a home healthcare provider, the participant will be contacted by the site 
at the end of the 4-week overdue period and instructed to stop taking study drug 
(mavacamten). Sites should conduct “post-treatment visit” (remote visit; participants 
will be followed up to 8 weeks after discontinuation of treatment, 20 weeks for 
participants with poor CYP-2C19 metabolism) to assess AEs and record concomitant 
medications. 


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i 
Sponsor signature page 
Authorization of the Sponsor 
A Phase III, Randomized, Double-blinded, Placebo-controlled Clinical Study with A 
Long-term Extension to Evaluate the Efficacy and Safety of Mavacamten in Chinese 
Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy. 
 
The clinical study protocol has been reviewed and approved by the representative of 
MyoKardia, Inc. 
 
 
Printed Name 
Signature 
 
Title 
Date (mm-dd-yyyy) 
  
 
 


Protocol No.: LB2001-301 
Confidential 
V3.0/ Dec 25, 2023 
ii 
Investigator’s signature page 
I have read and understood the contents of the clinical protocol, A Phase III, 
Randomized, Double-blinded, Placebo-controlled Clinical Study with A Long-term 
Extension to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults with 
Symptomatic Obstructive Hypertrophic Cardiomyopathy, and I agree to the following: 
I have reviewed this protocol and agree to implement this protocol in compliance with 
the ethical principles deriving from the Declaration of Helsinki, Good Clinical Practice 
of International Conference on Harmonization, and the requirements of any regulatory 
authority and/or institutional review committee/independent ethics committee 
(IRB/IEC). 
I agree to allow the Sponsor's representatives and relevant regulatory authorities to 
access my participant study records so that they can verify the data I or my designee 
have entered into the CRF. I understand the responsibilities as a Principal Investigator. 
I understand that the Sponsor may decide to suspend or prematurely terminate this study 
at any time for any reasons; such decisions will be communicated to me in writing. 
Conversely, if a decision is made to withdraw my center from this study, I will 
immediately notify the Sponsor in writing. 
 
 
 
 
Printed Name 
Signature 
 
Title 
Date (mm-dd-yyyy) 
 

SAP_001.pdf: 
MYK-461-005:  Statistical Analysis Plan 
MyoKardia, Inc. 
Version 2.0
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. 
1000 Sierra Point Parkway 
Brisbane, CA 94005 
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. 
 
 


MYK-461-005:  Statistical Analysis Plan 
MyoKardia, Inc. 
Version 2.0
Page 2
 
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 
 
 
Authored by: Wanying Li, Ph.D. 
 
Signature:  [See Attached E-Signature] 
Date: _________ 
 
 
 
Approved by:  
 
Biometrics: Liang Fang, Ph.D. 
 
Signature:  [See Attached E-Signature] 
Date: _________ 
 
 
 
Clinical Research: Amy Sehnert, M.D. 
 
Signature:  [See Attached E-Signature] 
Date: _________ 
 
 
 
 
 


MYK-461-005:  Statistical Analysis Plan 
MyoKardia, Inc. 
Version 2.0
Page 3
 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY OBJECTIVES ..............................................................................................10 
2.1. 
Primary Objective .......................................................................................................10 
2.2. 
Secondary Objectives .................................................................................................10 
2.3. 
Exploratory Objectives ...............................................................................................10 
2.4. 
CMR Imaging Substudy Objective .............................................................................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 
8. 
EFFICACY ANALYSES ...........................................................................................19 
8.1. 
Primary Efficacy Endpoints ........................................................................................20 
8.2. 
Secondary Efficacy Endpoints ....................................................................................20 
8.3. 
Exploratory Efficacy Analysis ....................................................................................22 
8.3.1. 
General Analysis Methods ..........................................................................................22 
8.3.2. 
CPET...........................................................................................................................22 


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8.3.3. 
Transthoracic Echocardiography (TTE; ECHO) ........................................................23 
8.3.4. 
NT-proBNP .................................................................................................................24 
8.3.5. 
PRO Analyses .............................................................................................................24 
8.3.5.1. 
PRO responder analysis ..............................................................................................25 
8.3.6. 
Accelerometer .............................................................................................................26 
8.3.7. 
hs-Cardiac Troponin I .................................................................................................26 
8.3.8. 
NYHA Class ...............................................................................................................27 
8.3.9. 
Additional Exploratory Analysis ................................................................................27 
9. 
PHARMACOKINETIC ANALYSES AND PHARMACODYNAMIC ...................27 
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 
11. 
PHARMACOGENOMIC/HCM GENOTYPE ...........................................................31 
12. 
CARDIAC MAGNETIC RESONANCE IMAGING SUBSTUDY ..........................32 
13. 
INTERIM ANALYSIS ...............................................................................................32 
14. 
SUMMARY OF CHANGES IN THE PROTOCOL PLANNED 
ANALYSES ...............................................................................................................32 
15. 
REFERENCES ...........................................................................................................33 
APPENDIX 1. ................................................................................................................................34 
APPENDIX 2. ................................................................................................................................39 


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APPENDIX 3. HCMSQ SCORING ALGORITHM ..................................................................42 
 
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 
 
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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1. 
INTRODUCTION 
Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is defined 
clinically by the presence of increased left ventricular (LV) wall thickness associated with 
nondilated ventricular chambers that is not solely explained by abnormal loading conditions, 
such as another cardiac or systemic disease (Gersh et al, 2011; Elliott 2014). The phenotypic 
hallmark of HCM is myocardial hypercontractility accompanied by reduced LV compliance, 
reflected clinically as reduced ventricular chamber size, often supranormal ejection fraction, and 
diastolic dysfunction. Mutations in cardiac myosin and other sarcomere proteins in individuals 
with HCM appear to increase net power generation by the sarcomere (Chuan et al, 2012; 
Sommese et al, 2013; Sung et al, 2012), consistent with the generally hypercontractile state and 
impaired compliance of the myocardium observed clinically. HCM may be associated with 
obstruction of the left ventricular outflow tract (LVOT) in ~70% of cases, referred to as 
obstructive HCM (oHCM), or in ~30% of cases be non-obstructive (nHCM). Current medical 
treatment consists of the use of beta blockers, verapamil, diltiazem, or disopyramide (when 
available), as described in the 2014 European Society of Cardiology (ESC) (Elliott 2014) and in 
the 2011 American College of Cardiology Foundation (ACCF)/American Heart Association 
(AHA) guidelines for the diagnosis and management of hypertrophic cardiomyopathy 
(Gersh 2011). However, despite these treatments, symptoms may persist. For patients with 
advanced symptomatic obstructive disease, treatment may include septal reduction therapies 
(SRTs) (eg, surgical myectomy or percutaneous alcohol septal ablation), which can be effective 
in reducing obstruction of the left ventricular outflow tract (LVOT) but are invasive procedures. 
No United States (US) Food and Drug Administration (FDA)-approved medical therapies exist 
for patients with symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM), and no 
interventional options are available, short of cardiac transplant. 
Mavacamten is a novel small molecule allosteric modulator of striated muscle myosin that 
selectively targets cardiac myosin and reversibly inhibits its binding to actin. 
s 
profile of myosin modulation is predicted to reduce dynamic LVOT obstruction in individuals 
with obstructive HCM (oHCM) by reducing systolic hypercontractility and dynamic obstruction 
in the near term and reducing ventricular hypertrophy with chronic treatment. MyoKardia is 
developing mavacamten for the treatment of adults with symptomatic oHCM to relieve 
obstruction, improve symptoms, and increase exercise capacity. 
MYK-461-005, EXPLORER-HCM, is a Phase 3 study designed to evaluate the safety and 
efficacy of a 30-week course of mavacamten compared with placebo in participants with 
symptomatic oHCM. At selected study sites, participants could also have been enrolled in a 
cardiac magnetic resonance (CMR) imaging substudy. This statistical analysis plan (SAP) 
describes all planned analyses for the main study and CMR substudy in protocol MYK-461-005 
and provides justifications of these analyses. 


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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 
2.3. 
Exploratory Objectives 
To assess the effect of a 30-week course of mavacamten on LVOT obstruction; disease 
biomarkers; symptoms, health-related quality of life, and work activity as assessed by patient-
reported outcomes (PRO); cardiac rhythm patterns as assessed by continuous cardiac rhythm 
monitoring; functional capacity as assessed by accelerometer. 
2.4. 
CMR Imaging Substudy Objective 
The objective of the substudy is to assess the effect of mavacamten on cardiac mass and structure 
as evaluated by CMR. 
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 
-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 
-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 
 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 
-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 
relative to placebo (see Section 12.2.1 of the protocol). The power calculation is derived 


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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 
 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 
study drug initiation date, or the randomization date if the study drug initiation date is missing): 


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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 n
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 
to Week 30 


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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 
Exploratory Efficacy Endpoints: 
 Proportion of subjects achieving a post-exercise LVOT peak gradient < 50 mmHg at 
Week 30 
 Proportion of subjects achieving a post-exercise LVOT peak gradient < 30 mmHg at 
Week 30 
 Proportion of subjects with any decrease in post-exercise LVOT peak gradient from 
baseline to Week 30 
 Proportion of subjects achieving complete response (NYHA Class I and LVOT peak 
gradient < 30 mmHg for all 3 types of gradients: resting, Valsalva, and post-exercise) 
at Week 30 
 Changes from baseline to Week 30 in cardiopulmonary function as assessed by CPET 
 Changes from baseline to Week 30 in echocardiographic indices of cardiac structure 
(eg, LV ventricular wall thickness, atrial and ventricular chamber size and volumes), 
as well as systolic and diastolic function 
 Change from baseline to Week 30 in N-terminal pro b-type natriuretic peptide 
(NT-proBNP) concentration over time 
 Changes from baseline to Week 30 in the following patient-reported endpoints: 
o Perceived health status/health-related QoL as assessed by the EuroQol 
5-dimensions 5-levels questionnaire (EQ-5D-5L) scores 
o Work productivity and activity impairment as assessed by the Work Productivity 
and Activity Impairment Questionnaire-Specific Health Problem (WPAI-SHP) 
scores 
o Perceived severity of symptoms as assessed by Patient Global Impression of 
Change (PGIC) and Patient Global Impression of Severity (PGIS) scores 
o Health-related QoL as assessed by the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) total symptom score and overall summary score 
o Severity of HCM symptoms as assessed by the Hypertrophic Cardiomyopathy 
Symptom Questionnaire (HCMSQ) total score and the 2 domain subscores 
tiredness and cardiovascular [CV] symptoms 
 Proportion of subjects who had clinically meaningful changes in KCCQ-23 scores  
 Proportion of subjects who had clinically meaningful changes in HCMSQ scores  


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 Changes from baseline to Week 30 in daily step count and other accelerometer 
parameters 
 Change from baseline to Week 30 in hs-cardiac troponin-I 
PK Endpoints: 
 Mavacamten plasma concentration over time 
 PK parameters using a population PK approach (to be summarized in a separate 
population PK report) 
Safety Endpoints: 
 Incidence of major adverse cardiac events (death, stroke, acute myocardial infarction) 
 Incidence of hospitalizations (both CV and non-CV) 
 Incidence of heart failure (HF) events, (includes HF hospitalizations and urgent 
emergency room/outpatient visits for HF) 
 Incidence of atrial fibrillation/flutter (new from screening) 
 Incidence of implantable cardioverter defibrillator (ICD) therapy and resuscitated 
cardiac arrest 
 Incidence of ventricular tachyarrhythmia (including ventricular tachycardia (VT), 
ventricular fibrillation, 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) 
 Change from baseline to Week 30 in cardiac rhythm patterns 
CMR Substudy Primary Endpoint: 
 Change from baseline to Week 30 in LV mass index 
CMR Substudy Exploratory Endpoints: 
 Change from baseline to Week 30 in myocardial fibrosis as measured by late 
gadolinium enhancement 
 Changes from baseline to Week 30 in cellular hypertrophy, left atrial volume and 
function, LV wall thickness and LV function  
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 
assignment 


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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 and have at least 1 detectable mavacamten plasma drug concentration 
 CMR Substudy Population: All subjects who consent to participate in the CMR 
substudy and have CMR scans available to evaluate at both Day 1 at Week 30, with 
analyses conducted according to the randomized treatment assignment 
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) 
 
-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.  
Selected efficacy endpoints (refer to Section 8) will be analyzed by the following subgroups at 
baseline: 
 Beta-blocker use (yes vs no; actual value) 
 Type of exercise testing (treadmill vs bicycle; actual value) 
 NYHA class (II vs III; actual value) 
 Consent for the CMR substudy (yes vs no; actual value) 
 Sex (male vs female) 
 Age (<= 49, 50-64, >=65) 
 BMI (< 30 vs >= 30)  
 Race (white vs not white)  
 Region (US vs ex-US) 
 Presence of HCM pathogenic mutation (pathogenic or likely pathogenic vs variant of 
uncertain significance (VUS) vs not pathogenic) 
 Time from diagnosis of oHCM (<= 5 years vs > 5 years)  
 Calcium channel blocker use (yes vs no) 
 SRT history (yes vs no)  
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 History of hypertension (yes vs no) 
 Resting LVEF (< 75% vs >= 75%)  
 LVOT resting peak gradient (<= 50 mmHg vs > 50 mmHg) 
 LVOT resting peak gradient (<= 30 mmHg vs > 30 mmHg) 
 
* (<= 14 vs > 14) 
 Left atrial volume index (<= median vs > median based on ITT population)  
 NT-proBNP (<=median vs >median based on ITT population) 
 hs-Cardiac troponin-I (<= upper limit of normal (ULN) vs > ULN) 
 
* >14 or hs-Cardiac Troponin >ULN vs others 
 Creatinine clearance (CrCl) (< 60 mL/min vs >= 60 mL/min) 
* The subgroup analysis that are related to 
 
: 
lateral, septal and average. 
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, 
31MMMYYYY), except if the month and year is equal to the last 


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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
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.
8.
EFFICACY ANALYSES
All efficacy analysis will be based on the ITT Population unless otherwise noted. Descriptive 
statistics for efficacy parameters by time point and change from baseline will be provided, 
including the estimates of treatment group differences and the 95% confidence intervals (CIs) 
based on normal approximation, as appropriate. Descriptive statistics for change from week 30 to 
week 38 may also be provided, as appropriate.  Stratified statistical tests will be performed for 
Cytochrome P450 (CYP) 2C19 genotypes and phenotypes will also be summarized.
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between-group comparisons. Unstratified tests may be performed as sensitivity analyses for 
binary response endpoints. The 3 stratification factors are:
NYHA class (II or III)
-blocker (yes or no)
Type of ergometer (treadmill or exercise bicycle)
Consent for the CMR substudy will not be included as a stratification factor to avoid creating 
small sample size problems for certain stratum. Assigned stratification by IXRS will be used in 
the main analyses.  Actual stratification as recorded on CRF will be used in sensitivity analyses.
8.1.
Primary Efficacy Endpoints
The primary efficacy endpoint is clinical response at Week 30, defined as achieving: 1) an 
improvement of 1.5 mL/kg/min in pVO2 as determined by CPET and a reduction 1 NYHA 
class, or 2) an improvement of 3.0 mL/kg/min in pVO2 with no worsening in NYHA class. If 
Week 30 pVO2 is missing, no imputation will be performed, and the participant will be considered 
as a non-responder. If pVO2 is available but NYHA class is missing at Week 30, the NYHA class 
at Week 30 will be imputed with the NYHA class at Week 26, if available. If there are multiple
records of NYHA class within Week 26 analysis window, the latest one will be used.  The clinical 
response status at Week 30 will be assessed after the imputations for applicable cases.  Participants 
whose response status at Week 30 is missing will be classified as nonresponders.    
The clinical response rate will be summarized for each treatment group with descriptive 
statistics. The estimates of treatment group differences and the 95% CIs based on normal 
approximation will be provided. The Cochran-Mantel-Haenszel (CMH) test for stratified 
categorical data will be used to test the statistical significance of the association between clinical 
response status (responder vs nonresponder) and treatment group (mavacamten vs placebo).
Unstratified analysis using a Chi-square test will be performed as a sensitivity analysis.
A forest plot summarizing the 95% CI of the difference in clinical response rates at Week 30 
between mavacamten and placebo treatment groups will be generated for the subgroups listed in 
Section 6.3 to evaluate the consistency of treatment effects in the subgroups.
8.2.
Secondary Efficacy Endpoints
Five secondary endpoints are defined and will be tested sequentially in the following order:
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 improvement from baseline in NYHA 
class 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 the NYHA class is missing at Week 30, it will be imputed with the NYHA class at Week 26, 
if available. If there are multiple records of NYHA class within Week 26 analysis window, the
*If the NYHA class is missing at Week 30, it will be imputed with the NYHA class at Week 26, 
if available. If there are multiple records of NYHA class within Week 26 analysis window, the
If
Week 30 pVO2 is missing, no imputation will be performed,
If pVO2 is available but NYHA class is missing at Week 30, the NYHA class 
at Week 30 will be imputed with the NYHA class at Week 26, 


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latest one will be used. The response status at Week 30 will be assessed after the imputations for 
applicable cases. Participants whose NYHA response status at Week 30 is missing will be 
classified as nonresponders.   
These endpoints will be summarized for each treatment group at each visit with descriptive 
statistics. The estimates of treatment group differences and the 95% CIs based on normal 
approximation will be provided.
The CMH test will be used to assess the categorical secondary endpoint (proportion of subjects 
with at least 1 class of improvement in NYHA) between the mavacamten and placebo groups.
Between-group comparisons of the continuous secondary efficacy endpoints will be based on
analysis of covariance (ANCOVA) for LVOT gradient and pVO2, and based on a mixed model 
for repeated measurements (MMRM) for KCCQ-23 CSS and HCMSQ SoB because these PROs 
were collected at multiple post-baseline visits.  For ANCOVA, treatment group (mavacamten vs 
placebo), baseline value of the corresponding endpoint of interest, and the 3 stratification factors 
(beta blocker use, NYHA class, ergometer type) will be treated as fixed effects. In MMRM, in 
addition to the fixed effects described above, time point (as a categorical variable) and the 
interaction between treatment and time point will be included. Subject will be treated as a 
random effect, and compound symmetric variance covariance component will be used. All post-
baseline data up to Week 30 will be included in the model.
An unstratified analysis will also be conducted as a sensitivity analysis using the Chi-square test 
for categorical endpoint.
A forest plot summarizing the 95% CI of the between-group difference for these 5 secondary 
endpoints at Week 30 will be generated for the subgroups listed in Section 6.3 to evaluate the 
consistency of treatment effects in the subgroups.
The KCCQ-23 is a self-administered 23-item questionnaire that quantifies physical limitations, 
symptoms, QoL, social interference, and self-efficacy (Green et al, 2000). The total symptom 
score is derived from the symptom frequency and symptom burden scores. The CSS is derived 
from the physical limitation and total symptom scores. The overall summary score is derived 
from the physical limitation, symptom, QoL, and social interference domains. Scores range from 
0 to 100, with higher scores reflecting better health status. KCCQ-23 will be collected on Day 1 
and at Week 6, Week 12, Week 18, Week 30/end of treatment (EOT), and Week 38/EOS and 
summarized by analysis visit as defined by the analysis window specified in Appendix 2
Table 10.  Baseline value is defined as the last non-missing KCCQ-23 value prior to or on the 
first dose date.
The CSS will be analyzed as a secondary efficacy endpoint as specified above, and the total 
symptom score and overall summary score will be analyzed as exploratory efficacy endpoints
using the method described in Section 8.3.1.
The HCMSQ is a self-administered, 11-item questionnaire that assesses the core symptoms of 
HCM (tiredness/fatigue, heart palpitations, chest pain, dizziness, and shortness of breath). During 
the screening period, participants will complete the HCMSQ for a minimum of 7 consecutive 
days. From Day 1 through Week 6, participants will complete the HCMSQ daily. For the 
remainder of the treatment period, participants will complete the HCMSQ for at least 7 
consecutive days prior to study visits at Weeks 10, 14, 18, 22, 26, 30 (EOT) and 38 (EOS). The 
weekly average HMCSQ scores will be derived using the scoring algorithm detailed in
latest one will be used. The response status at Week 30 will be assessed after the imputations for 
applicable cases. Participants whose NYHA response status at Week 30 is missing will be 
classified as nonresponders.
For ANCOVA, treatment group (mavacamten vs 
placebo), baseline value of the corresponding endpoint of interest, and the 3 stratification factors
(beta blocker use, NYHA class, ergometer type) will be treated as fixed effects. I


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Appendix 3, and summarized by analysis visit as defined by the analysis window in Appendix 2
Table 11.  
Because the weekly average HCMSQ scores only include data up to 7 days for calculation, the 
data collected outside the 7-day period will be excluded from analysis.  At each visit, the 7-day 
period will be determined so that the last day of the period is the last day with non-missing 
HCMSQ score prior to or on the actual clinic visit (or first dose date if for baseline).  If the 
participant completes the questionnaire fewer than 4 days over the 7-day period, the weekly 
average HCMSQ scores for that visit will be treated as missing.
Shortness of breath subscore will be analyzed as secondary efficacy endpoint as specified above, 
and the other subscores (tiredness and cardiovascular symptoms) in addition to the total score 
will be analyzed as exploratory efficacy endpoints using the method described in Section 8.3.1.  
8.3.
Exploratory Efficacy Analysis
8.3.1.
General Analysis Methods
All the exploratory endpoints described in this section will be summarized for each treatment 
group at each visit with descriptive statistics. The estimates of treatment group mean differences 
and the 95% CIs based on normal approximation will be provided.
The comparison of the exploratory efficacy endpoints between the mavacamten and placebo 
groups will be based on change from baseline at Week 30. For continuous endpoints, stratified 
analyses using the ANCOVA or MMRM may be used for these comparisons for continuous 
endpoints. In ANCOVA, treatment group (mavacamten vs placebo), baseline value of the 
corresponding endpoint of interest, and the 3 stratification factors (beta blocker use, NYHA 
class, ergometer type) will be treated as fixed effects. In MMRM, in addition to the fixed effects 
described above, time point (as categorical variable) and the interaction between treatment and 
timepoint will be included. Subject will be treated as a random effect, and a compound 
symmetric variance covariance component will be used. All post-baseline data up to Week 30 
will be included in the model. For categorical endpoints, stratified analyses using the CMH test 
will be used. The p-values generated from these analyses will not be adjusted for multiplicity and 
will be considered descriptive.
In the subsequent subsections, for each of the exploratory endpoints, details are provided on: 1) 
specific parameters to be analyzed, 2) figures to be generated to visually explore the 
relationships between the selected endpoints, 3) figures to be generated to assess the treatment 
effects in subgroups, and 4) additional endpoint-specific exploratory analyses.
8.3.2.
CPET
Exploratory efficacy endpoints for CPET parameters to be summarized will include, but are not 
limited to, the following:
Volume expired (VE)/ carbon dioxide production (VCO2)
VE/VCO2 slope (ventilatory efficiency)
Circulatory power
Ventilatory Power
The comparison of the exploratory efficacy endpoints between the mavacamten and placebo 
groups will be based on change from baseline at Week 30. For continuous endpoints, stratified 
analyses using the ANCOVA or MMRM may be used for these comparisons for continuous 
endpoints. In ANCOVA, treatment group (mavacamten vs placebo), baseline value of the
corresponding endpoint of interest, and the 3 stratification factors (beta blocker use, NYHA 
class, ergometer type) will be treated as fixed effects. In MMRM, in addition to the fixed effects
described above, time point (as categorical variable) and the interaction between treatment and 
timepoint will be included. Subject will be treated as a random effect, and a compound 
symmetric variance covariance component will be used. All post-baseline data up to Week 30
will be included in the model. For categorical endpoints, stratified analyses using the CMH test
will be used. The p-values gener
8.3.2.
CPET


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Peak workload
Respiratory exchange ratio (RER)
% Predicted peak VO2
The distribution of the changes in selected CPET parameters by treatment group will be 
visualized to give a more comprehensive description of the data.
8.3.3.
Transthoracic Echocardiography (TTE; ECHO)
The proportion of subjects achieving a post-exercise LVOT peak gradient < 50 mmHg at Week 
30 and the proportion of subjects achieving a post-exercise LVOT peak gradient < 30 mmHg at 
Week 30 will be summarized using descriptive statistics and compared between the mavacamten
and placebo groups using the CMH test. Participants whose baseline post-exercise LVOT peak 
gradient were < 50 mmHg or < 30 mmHg will be excluded from the analyses. The proportion of 
subjects with LVEF < 50% at Week 30 will be summarized by treatment group using descriptive 
statistics.
In addition, the following ECHO parameters (including, but not limited to) will also be analyzed
as exploratory efficacy endpoints. Indices parameters (eg, LV end-diastolic volume index 
[LVEDVI]) will be derived by dividing each respective parameter by BSA calculated using the 
height at baseline and weight at each respective visit.
Systolic function:
o
Left ventricular ejection fraction (LVEF)
o
Left ventricular fractional shortening (LVFS)
o
Left ventricular stroke volume (LVSV)
o
Left ventricular Cardiac Output (LVCO)
Diastolic function
o
, average)
o
o
E/A ratio
Structural parameters
o
Interventricular septal thickness (IVS)
o
Posterior wall thickness
o
Maximal LV wall thickness (at baseline)
o
LVOT gradient (resting, Valsalva, and post exercise)
o
LV end-diastolic volume
o
LV end-diastolic volume index
o
LV end-systolic volume
o
LV end-systolic volume index
8.3.3.
Transthoracic Echocardiography (TTE; ECHO)


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o
Left atrial (LA) volume
o
LA volume index (LAVI)
o
LV mass index
Other
o
Presence of systolic anterior motion (SAM) of the mitral valve
o
Presence of mitral regurgitation (MR)
The following figures will be presented for ECHO data:
Mean (+/-SD) over time line plots for selected ECHO parameters, including LVOT 
gradient (resting, Valsalva, and post exercise
(septal, lateral, 
average)
Forest plots of the 95% CI of the mean difference in change from baseline at Week 30 
between the mavacamten and placebo groups for all ECHO parameters listed above
Forest plots of the 95% CI of the mean difference in change from baseline at Week 30 
in key ECHO parameters (eg,
the mavacamten and 
placebo groups for the subgroups listed in Section 6.3.
8.3.4.
NT-proBNP
Median (+/- Q1, Q3) over time line plots will be generated for NT-proBNP concentration. 
8.3.5.
PRO Analyses
The EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire is a validated instrument of 
general QoL and is critical for acceptance by many health technology assessment bodies for 
coverage decisions. The tool is translated in multiple languages, is validated on various 
electronic platforms, and takes only a few minutes to administer. EQ-5D-5L will be collected on 
Day 1 and at Weeks 6, 12, 18, 30/EOT, and 38/EOS and summarized based on the analysis 
windows defined in Appendix 2 Table 10.  Baseline value is defined as the last non-missing EQ-
5D-5L value on or prior to the first dose date.
The PGIS questionnaire is a single-item questionnaire that asks participants to rate their overall 
symptom severity in the past week on a 5-point categorical rating scale (none, mild, moderate, 
severe, very severe). PGIS will be collected at screening, Weeks 6, 10, 14, 18, 22, 26, 30/EOT, 
and 38/EOS, and summarized based on the analysis windows defined in Appendix 2 Table 10.  
Baseline value is defined as the last non-missing PGIS value on or prior to the first dose date.
The PGIC questionnaire is a single-item questionnaire that asks participants to rate their overall 
change in symptom severity over time (since the participant started taking the study drug) on a 
7-point categorical rating scale (very much better to very much worse). PGIC will be collected 
on Weeks 6, 10, 14, 18, 22, 26, 30/EOT, and 38/EOS, and summarized based on the analysis 
windows defined in Appendix 2 Table 10. 
The WPAI-SHP questionnaire was created as a patient-reported quantitative assessment of 
ability to work and perform regular activities. Specifically, the WPAI-SHP asks about the impact 
of a specific health problem (in this case HCM) on absenteeism, presenteeism, and daily activity 
8.3.4.
NT-proBNP


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impairment. Baseline value is defined as the last non-missing WPAI-SHP value on or prior to the 
first dose date. 
Compliance for each PRO assessment will be summarized by visit and treatment group for the 
number of subjects that met the compliance criteria of the respective assessment, and for the 
average number of days a subject completed a questionnaire (if collected over a period of days). 
8.3.5.1. 
PRO responder analysis 
Responder analysis will be performed for each of the following PRO scores: 
 HCMSQ: Shortness of breath, Tiredness, Cardiovascular symptoms, Total  
 KCCQ-23: TSS, CSS and OSS 
Responders are defined as the participants who achieved clinically meaningful changes from 
baseline.  The thresholds for clinically meaningful changes were derived following the 
psychometric analysis plan (PAP) using data from Study MYK-461-006 (MAVERICK-HCM), a 
phase 2 proof-of-concept study in non-obstructive HCM. Another set of thresholds will also be 
derived as described in the PAP using the data from this study (MYK-461-005; EXPLORER-
HCM) without actual treatment information. For KCCQ-23, thresholds reported in the literature 
for heart failure will be included, as well.  
Table 1: 
Responder Thresholds for HCMSQ  
 
MAVERICK-HCM 
EXPLORER-HCM 
Total Score 
 -2 
TBD 
Shortness of Breath 
 -2 
TBD 
Tiredness 
 -1 
TBD 
Cardiovascular Symptoms 
 -1 
TBD 
 
Table 2: 
Responder Thresholds for KCCQ-23  
 
MAVERICK-HCM 
Literature* 
EXPLORER-HCM 
Overall summary score (OSS) 
 10 
 5 
TBD 
Clinical summary score (CSS) 
 10 
 5 
TBD 
Total summary score (TSS) 
 10 
 5 
TBD 
*  Spertus J, Peterson E, Conard MW, et al., 
-15 (2005). 
The responder rate (based on each set of responder thresholds) will be summarized by visit and 
treatment arm. Participants who cannot be qualified as responders in the study due to their 
baseline scores will be excluded. For the HCMSQ instrument, these are participants who have 
missing value at baseline or have a baseline score < 0 - clinically meaningful threshold. For the 
KCCQ-23 instrument, these are participants who have missing value at baseline or have a 
baseline score > 100  clinically meaningful threshold.  Participants who have missing data at the 
post-baseline visit will be considered non-responders for that visit. 


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Responder rate at Weeks 30 will also be compared between treatment groups using CMH test 
with stratification factors: NYHA class (II or III), and 
-blocker (yes or 
no), and type of ergometer used during the study (treadmill or exercise bicycle).  The forest plots 
will be used to illustrate the response rate differences between treatment groups and the 
associated 95% CIs. 
A more detailed analysis of PRO data will be specified in the PAP and the results will be 
summarized in a separate report. 
8.3.6. 
Accelerometer  
Participants will be provided with an accelerometer to be worn on the wrist from screening to 
Day 1, and from Week 26 to Week 30 to collect data on physical activity. The following 
parameters and the change from baseline will be summarized by treatment group using 
descriptive statistics and will include estimates of treatment group differences and 95% CIs 
based on normal approximation for the ITT population. 
 Average daily accelerometry unit (ADAU) is the average of daily square-root of 
(Wear-Filtered Axis X count^2+ Wear-Filtered Axis Y count^2 + Wear-Filtered Axis 
Z count^2) 
 Average daily step counts (wear-filtered) 
 Average daily active hours: the average of the wear-filtered daily hours in activity 
level higher than sedentary 
 Average daily hours in moderate or higher activity (wear-filtered) 
Accelerometer compliance is defined as device wear time  1200 minutes/day. All compliant 
days within the following visit windows will be included in the analysis: 
Table 3: 
Accelerometry Data Analysis Windows 
Analysis Visit 
Analysis Visit Window 
Baseline 
Screening  analysis day  1 
Week 26 
169 < analysis day  239 
Compliance will be summarized by visit and treatment for the number of subjects that met 
compliance criteria 
 1200 minutes/day) for at least 1 day, and will be summarized in those 
compliant subjects for their average number of wear minutes per day and their average number 
of compliant days using descriptive statistics. 
8.3.7. 
hs-Cardiac Troponin I 
Median (+/- Q1, Q3) over time line plots will be generated for hs-Cardiac Troponin I concentration. 
A shift table of hs-cardiac troponin-I (<=ULN and >ULN) by treatment group and visit will be 
provided. A boxplot of change from baseline in cardiac troponin-I by treatment group and visit 
will also be presented. 


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8.3.8.
NYHA Class
A shift table of NYHA class from baseline will be summarized by visit. The change from 
baseline to Week 30 in NYHA class expressed as numerical numbers will also be analyzed using 
the methods as described in Section 8.3.1.
8.3.9.
Additional Exploratory Analysis
Correlation analyses and associated visualization may be performed among the efficacy, PK and 
safety data to provide insights on disease nature and drug mechanism, which include but not 
limited to:
Changes in echocardiographic features (eg, LAVI, LVEF, LVOT peak gradient) vs 
EKG patterns enabled by AI algorithms 
Change in NT-proBNP vs Change in pVO2
Change in NT-proBNP vs Change in hs-Cardiac troponin I
Change in NT-proBNP vs Change in LVEF or occurrence of LVEF<50%
Change in NT-proBNP vs Incidence of atrial fibrillation
Change in pVO2 vs Change in NYHA class
Change in HR (from ECHO) vs Change in LVEF 
9.
PHARMACOKINETIC ANALYSES AND PHARMACODYNAMIC
The PK and PK/PD analyses described in this section will be based on the PK Populations. PK 
data from this study may be included as part of a population PK analysis and summarized in a 
separate report. Mavacamten plasma concentration values < LLOQ will be imputed following 
the imputation methods described in Section 6.4.  
Mavacamten plasma concentrations at each visit will be summarized for overall and by 
CYP2C19 phenotype status using descriptive statistics.  The distribution of mavacamten plasma 
concentrations at each visit will also be summarized by category of <350, 350 to 700, >700 to 
<1000, and >=1000.
The following PK/PD relationships will be presented in scatterplots:
Mavacamten concentration versus post-exercise LVOT gradient change from baseline 
through Week 30
Mavacamten concentration versus LVEF change from baseline through Week 30
Mavacamten concentration versus LVEF from baseline through Week 30
Mavacamten concentration versus pVO2 (determined by CPET) change from baseline 
through Week 30
Mavacamten concentration versus NT-proBNP change from baseline through Week 30
PHARMACOKINETIC ANALYSES AND PHARMACODYNAMIC


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Selected efficacy endpoints (e.g. primary endpoint, change in pVO2, NYHA improvement and 
change in post-exercise LVOT peak gradient) will be summarized descriptively by the Week 30 
mavacamten concentration categories (<350, 350 to 700, >700 to <1000, and >=1000). 
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 
also be provided. 


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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 
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):
12-lead Electrocardiogram


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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 
and a horizontal line corresponding to 2 × ULN for TBL.


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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 
× 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
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 wit
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.
11.
PHARMACOGENOMIC/HCM GENOTYPE
HCM genotype, including HCM genes with identified variants (pathogenic or not pathogenic) 
based on current and previous testing will be summarized by treatment group and overall. 
Participants with no past or current HCM genotype test results will be categorized as Unknown. 
If a participant has both past and current HCM genotype test result, the current result will be 
used for data analysis.  A by-subject listings of the results from current and previous HCM 
genotype testing will be provided.
Cardiac Rhythm Monitoring (Including Holter Monitor)
PHARMACOGENOMIC/


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12.
CARDIAC MAGNETIC RESONANCE IMAGING SUBSTUDY
Results from the CMR imaging substudy will be summarized by treatment group using 
descriptive statistics for the CMR Substudy Population. Changes in LV mass index, myocardial 
fibrosis, cellular hypertrophy, LA structure and function, and ventricular structure and function 
will be summarized. Within-group 30-week changes from baseline will be assessed against a null 
of zero change using Wilcoxon Signed Ranks tests. Between-group differences in the magnitude 
and direction of those changes will be evaluated using Wilcoxon-Mann-Whitney tests.
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
Additional analyses may be performed to address the COVID-19 impact on efficacy, safety and 
other study conduct as appropriate.
Other changes are listed below:
1.
Specify KCCQ-23 Clinical Summary Score and HCMSQ Shortness-of-Breath are to be 
secondary endpoints based on the recommendations from FDA.
2.
Added KCCQ-23 responder (proportion of subjects with clinically meaningful changes) 
and HCMSQ responder to exploratory endpoints based on the recommendation from 
FDA.
3.
Added two exploratory endpoints: 1) Proportion of subjects with any decrease in post-
exercise LVOT peak gradient from baseline to Week 30; 2) Proportion of subjects 
achieving complete response at Week 30.
4.
Removed HCM risk prediction score from exploratory objectives and exploratory 
endpoints because the scoring algorithm is heavily dependent on LVOT peak gradient 
which compromises the score interpretation under mavacamten treatment.
5.
Moved cardiac rhythm patterns from exploratory efficacy endpoint to safety endpoint.
6.
Removed per-protocol population and PK/PD analysis population as no analyses are 
planned for these two populations.
7.
Modified the PK analysis population and CMR substudy population definition to better 
align with the analysis intention.
8.
TEAE are to be summarized by SOC and PT instead of by SOC, HLGT, HLT, and PT.
9.
Summary of pregnancy will not include the pregnancy test results from the partners of 
participants because they were not collected in the study.
10.
Updated language in the DILI section.
CARDIAC MAGNETIC RESONANCE IMAGING SUBSTUDY


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15. 
REFERENCES 
Chuan P, Sivaramakrishnan S, Ashley EA, Spudich JA. Cell-Intrinsic Functional Effects of the 
-Cardiac Myosin Arg-403-Gln Mutation in Familial Hypertrophic Cardiomyopathy. 
Biophysical Journal. 2012;102(12):2782 90. 
Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and 
management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35(39):2733-2779. 
doi:10.1093/eurheartj/ehu284. 
Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA 
Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy. Journal of 
the American College of Cardiology. 2011;58(25). 
Green C, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City 
Cardiomyopathy Questionnaire: a new health status measure for heart failure. Journal of 
the American College of Cardiology. 2000;35(5):1245 55. 
Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H, Edvardsen T, et al. 
Recommendations for the Evaluation of Left Ventricular Diastolic Function by 
Echocardiography: An Update from the American Society of Echocardiography and the 
European Association of Cardiovascular Imaging. Journal of the American Society of 
Echocardiography. 2016;29(4):277 314. 
Sommese RF, Sung J, Nag S, Sutton S, Deacon JC, Choe E, et al. Molecular consequences of the 
R453C hypertrophic cardiomyopathy mutation on human -cardiac myosin motor 
function. Proceedings of the National Academy of Sciences. 2013;110(31):12607 12. 
Sung J, Choe E, Elting M, Nag S, Sutton S, Deacon J, et al. Single Molecule Studies of 
- 
-Cardiac Myosin to Elucidate Molecular Mechanism of 
Familial Hypertrophic and Dilated Cardiomyopathies. Biophysical Journal. 2012;102(3). 
 
 


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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samplen 
 
 
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 


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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 
HCM genotypingr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogeneticss 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory biomarkers (blood) 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
Symptom Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA functional classification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Patient-Reported Outcomes 
See Table 2 in the Protocol for schedule of PRO assessments 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMR substudyv 
 
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-
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 
 
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 
 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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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 
 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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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 
 


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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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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 


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APPENDIX 3. HCMSQ SCORING ALGORITHM 
The HCMSQ is completed each day for 7 days, and each of the items is scored computing a 
score for each day the diary is completed and then averaging score over the 7-day period. This is 
referred to as the item weekly score. A weekly score is calculated if there are at least 4 days of 
data (i.e., no more than 3 days missing); otherwise the weekly score is set to missing. Each item 
should have the same number of daily entries as the electronic diary did not allow for items to be 
skipped. Three domain scores and one total score is calculated from 8 items of the HCMSQ: 
 Shortness of Breath domain: this is the sum of the item scores for items 1-3 and 
subscale 
score to missing for that day
endorsed, impute score as the mean of items 1, 2, and 6 for that day. The potential 
score range is 0 to 18, where lower scores indicate less shortness of breath.  
 Tiredness domain: only one item contributes to this domain; the domain score is the 
item score for item 7. The potential score range is 0 to 4, where lower scores indicate 
less tiredness. 
 Cardiovascular Symptoms domain: this is the sum of the item scores for 
items 8-10. The potential score range is 0 to 12, where lower scores indicate less 
cardiovascular symptoms. 
 Total Score: the total score is an equally weighted sum of the three domains. It is 
calculated as the sum of the Shortness of Breath domain divided by 4 (as there are 
4 items in the domain), the Tiredness domain (1 item), and the Cardiovascular 
Symptoms Domain divided by 3 (as there are 3 items in the domain);  
ated as missing 
for that day.The potential score range is 0 to 12.5, where lower scores indicate less 
symptoms.