Clinical trial NCT03496168
Conditions: Hypertrophic Cardiomyopathy
Keywords: Symptomatic Obstructive Left ventricular outflow tract gradient
Sponsor: Bristol-Myers Squibb
Start date: 2018-04-26; Completion date: 2023-11-09
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter open-label study of the administration of mavacamten in participants with symptomatic obstructive HCM (oHCM) who previously participated in study MYK-461-004 (PIONEER-HCM).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: mavacamten
Intervention descriptions: intervention 1: mavacamten capsules

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
An Open-label Extension Study of Mavacamten (MYK-461) in Adults 
with Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously 
Enrolled in Study MYK-461-004 (PIONEER-HCM) 
 
NCT Number: NCT03496168 
Document Date (Date in which document was last revised): 27 October 2021 
 
 
 


Mavacamten (MYK-461): Protocol 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
MYK-461-008 
Protocol Title: 
AN OPEN-LABEL EXTENSION STUDY OF MAVACAMTEN 
(MYK-461) IN ADULTS WITH SYMPTOMATIC OBSTRUCTIVE 
HYPERTROPHIC CARDIOMYOPATHY PREVIOUSLY 
ENROLLED IN STUDY MYK-461-004 (PIONEER-HCM) 
Indication: 
Hypertrophic Cardiomyopathy 
Phase: 
2 
Investigational 
Medicinal Product: 
Mavacamten (MYK-461) 
Sponsor: 
MyoKardia, Inc. 
1000 Sierra Point Parkway 
Brisbane, CA 94005 
USA 
Key Sponsor Contacts: 
 
Medical Monitor 
 
 
 
 
Clinical Trial Lead 
 
  
Original Protocol Date 
12 January 2018 
Amendment 1 
03 April 2018 
Amendment 2 
11 April 2019 
Amendment 3 
22 January 2021 
Amendment 4 
27 October 2021 
Confidentiality Statement 
This document contains trade secrets or otherwise confidential and/or proprietary information of MyoKardia, 
Inc. Access to and use of this information is strictly limited and controlled by MyoKardia, Inc. Acceptance of 
this document constitutes agreement by the recipient that the contents will be not be copied, distributed, or 
otherwise disclosed to third parties, and will not be used in any way, except as expressly authorized by 
MyoKardia, Inc. 
 
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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES TABLE 
Protocol Amendment 4: 27 October 2021 
Overall Rationale for the Amendment 
The primary objectives of this amendment were to: 
• Align the protocol language with updates to the Investigator’s Brochure (IB) Ed 8.1 
• Add an additional telehealth visit at Week 222 
Changes are summarized in the table below.  
Summary of Changes 
Additional changes were made to add clarity, consistency in terminology, and accuracy 
throughout the document. 
Summary of Change  
Reason for Change 
Section(s) 
Home health assessments were removed 
and direct-to-participant delivery of 
mavacamten was retained 
Home health assessments removed 
due to stabilization of COVID-19 
pandemic 
Global 
 
Medical Monitor 
 
 
Email address updated 
Title Page 
 
Clinical Trial Lead 
 
 
 added as a Key Sponsor 
Contact 
Title Page 
Added telehealth assessment to Week 222 Administrative error - this was missed 
in protocol amendment 3 
Synopsis, 
Table 3, 
Study Schema 
Participants must use highly effective 
birth control from 43 months after last 
dose of investigational medicinal product 
Align with IB Ed 8.1 
Synopsis, 
Section 5.2., 
Section 8.2.2., 
Section 8.2.3. 
The following abbreviations were deleted: 
ECHO = echocardiogram  
ID = identification 
MAD = multiple ascending dose 
SAD = single ascending dose 
These abbreviations are not used in 
the body of protocol amendment 4 
List of Abbreviations 
Updated information on completed and 
ongoing studies with mavacamten and 
number of participants enrolled 
Align with IB Ed 8.1 
Section 1.2. 
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Summary of Change  
Reason for Change 
Section(s) 
Updated text describing clinical benefits 
and known risks of mavacamten 
Align with IB Ed 8.1 
Section 1.3. 
Updated Study Schema to include 
telehealth visit at Week 222 and Early 
Termination 
To align with Table 3 
Study Schema 
Deleted IMP Compliance for Week 222 
Week 222 is now a telehealth visit 
Table 3 
Updated text on symptomatic overdose 
Align with IB Ed 8.1 
Section 7.6. 
Added term dizziness as a likely risk of 
mavacamten use 
Align with IB Ed 8.1 
Section 8.1. 
Updated so participants will report 
pregnancies any time from first dose to 
43 months after last dose of mavacamten 
Align with IB Ed 8.1 
Section 8.2.3. 
Participants must abstain from blood or 
plasma donation for 34 months after the 
final study visit 
Align with data on long terminal 
elimination half-life of mavacamten in 
IB Ed 8.1 
Section 9.4. 
 
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PROTOCOL SYNOPSIS 
Title 
An Open-label Extension Study of Mavacamten (MYK-461) in Adults 
with Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously 
Enrolled in Study MYK-461-004 (PIONEER-HCM) 
Study Number 
MYK-461-008 
Study Phase 
2 
Number of Centers 
Up to 5 sites in the United States 
Primary Objective 
To assess the long-term safety and tolerability of mavacamten in 
individuals with symptomatic obstructive hypertrophic cardiomyopathy 
(oHCM) 
Secondary Objectives 
To assess in individuals with symptomatic oHCM the long-term effects of 
mavacamten on: 
• 
Left ventricular outflow tract (LVOT) obstruction 
• 
Functional capacity 
• 
oHCM symptoms 
Pharmacokinetic 
Objective 
To perform population pharmacokinetics (PK) analyses in individuals 
with symptomatic oHCM receiving mavacamten 
Study Design 
This is a Phase 2, open-label, multicenter study of adults with 
symptomatic oHCM who completed Study MYK-461-004 
(PIONEER-HCM). 
Participants in this study will be screened to ensure they continue to meet 
eligibility criteria. Participants are allowed to stay on background therapy 
with either beta blockers or calcium channel blockers. 
Background cardiomyopathy therapy (eg, beta-blocker, verapamil, or 
diltiazem) may be adjusted or stopped after a participant has received 
24 weeks of mavacamten treatment in this study as determined by the 
Investigator in conjunction with the MyoKardia Medical Monitor. 
Once enrolled into Study MYK-461-008, participants will undergo 
baseline assessments and receive mavacamten once daily (QD) for a 
duration of up to approximately 5 years or until mavacamten becomes 
commercially available (at the discretion of MyoKardia). 
Target dosing will be individualized for each participant based on his or 
her PK data obtained in the MYK-461-004 study. Specifically, the Target 
Dose for each participant will be individualized to obtain a steady-state 
trough plasma concentration of approximately 250 ng/mL to 500 ng/mL, 
based on PK modeling. 
The starting dose will be 5 mg for all participants. Participants will return 
at Week 4 (± 4 days) for a plasma PK sample to measure drug levels and 
to undergo echocardiography to determine LVOT gradient (at rest, after a 
Valsalva maneuver, and after exercise) and left ventricular ejection 
fraction (LVEF). Participants will return at Week 6 (± 7 days) for 
evaluation of Week 4 results and dose adjustment to Target Dose. 
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Dose adjustment may also take place beyond Week 6 based on results of 
transthoracic echocardiogram (TTE), stress echocardiography and/or PK 
evaluation and based upon the opinion of the Investigator in conjunction 
with the MyoKardia Medical Monitor. 
A stress echocardiogram will be administered at Week 48 and Week 72 to 
evaluate the post-exercise LVOT gradient and to determine whether 
further dose adjustment may be needed. If the post-exercise LVOT 
gradient is measured ≥ 50 mmHg, further dose adjustment may be 
considered and discussed with the MyoKardia Medical Monitor. 
Dose adjustments beyond the Target Dose may only be exceeded for each 
given participant following discussion between the Investigator and the 
MyoKardia Medical Monitor. Lower doses are permissible. 
The dose will not be increased if one or more of the following criteria are 
met: 
• 
LVEF is < 55%, and/or 
• 
LVOT gradient is < 30 mmHg after exercise, and/or 
• 
Trough mavacamten plasma concentration is > 350 ng/mL, 
and/or 
• 
A dose increase is not warranted in the clinical judgment of the 
Investigator 
Dose Reduction Rule: The dose may be reduced or discontinued in the 
case of an exaggerated pharmacologic effect at any time during the study 
based on the clinical judgment of the Investigator. 
Participants who have had a dose adjustment (either in mavacamten or 
background cardiomyopathy therapy) should return to the clinic 
approximately 28 days later (± 7 days) for an unscheduled visit with 
resting TTE to confirm safety. Repeat of post-exercise echocardiographic 
assessment of LVOT gradient will be at the Investigator’s discretion. 
Based on results and clinical symptoms at follow-up visits, subsequent 
dose adjustments will be discussed with the MyoKardia Medical Monitor. 
Temporary Discontinuation: If results as reported by the central 
laboratories from any visit show mavacamten plasma concentration is 
≥ 1000 ng/mL, or LVEF < 50% (as read by site), or Fridericia-corrected 
QT interval (QTcF) meets the following criteria, the participant will be 
notified by the study site/Investigator for further instructions. 
• 
If QRS is narrow (< 120 milliseconds), then temporary 
discontinuation criteria are the smaller of: 15% increase from 
baseline QTcF OR QTcF ≥ 520 milliseconds 
• 
If QRS is wide (≥ 120 milliseconds), then temporary 
discontinuation criteria are the smaller of: a 15% increase from 
baseline QTcF OR QTcF ≥ 550 milliseconds 
If the participant is taking 5, 10, or 15 mg, study drug will be temporarily 
discontinued and he or she will return for an unscheduled visit (with 
electrocardiogram [ECG] and TTE assessments) 2 to 4 weeks later. 
If LVEF ≥ 55% (as read by site) and QTcF < 500 milliseconds at the 
unscheduled visit, then the study drug will be restarted at a lower dose as 
shown below (previous dose → restart dose): 
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• 
5 mg → resume 5 mg 
• 
10 mg → 5 mg 
• 
15 mg → 10 mg 
Participants on 5 mg who have been temporarily discontinued on 
treatment based on clinical evaluation can be considered for dose 
reintroduction at 5 mg following agreement between the Investigator and 
the MyoKardia Medical Monitor. 
If LVEF, plasma drug concentration, and/or QTcF persist out of range at 
the follow-up visit, then the participant will be discontinued from the 
study. 
Participants who prematurely discontinue from the PIONEER-OLE study 
may be considered for rescreening for participation. 
After Week 6, additional study visits will occur at Week 8 (± 7 days), 
Week 12 (± 7 days), and every 12 weeks (± 7 days) thereafter. 
Participants also will be contacted by phone in between clinic visits, at 
Week 18 and every 12 weeks thereafter. An end of study (EOS) visit will 
occur 8 weeks (± 7 days) after the last administration of study drug. Visits 
(including the Screening visit which serves as the baseline) will entail 
recording vital signs, targeted physical examination, ECGs, safety 
laboratory tests, N-terminal pro B-type natriuretic peptide (NT-proBNP), 
adverse events (AEs), New York Heart Association (NYHA) functional 
class, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and 
concomitant medications. Predose blood samples for assessment of drug 
concentration will be obtained at the time points indicated in the Schedule 
of Assessments. A standard TTE (including but not limited to assessment 
of LVOT gradient at rest and after Valsalva) will be performed at baseline 
and at the time points indicated in the Schedule of Assessments. In 
addition, a stress echocardiogram (with assessment of LVOT gradient 
post-exercise) will also be performed at baseline and at the time points 
indicated in the Schedule of Assessments. 
For females of childbearing potential, pregnancy testing will be 
performed in clinic or at home every 4 weeks. 
Participants will be followed through completion of EOS procedures. All 
AEs, including serious adverse events (SAEs), will be collected from the 
time of informed consent through the duration of the study, up to and 
including the Week 260/EOS visit. If there is a significant clinical 
abnormality or clinically significant laboratory abnormality in need of 
monitoring, the participant will be followed until resolution of the 
abnormality or until it is considered stable in the opinion of the 
Investigator. 
End of Study (Week 260)  
Participants who prematurely discontinue the study will attend an early 
termination visit and return to the study site 8 weeks later for an EOS 
visit.  
Participants who complete 252 weeks of mavacamten treatment and do 
not rollover onto commercially available mavacamten will attend an end 
of treatment visit and return to the study site 8 weeks later for an EOS 
visit.  
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Participants who rollover onto commercially available mavacamten at any 
time will be contacted 8 weeks later by telephone or other technology for 
an EOS follow-up to assess AEs, concomitant medications, and 
pregnancy. 
Telehealth Assessments 
Telehealth assessments (conducted via telephone or other technology 
based on standard at institution) will be conducted at Weeks 18, 30, 42, 
54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 
234, and 246 to assess AEs, concomitant medications, and pregnancy.  
Number of Participants 
Up to 20 individuals with symptomatic oHCM will be enrolled. 
Study Treatment 
Participants will receive mavacamten immediate-release capsules 5, 10, 
or 15 mg administered QD. The starting dose will be 5 mg for all 
participants. 
Each participant has had a Target Dose determined based on his or her 
PK data from Study MYK-461-004. These doses may only be exceeded 
for each given participant following discussion between the Investigator 
and the MyoKardia Medical Monitor. Lower doses are permissible. 
The Investigator, in conjunction with the Medical Monitor, may also elect 
to dose reduce a participant after they are on a stable dose of 10 mg or 
15 mg treatment for 24 weeks or longer. Participants that have been dose 
reduced will undergo a follow-up visit 4 to 8 weeks (± 7 days) later (to 
mirror Week 8 assessments, including a TTE assessment). Based on 
results and clinical symptoms at follow-up visits, subsequent dose 
decisions will be discussed with the MyoKardia Medical Monitor. This 
cycle of potential dose reduction and follow-up can be repeated more than 
once (after at least 24 weeks on a stable dose of 10 mg or 15 mg 
treatment) and will need to be discussed with the MyoKardia Medical 
Monitor each time before it is carried out. 
Study Duration 
The study duration is 264 weeks (up to 4 weeks Screening, 252 weeks 
treatment [5 years], and 8 weeks posttreatment follow-up) unless the 
development of mavacamten is stopped or until mavacamten becomes 
commercially available (at the discretion of MyoKardia). If mavacamten 
clinical development is discontinued, this study will be terminated. The 
EOS is defined as the date of the last observation of the last participant. 
Inclusion Criteria 
Each participant must meet the following criteria to be included in this 
study: 
1. Has completed Study MYK-461-004. Prior participation in a 
non-interventional observational study is allowed. 
2. Able to understand and comply with the study procedures, 
understand the risks involved in the study, and provide written 
informed consent according to federal, local, and institutional 
guidelines before the first study-specific procedure 
3. Body weight > 45 kg at Screening 
4. Has safety laboratory parameters (chemistry and hematology) 
within normal limits (according to the central laboratory 
reference range) at Screening; however, a participant with safety 
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laboratory parameters outside normal limits may be included if he 
or she meets all of the following criteria: 
• The safety laboratory parameter outside normal limits is 
considered by the Investigator to be clinically unimportant 
• If there is an alanine aminotransferase or aspartate 
aminotransferase result, the value must be < 3 × the upper 
limit of the laboratory reference range 
• The body size–adjusted estimated glomerular filtration rate is 
≥ 30 mL/min/1.73 m2 
5. Female participants must not be pregnant or lactating and, if 
sexually active, must use one of the following highly effective 
birth control methods from the Screening visit through 4 months 
after the last dose of investigational medicinal product. 
• combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation or 
progestogen-only hormonal contraception associated with 
inhibition of ovulation by oral, implantable, or injectable route 
of administration 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal occlusion 
• Female participant is surgically sterile for 6 months or 
postmenopausal for 1 year. Permanent sterilization includes 
hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy, and/or documented bilateral tubal occlusion at 
least 6 months prior to Screening. Females are considered 
postmenopausal if they have had amenorrhea for at least 
1 year or more following cessation of all exogenous hormonal 
treatments and follicle-stimulating hormone levels are in the 
postmenopausal range. 
Male partners must also use a contraceptive (eg, barrier, condom, 
or vasectomy) 
Exclusion Criteria 
A participant who meets any of the following exclusion criteria may not 
participate in this study: 
1. Has QTcF > 500 milliseconds or any other ECG abnormality 
considered by the Investigator to pose a risk to participant safety 
(eg, second-degree atrioventricular block type II) 
2. Since enrollment into Study MYK-461-004, has developed 
obstructive coronary artery disease (> 70% stenosis in one or 
more arteries) or known moderate or severe aortic valve stenosis 
3. Since enrollment into Study MYK-461-004, has developed any 
acute or serious comorbid condition (eg, major infection or 
hematologic, renal, metabolic, gastrointestinal, or endocrine 
dysfunction) that, in the opinion of the Investigator or Medical 
Monitor, would pose a risk to participant safety or interfere with 
the study evaluation, procedures, or completion 
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4. Has a positive serologic test at Screening for infection with 
human immunodeficiency virus, hepatitis C virus, or hepatitis B 
virus 
5. Since enrollment into Study MYK-461-004, has developed 
clinically significant malignant disease 
6. Is taking prohibited concomitant medications; background 
therapy on beta blockers or calcium channel blockers is allowed 
as long as the participant has been on a stable dose for at least 
14 days prior to Screening 
7. Has evidence of current abuse of drugs or alcohol or a history of 
abuse that, in the Investigator's opinion, would cause the 
participant to be noncompliant or would otherwise increase the 
risk to the participant 
8. Is unable to comply with the study requirements, including the 
number of required visits to the clinical site. 
Endpoints 
Safety 
• 
Frequency and severity of treatment-emergent AEs and SAEs 
• 
Frequency of cardiovascular (CV) death 
• 
Frequency of sudden death 
• 
Frequency of CV hospitalization 
• 
Frequency of heart failure due to systolic dysfunction defined as a 
symptomatic LVEF < 50% 
• 
Frequency of myocardial infarction 
• 
Frequency of ventricular arrhythmias (ventricular tachycardia, 
ventricular fibrillation, ventricular flutter, torsade de pointe) 
• 
Frequency of syncope 
• 
Frequency of seizures 
• 
Frequency of stroke 
• 
Frequency of LVEF < 50% as measured by echocardiography 
• 
QT and QTcF intervals over time 
Efficacy and pharmacodynamics 
• 
Post-exercise, post-Valsalva, and resting LVOT gradient over 
time 
• 
NYHA functional class over time 
• 
KCCQ scores over time 
• 
NT-proBNP over time 
• 
Frequency of septal reduction therapy 
Pharmacokinetics 
• 
Mavacamten plasma concentration over time 
• 
Population PK 
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Sample Size and 
Statistical 
Considerations 
No statistical hypothesis testing will be performed. Data will be 
summarized in tabular format, and concentration response plots may be 
constructed for selected variables. The sparse PK data will be combined 
with that of other studies to construct a population PK model across all 
studies. 
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 participant management in these situations 
is outlined in Appendix 4. 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................2 
PROTOCOL SYNOPSIS.................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................15 
LIST OF FIGURES .......................................................................................................................15 
LIST OF ABBREVIATIONS ........................................................................................................16 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Background .................................................................................................................18 
1.2. 
Clinical Studies ...........................................................................................................18 
1.3. 
Known and Potential Benefits and Risks ....................................................................18 
2. 
RATIONALE FOR THE STUDY AND FOR DOSE AND DOSING 
SCHEDULE ...............................................................................................................19 
2.1. 
Rationale for the Study ...............................................................................................19 
2.2. 
Rationale for Dose and Dosing Schedule ...................................................................19 
3. 
STUDY OBJECTIVES ..............................................................................................21 
3.1. 
Primary Objective .......................................................................................................21 
3.2. 
Secondary Objectives .................................................................................................21 
3.3. 
Pharmacokinetic Objective .........................................................................................21 
4. 
OVERALL STUDY DESIGN AND PLAN ...............................................................21 
4.1. 
Study Duration ............................................................................................................25 
5. 
SELECTION AND WITHDRAWAL OF STUDY POPULATION .........................30 
5.1. 
General Study Population and Clinical Sites ..............................................................30 
5.2. 
Inclusion Criteria ........................................................................................................30 
5.3. 
Exclusion Criteria .......................................................................................................31 
5.4. 
Screening and Enrollment ...........................................................................................31 
5.5. 
Withdrawal of Participants .........................................................................................32 
5.5.1. 
Withdrawal from the Study ........................................................................................32 
5.5.2. 
Handling of Participants After Permanent Treatment Discontinuation ......................33 
6. 
RANDOMIZATION AND BLINDING PROCEDURES .........................................33 
6.1. 
Randomization ............................................................................................................33 
6.2. 
Study Blinding ............................................................................................................33 
7. 
STUDY TREATMENT ..............................................................................................33 
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7.1. 
Formulation, Packaging, and Labeling of Study Drug ...............................................33 
7.2. 
Administration and Schedule of Study Drug ..............................................................34 
7.3. 
Treatment Compliance ................................................................................................34 
7.4. 
Hepatotoxicity Stopping and Rechallenge Rules .......................................................34 
7.4.1. 
Criteria for Permanent Withholding of Mavacamten Due to Potential 
Hepatotoxicity .............................................................................................................34 
7.4.2. 
Criteria for Conditional Withholding of Mavacamten Due to Potential 
Hepatotoxicity .............................................................................................................35 
7.4.3. 
Criteria for Rechallenge of Mavacamten After Potential Hepatotoxicity ..................36 
7.5. 
Guidelines for the Management of Exaggerated Pharmacologic Effect 
(Systolic Dysfunction), Excessive QT Prolongation, or Higher Than 
Expected Plasma Concentration .................................................................................36 
7.6. 
Overdose .....................................................................................................................36 
7.6.1. 
Reporting and Follow-up of Overdose .......................................................................37 
7.7. 
Prior and Concomitant Treatment ..............................................................................37 
7.7.1. 
Prior Therapy ..............................................................................................................37 
7.7.2. 
Concomitant Therapy .................................................................................................37 
7.7.3. 
Prohibited Therapy .....................................................................................................37 
8. 
RISKS AND PRECAUTIONS ...................................................................................38 
8.1. 
General ........................................................................................................................38 
8.2. 
Pregnancy ...................................................................................................................38 
8.2.1. 
Avoidance of Pregnancy .............................................................................................38 
8.2.2. 
Acceptable Forms of Contraception ...........................................................................38 
8.2.3. 
Reporting and Follow-up of Pregnancies ...................................................................39 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................39 
9.1. 
Efficacy and Pharmacodynamic Assessments ............................................................39 
9.1.1. 
Echocardiography .......................................................................................................39 
9.1.1.1. 
Resting Transthoracic Echocardiography ...................................................................39 
9.1.1.2. 
Stress Echocardiography ............................................................................................39 
9.1.2. 
New York Heart Association Functional Class ..........................................................40 
9.1.3. 
Kansas City Cardiomyopathy Questionnaire ..............................................................40 
9.2. 
Pharmacokinetic Assessments ....................................................................................40 
9.2.1. 
Pharmacokinetic Assessments ....................................................................................40 
9.2.2. 
NT-proBNP .................................................................................................................40 
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9.3. 
Safety Assessments .....................................................................................................41 
9.3.1. 
Medical History ..........................................................................................................41 
9.3.2. 
Physical Examination .................................................................................................41 
9.3.3. 
12-lead ECG ...............................................................................................................41 
9.3.4. 
Vital Signs ..................................................................................................................41 
9.3.5. 
Other Safety Assessments ...........................................................................................42 
9.4. 
Participant Restrictions During this Study .................................................................42 
9.5. 
Study Procedures by Visit ..........................................................................................42 
9.6. 
Visit Scheduling ..........................................................................................................42 
10. 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS, SERIOUS ADVERSE EVENTS, AND ADVERSE EVENTS OF 
SPECIAL INTEREST ................................................................................................42 
10.1. 
Definitions of Pretreatment Adverse Events, Adverse Events, Serious 
Adverse Events, and Adverse Events of Special Interest ...........................................43 
10.1.1. 
Pretreatment Adverse Events ......................................................................................43 
10.1.2. 
Adverse Events ...........................................................................................................43 
10.1.3. 
Serious Adverse Event ................................................................................................44 
10.1.4. 
Adverse Events of Special Interest .............................................................................45 
10.2. 
Collection and Reporting of Adverse Events .............................................................45 
10.2.1. 
Pretreatment Adverse Events and Adverse Events Collection Periods ......................45 
10.2.2. 
Pretreatment Adverse Events and Adverse Events Reporting Periods .......................46 
10.2.2.1. 
Event description ........................................................................................................46 
10.2.2.2. 
Start Date/Time and Stop Date/Time .........................................................................46 
10.2.2.3. 
Relationship to Study Drug (Suspected Adverse Reactions) .....................................46 
10.2.2.4. 
Severity/Intensity ........................................................................................................47 
10.2.2.5. 
Seriousness .................................................................................................................47 
10.2.2.6. 
Outcome ......................................................................................................................47 
10.2.3. 
Reporting of Serious Adverse Events .........................................................................47 
10.2.4. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................47 
10.3. 
Suspected Unexpected Serious Adverse Event Reactions ..........................................48 
11. 
STATISTICAL METHODS .......................................................................................48 
11.1. 
Determination of Sample Size ....................................................................................48 
11.2. 
Study Endpoints ..........................................................................................................48 
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11.2.1. 
Safety Endpoints .........................................................................................................48 
11.2.2. 
Efficacy and Pharmacodynamic Endpoints ................................................................49 
11.2.3. 
Pharmacokinetic Endpoints ........................................................................................49 
11.3. 
Statistical Analysis ......................................................................................................49 
11.3.1. 
Analysis Populations ..................................................................................................49 
11.3.2. 
General Considerations ...............................................................................................49 
11.3.3. 
Participant Disposition ................................................................................................49 
11.3.4. 
Demographics and Baseline Characteristics ...............................................................49 
11.3.5. 
Extent of Study Treatment Exposure and Compliance ...............................................50 
11.3.6. 
Efficacy and Pharmacodynamic Analyses ..................................................................50 
11.3.7. 
Pharmacokinetic Analyses ..........................................................................................50 
11.3.8. 
Safety Analyses ..........................................................................................................50 
11.3.8.1. 
Adverse Events ...........................................................................................................50 
11.3.8.2. 
12-Lead Electrocardiogram ........................................................................................51 
11.3.8.3. 
Laboratory Data ..........................................................................................................52 
11.3.8.4. 
Vital Signs Data ..........................................................................................................53 
11.3.8.5. 
Other Safety Analyses ................................................................................................53 
11.3.9. 
Interim Analyses .........................................................................................................53 
11.3.10. 
Exploratory Analyses ..................................................................................................53 
12. 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS .............................53 
12.1. 
Compliance Statement ................................................................................................53 
12.2. 
Informed Consent .......................................................................................................53 
12.3. 
Ethics Committee ........................................................................................................54 
13. 
ADMINISTRATIVE PROCEDURES .......................................................................54 
13.1. 
Sponsor’s Responsibilities ..........................................................................................54 
13.1.1. 
Participant Confidentiality ..........................................................................................55 
13.1.2. 
Study Supplies ............................................................................................................55 
13.1.3. 
Investigator Training ..................................................................................................56 
13.1.4. 
Ongoing Communication of Safety Information During the Study ...........................56 
13.1.5. 
Study Monitoring ........................................................................................................56 
13.1.6. 
Study Auditing and Inspecting ...................................................................................56 
13.2. 
Investigator’s Responsibilities ....................................................................................56 
13.2.1. 
Screening Log .............................................................................................................56 
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13.2.2. 
Mavacamten Accountability .......................................................................................57 
13.2.3. 
Reporting and Recording of Study Data .....................................................................57 
13.2.4. 
Source Data and Source Documents ...........................................................................57 
13.2.5. 
Participant Identification Information ........................................................................58 
13.2.6. 
Records Retention .......................................................................................................58 
13.2.7. 
Protocol Deviations ....................................................................................................58 
13.2.8. 
Blood Sample Collection/Storage ...............................................................................58 
13.3. 
Clinical Trial Insurance ..............................................................................................59 
13.4. 
Protocol Amendments and Study Administrative Letters ..........................................59 
14. 
DATA QUALITY ASSURANCE ..............................................................................59 
15. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................59 
15.1. 
Use of Computerized Systems ....................................................................................59 
15.2. 
Study Records .............................................................................................................60 
16. 
PUBLICATION ..........................................................................................................60 
17. 
REFERENCE LIST ....................................................................................................62 
APPENDIX 1. LABORATORY ASSESSMENTS ....................................................................64 
APPENDIX 2. PROHIBITED MEDICATIONS ........................................................................65 
APPENDIX 3. POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING AND 
ADDITIONAL ASSESSMENTS REPORTING .......................................................66 
APPENDIX 4. MANAGEMENT OF PARTICIPANTS WHO ARE UNABLE TO 
ATTEND ONSITE STUDY VISITS FOR PROTOCOL-SPECIFIED 
ASSESSMENTS AND MAVACAMTEN DOSE ADJUSTMENTS (EG, 
COVID-19 OR OTHER PANDEMICS, NATURAL DISASTERS, OR 
MAJOR DISRUPTIONS) ..........................................................................................68 
APPENDIX 5. INVESTIGATOR’S SIGNATURE....................................................................70 
 
LIST OF TABLES 
Table 1 
Individualized Target Doses .......................................................................................20 
Table 2 
Schedule of Assessments – Screening Through Year 2 .............................................26 
Table 3 
Schedule of Assessments – Year 3 Through End of Study ........................................28 
Table 4 
New York Heart Association Functional Classification of Heart Failure ..................40 
 
LIST OF FIGURES 
Figure 1 
Study Schema .............................................................................................................22 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
β-hCG 
beta−human chorionic gonadotropin 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CRF 
case report form 
CV 
cardiovascular 
CYP 
cytochrome 
DILI 
drug-induced liver injury 
EC 
ethics committee; refers to an IRB or IEC or equivalent 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCM 
hypertrophic cardiomyopathy 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
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IXRS 
interactive response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
LVOT 
left ventricular outflow tract 
MedDRA 
Medical Dictionary for Regulatory Activities 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
NYHA 
New York Heart Association 
oHCM 
obstructive hypertrophic cardiomyopathy 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
preferred term 
PTAE 
Pretreatment adverse event 
QD 
once daily 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reactions 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TTE 
transthoracic echocardiography, transthoracic echocardiogram 
ULN 
upper limit of normal 
US 
United States 
UV 
unscheduled visit 
Wk 
week 
 
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1. 
INTRODUCTION 
1.1. 
Background 
Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is defined 
clinically as unexplained left ventricular (LV) hypertrophy in the absence of known causes such 
as pressure overload, systemic diseases, or infiltrative processes (Gersh et al, 2011). 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 
participants 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 in participants with HCM. 
Mavacamten is a novel small molecule allosteric modulator of striated muscle myosin that 
selectively targets cardiac myosin and reversibly inhibits its binding to actin. Mavacamten’ s 
profile of myosin modulation is predicted to reduce dynamic left ventricular outflow tract 
(LVOT) obstruction in participants 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. 
In nonclinical studies, mavacamten was specific for striated muscle myosin and selective for the 
cardiac isoform (see the mavacamten Investigator’s Brochure [IB]). Its targeted mechanism of 
action and high degree of specificity were reflected in its pharmacology in vitro and in vivo, as 
well as in the toxicology and safety pharmacology. In a feline model of HCM with LVOT 
obstruction, treatment with mavacamten reduced contractility and relieved obstruction in an 
exposure-dependent manner (Stern et al, 2016). The totality of the pharmacodynamic (PD) and 
tolerability data observed to date can be interpreted as direct or indirect consequences of reduced 
cardiac contractility. 
Please refer to the mavacamten IB for more detailed information on mavacamten. 
1.2. 
Clinical Studies 
As of 30 October 2020, 15 clinical studies to investigate the safety and tolerability, efficacy, and 
pharmacokinetic (PK) profile of mavacamten have been completed. A total of 635 participants 
with HCM, healthy participants, or participants with hepatic impairment were enrolled across the 
completed studies, 464 of whom were exposed to at least 1 dose of mavacamten. Additionally, 
294 participants have been enrolled across 3 ongoing studies of mavacamten. The results of the 
completed studies, as well as a description of the design and participants of the ongoing studies, 
are described in the IB. 
1.3. 
Known and Potential Benefits and Risks 
In nonclinical studies, 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. Experiments with isolated adult rat ventricular myocytes in vitro and with anesthetized 
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rats in vivo have established that the pharmacological effects of mavacamten may be 
counteracted by positive inotropes (isoproterenol, dobutamine, or levosimendan). 
Of the 18 clinical studies of mavacamten to date, clinical study reports are available for 15 
studies. Overall, mavacamten appears well-tolerated with little evidence for off-target toxicity. In 
participants with oHCM, the clinical benefits of mavacamten treatment in the extension study 
(MAVA-LTE), which relies exclusively on clinical measures of cardiac function (including site-
read echocardiographic measures) and participants’ symptoms to guide dose titration, are 
consistent with the EXPLORER-HCM parent study, in which dose optimization was guided in 
part by plasma drug concentrations, specifically:  
• reduced LVOT gradients  
• improved New York Heart Association (NYHA) class  
• improved diastolic function  
• decreased left atrial volume index 
• reduced wall stress (as measured by N-terminal pro B-type natriuretic peptide 
[NT-proBNP])  
The known risks of mavacamten use from available nonclinical and/or clinical data to date 
include dizziness and cardiac failure due to systolic dysfunction (symptomatic left ventricular 
ejection fraction [LVEF] < 50%). Systolic heart failure is due to mavacamten’s exaggerated on-
target effect of reduction in cardiac contractility (ie, reduced LVEF). Potential risks of 
mavacamten use include embryofetal toxicity (observed in animal studies only), heart failure due 
to interaction with cytochrome (CYP) 2C19 and potent 3A4 inhibitors, and arrhythmia due to QT 
prolongation (observed in animal species and healthy volunteers). 
2. 
RATIONALE FOR THE STUDY AND FOR DOSE AND DOSING 
SCHEDULE 
2.1. 
Rationale for the Study 
This study is an open-label extension of Study MYK-461-004 (PIONEER-HCM) to assess long-
term safety, tolerability, and efficacy of mavacamten in participants with oHCM who had 
previously participated in the PIONEER-HCM study. 
MyoKardia has designed the current study to generate long-term data in participants with 
symptomatic oHCM, using an approach that conforms to established ethical standards of safe 
human experimentation and the requirements of Good Clinical Practice (GCP). 
2.2. 
Rationale for Dose and Dosing Schedule 
Given that the mavacamten PK parameters of each PIONEER-HCM participant are known based 
on mavacamten plasma concentration measurements taken during that study, an individualized 
mavacamten dose was computed for each participant (Table 1) to target a mavacamten plasma 
concentration of 250 to 500 ng/mL. These plasma concentration levels have generally been 
associated with a marked reduction in LVOT gradient, and they have been well-tolerated without 
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excessive reductions in LVEF. To maximize safety, the starting dose will be 5 mg for all 
participants. If applicable, a dose increase to the Target Dose will occur at Week 6 based on 
Week 4 determinations of LVOT gradient, LVEF, and mavacamten plasma concentration (see 
Section 4). 
Table 1 
Individualized Target Doses 
Participant Identification in Study MYK-461-004 
Target Dose (mg) 
10 
10 
5 
5 
10 
15 
5 
5 
10 
10 
10 
5 
5 
10 
15 
10 
15 
10 
10 
10 
 
For eligible participants, a dose increase beyond the Target Dose at a later time point beyond 
Week 6 may also be possible; the Investigator first should discuss this with and get approval 
from the MyoKardia Medical Monitor (see Section 4). 
At Week 48 and Week 72, a stress echocardiogram will be performed. If the post-exercise LVOT 
gradient is ≥ 50 mmHg, further dose adjustment may be considered and discussed with the 
MyoKardia Medical Monitor. If dose adjustment occurs at Week 24 or beyond, a follow-up visit 
should be scheduled 4 weeks later (± 7 days) to include a transthoracic echocardiography (TTE) 
assessment. 
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Dose adjustment may also take place beyond Week 6 based on results of TTE, stress 
echocardiography and/or PK evaluation, and based upon the opinion of the Investigator in 
conjunction with the MyoKardia Medical Monitor. 
The Investigator, in conjunction with the Medical Monitor, may also elect to dose reduce a 
participant after they are on a stable dose of 10 or 15 mg mavacamten for 24 weeks or longer. 
Participants that have been dose reduced will undergo a follow-up visit 4 to 8 weeks (± 7 days) 
later (to mirror Week 8 assessments, including a TTE assessment). Based on results and clinical 
symptoms at follow-up visits, subsequent dose decisions will be discussed with the MyoKardia 
Medical Monitor. This cycle of potential dose reduction and follow-up can be repeated more 
than once (after at least 24 weeks on a stable dose of 10 or 15 mg treatment) and will need to be 
discussed with the MyoKardia Medical Monitor each time before it is carried out. 
3. 
STUDY OBJECTIVES 
3.1. 
Primary Objective 
The primary objective of this study is: 
• To assess the long-term safety and tolerability of mavacamten in individuals with 
symptomatic oHCM 
3.2. 
Secondary Objectives 
The secondary objectives of this study are to assess in individuals with symptomatic oHCM the 
long-term effect of mavacamten on: 
• LVOT obstruction 
• Functional capacity 
• oHCM symptoms 
3.3. 
Pharmacokinetic Objective 
The PK objective of this study is: 
• To perform population PK analyses in individuals with symptomatic oHCM receiving 
mavacamten 
4. 
OVERALL STUDY DESIGN AND PLAN 
This is a Phase 2, open-label extension, multicenter study of individuals with symptomatic 
oHCM who completed Study MYK-461-004 (PIONEER-HCM). 
Participants in this study will be screened to ensure they continue to meet eligibility criteria. 
Participants are allowed to stay on background therapy with either beta blockers or calcium 
channel blockers provided they have been on a stable dose for at least 14 days prior to Screening. 
Once enrolled into Study MYK-461-008, participants will undergo baseline assessments and 
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receive mavacamten QD for a duration of up to approximately 5 years (Figure 1) or until 
mavacamten becomes commercially available (at the discretion of MyoKardia).  
The starting dose will be 5 mg. Participants will return at Week 4 for a plasma PK sample to 
measure drug levels and for an echocardiogram to determine LVOT gradient at rest and after 
exercise as well as to measure LVEF. If mavacamten clinical development is discontinued, this study 
will be terminated. The end of study (EOS) is defined as the date of the last observation of the last 
participant. 
Figure 1 
Study Schema 
  
 
 
Abbreviations: EOS, end of study; ET, early termination; EOT, end of treatment; NT-proBNP, N-terminal pro 
B-type natriuretic peptide; PK, pharmacokinetic blood sample taken; QD, once daily; TTE, transthoracic 
echocardiogram. 
Note: Dose reduction rule applies throughout. 
Note: For all females of childbearing potential, a pregnancy test will be taken every 4 weeks at home when no clinic 
visit is scheduled. 
a Dose adjustment to individual targeted dose: dose calculated to achieve mavacamten plasma concentration of  
250-500 ng/mL in each participant. Dose adjustment may also take place beyond Week 6 based on results of 
TTE/stress echocardiogram and PK evaluation and based upon the opinion of the Investigator in conjunction with 
the MyoKardia Medical Monitor. Dose adjustments beyond the previous Target Dose may only be exceeded for 
each given participant following discussion between the Investigator and the MyoKardia Medical Monitor. Lower 
doses are permissible. 
b Includes a stress TTE at Screening (Baseline), Weeks 4, 48, 72, 156, 204, 252/EOT, and 260/EOS. These are in 
addition to resting and post-Valsalva TTEs at all visits indicated with a vertical arrow. 
Dose adjustment may occur at Week 6 based on Week 4 assessments. Target dosing will be 
individualized for each participant based on his or her PK data obtained in the MYK-461-004 
study (Table 1). Specifically, the Target Dose for each participant is the dose associated with a 
steady-state trough plasma concentration of approximately 250 ng/mL to 500 ng/mL, and the 
Target Dose for a given participant may not exceed the dose (unless previously discussed 
between the Investigator and the MyoKardia Medical Monitor) as detailed in Table 1, although 
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lower doses are permissible. Participants will return at Week 6 for the results and dose 
adjustment. Note that at Week 4, the LVOT gradient will be measured at rest with Valsalva 
maneuver and post-exercise. If the LVOT gradient post-exercise is < 30 mmHg, then the dose 
will not be increased at Week 6. 
The dose may be increased at Week 6 to the Target Dose provided in Table 1 unless one or more 
of the following criteria are met at Week 4: 
• LVEF is < 55%, and/or 
• LVOT gradient is < 30 mmHg after exercise, and/or 
• Trough mavacamten plasma concentration is > 350 ng/mL, and/or 
• A dose increase is not warranted in the clinical judgment of the Investigator 
Note: if a participant is eligible for a dose increase at Week 6 but the dose is not increased due to 
Investigator judgment, a dose increase to the participant’s Target Dose at a later time point 
beyond Week 6 may be possible; the Investigator should first discuss this with and get approval 
from the MyoKardia Medical Monitor. 
For eligible participants, a dose increase beyond the Target Dose at a later time point beyond 
Week 6 may also be possible; the Investigator first should discuss this with and get approval 
from the MyoKardia Medical Monitor. 
If one or more of the above 4 criteria are present, no dose increase will occur. Also, a dose 
decrease or discontinuation may be instituted at Week 6 or at any other visit according to the 
dose reduction rule described below. 
Participants who have had a dose adjustment (either in mavacamten or background 
cardiomyopathy therapy) should return to the clinic approximately 28 days later (± 7 days) for an 
unscheduled visit with resting TTE to confirm safety. Repeat of post-exercise echocardiographic 
assessment of LVOT gradient will be at the Investigator’s discretion. Based on results and 
clinical symptoms at follow-up visits, subsequent dose adjustments will be discussed with the 
MyoKardia Medical Monitor. 
Dose Reduction Rule: The dose may be reduced or discontinued in the case of an exaggerated 
pharmacologic effect at any time during the study based on the clinical judgment of the Investigator. 
If results as reported by the central laboratories from any visit show mavacamten plasma 
concentration is ≥ 1000 ng/mL, or LVEF < 50% (as read by site), or Fridericia-corrected QT 
interval (QTcF) meets the following criteria, the participant will be notified by the study 
site/Investigator with further instructions: 
• If QRS is narrow (< 120 milliseconds), then temporary discontinuation criteria are the 
smaller of: 15% increase from baseline QTcF OR QTcF ≥ 520 milliseconds 
• If QRS is wide (≥ 120 milliseconds), then temporary discontinuation criteria are the 
smaller of: a 15% increase from baseline QTcF OR QTcF ≥ 550 milliseconds 
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Dosing with study drug will be immediately stopped and the following procedures implemented: 
• If the participant is taking 5, 10, or 15 mg, study drug will be temporarily 
discontinued and he or she will return for an unscheduled visit (with 
electrocardiogram [ECG] and TTE assessments) 2 to 4 weeks later 
• If LVEF ≥ 55% (as read by site) and QTcF < 500 milliseconds at the unscheduled 
visit, then the study drug will be restarted at a lower dose, as shown below (previous 
dose → restart dose): 
− 5 mg → resume 5 mg 
− 10 mg → 5 mg 
− 15 mg → 10 mg 
Participants on 5 mg who have been temporarily discontinued on treatment based on clinical 
evaluation can be considered for dose reintroduction at 5 mg following agreement between the 
Investigator and the MyoKardia Medical Monitor. 
If LVEF (as read by site), plasma drug concentration, and/or QTcF persist out of range at the 
follow-up visit, then the participant will be discontinued from the study. 
The Investigator, in conjunction with the Medical Monitor, may also elect to dose reduce a 
participant after they are on a stable dose of 10 or 15 mg mavacamten for 24 weeks or longer. 
Participants that have been dose reduced will undergo a follow-up visit 4 to 8 weeks (± 7 days) 
later (to mirror Week 8 assessments, including a TTE assessment). Based on results and clinical 
symptoms at follow-up visits, subsequent dose decisions will be discussed with the MyoKardia 
Medical Monitor. This cycle of potential dose reduction and follow-up can be repeated more 
than once (after at least 24 weeks on a stable dose of 10 or 15 mg treatment) and will need to be 
discussed with the MyoKardia Medical Monitor each time before it is carried out. 
After Week 6, additional clinic visits will occur at Week 8 (± 7 days), Week 12 (± 7 days), and 
every 12 weeks (± 7 days) thereafter. Between clinic visits, participants will also be contacted by 
phone at Week 18 and every 12 weeks thereafter. An EOS visit will occur 8 weeks (± 7 days) 
after the last administration of study drug. Visits will entail recording vital signs, targeted 
physical examination, ECG, safety laboratory tests, NT-proBNP, adverse events (AEs), NYHA 
functional class, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and concomitant 
medications, as detailed in Table 2 and Table 3. Predose blood samples for assessment of drug 
concentrations will be performed at the visits indicated in Table 2 and Table 3. Resting and post-
Valsalva TTEs and stress TTEs to determine post-exercise LVOT gradient will be performed at 
baseline and post-baseline, as indicated in Table 2 and Table 3. For females of childbearing 
potential, pregnancy testing will be performed in the clinic or at home every 4 weeks. 
Participants will be followed through completion of EOS procedures. All AEs, including SAEs, 
will be collected from the time of informed consent through the duration of the study, up to and 
including the EOS visit. If there is a significant clinical abnormality or clinically significant 
laboratory abnormality in need of monitoring, the participant will be followed until resolution of 
the abnormality or until it is considered stable in the opinion of the Investigator. 
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 
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for scheduled assessments and dispensation of mavacamten. Guidance on participant 
management in these situations is outlined in Appendix 4. 
4.1. 
Study Duration 
The expected study duration is approximately 264 weeks: up to 4 weeks for Screening, a 
252-week (5-year) treatment period, and an 8-week posttreatment follow-up period, or until 
mavacamten becomes commercially available. If mavacamten clinical development is 
discontinued, this study will be terminated. The EOS is defined as the date of the last observation 
of the last participant. 
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Table 2 
Schedule of Assessments – Screening Through Year 2 
 
Year 1 
Year 2 
Assessmenta 
Screening 
Days -28 
to -1 
Day 
1 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
12 
Wk 
18 
Wk 
24 
Wk 
30 
Wk 
36 
Wk 
42 
 
Wk 
48 
Wk 
54 
Wk 
60 
Wk 
66 
Wk 
72 
Wk 
78 
Wk 
84 
Wk 
90 
Wk 
96 
Wk 
102 
Telehealth Visitb 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
AEs/SAEe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationf 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ECGg 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Resting TTEh 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Stress TTEh 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Mavacamten 5 mg daily 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose adjustment up to targeti 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP compliance checkj 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hepatitis panel and HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samplek 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
Chemistry 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
Hematology 
X 
 
X 
 
` 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
NT-proBNPl 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
FSHm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (β-hCG)n 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NYHA class, KCCQ 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Abbreviations: β-hCG, beta−human chorionic gonadotropin; AE, adverse event; BP, blood pressure; ECG, electrocardiogram; eCRF, electronic case report form; 
FSH, follicle-stimulating hormone; HCM, hypertrophic cardiomyopathy; HIV, human immunodeficiency virus; IMP, investigational medical product; KCCQ, 
Kansas City Cardiomyopathy Questionnaire; LVOT, left ventricular outflow tract; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York 
Heart Association; PK, pharmacokinetic(s); SAE, serious adverse event; TTE, transthoracic echocardiography; Wk, week. 
Note: The Week 4 visit has a visit window of ± 4 days; all remaining visits have a window of ± 7 days. 
 
 
 
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Table 2 
Schedule of Assessments – Screening Through Year 2 (Continued) 
a At the Investigator’s discretion, unscheduled visits may be conducted at the investigational site for the assessment of AEs, physical examinations, vital signs, 
laboratory tests, drug dispensing, ECGs, and/or TTEs (see Table 3). Unscheduled safety assessments will be conducted for participants who temporarily 
discontinue study drug prior to resuming dosing, as outlined in Appendix 4. Study drug will be dispensed at the unscheduled visit; however, participants will 
not resume dosing until notified by the study site. All information collected from unscheduled visits will be recorded on the eCRF and included in the clinical 
database. 
b Assessments as part of telehealth visits are to be conducted via telephone or other technology based on standard at institution. 
c A complete medical history will be recorded at the Screening visit, which will include evaluation (past or present) of the following: general, head and neck, 
eyes, ears, nose, throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, gynecological/urogenital, musculoskeletal/extremities, skin, 
neurological/psychiatric, endocrine/metabolic, hematologic/lymphatic, allergies/drug sensitivities, past surgeries, substance abuse, or any other diseases or 
disorders as well as participation in clinical studies (study medication and/or device or other therapy). Specific history related to a participant’s HCM diagnosis 
will also be collected. 
d Vital signs will be taken in the sitting position prior to dosing and will include heart rate and BP after resting for at least 5 minutes. BP should be taken via an 
automated recorder. Respiratory rate will be obtained at Screening after resting for at least 5 minutes. Temperature will be obtained at Day 1.  
e Any changes in baseline conditions that occur after the informed consent form is signed, but prior to the first dose of IMP, are recorded on the medical history 
eCRF, unless the change is related to a study procedure, in which case it is considered an AE. All changes that occur after administration of the first dose of 
IMP and meet the definition of an AE are recorded as AEs. 
f At Screening, a complete physical examination will be conducted, including a neurological examination (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, cardiovascular, 
neurological, and respiratory systems. At all other onsite visits, an abbreviated cardiopulmonary physical examination will be conducted, with other systems 
assessed as directed by interval history; weight will also be recorded at all physical examinations. 
g A 12-lead ECG will be performed after 10 minutes of rest. On Day 1, ECG will be performed predose. 
h Instantaneous peak LVOT gradient (baseline) and provoked peak LVOT gradient (Valsalva maneuver) will be assessed. Ejection fraction (2-dimensional), left 
ventricular fractional shortening, global longitudinal strain by speckle tracking, and velocity timing interval will be analyzed. Resting TTE should be performed 
prior to stress echocardiography. All stress echocardiograms should include a 4-hour fast prior to exercise. If the post-exercise LVOT gradient is measured 
≥ 50 mmHg, further dose adjustment may be considered and discussed with the MyoKardia Medical Monitor. If dose adjustment occurs at Week 24 or beyond, 
a follow-up visit (to mirror Week 8 assessments) should be scheduled 4 weeks later (± 7 days) to include a TTE assessment. All stress echocardiography visits 
will be conducted in the clinic. 
i Dose adjustment is optional. Dose adjustments beyond the Target Dose may only be exceeded for each given participant following discussion between the 
Investigator and the MyoKardia Medical Monitor. Lower doses are permissible. 
j Compliance with study drug will be monitored by capsule count at each clinic visit. 
k A blood sample will be collected prior to dosing for assessment of trough study drug plasma concentrations. On days of visits, participants should not take their 
daily dose prior to visit. Study drug will be administered on site to facilitate collection of this sample. 
l The blood draw for NT-proBNP will occur prior to stress echocardiography. 
m FSH testing at Screening for postmenopausal females to confirm postmenopausal status. 
n Pregnancy test (serum or urine) for females of childbearing potential, based on standard at institution. A urine pregnancy test is performed at home every 
4 weeks when no clinic visit is scheduled. 
 
 
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Table 3 
Schedule of Assessments – Year 3 Through End of Study 
 
Year 3 
Year 4 
Year 5 
 
Assessment 
Wk 
108a 
Wk 
114 
Wk 
120a 
Wk 
126 
Wk 
132a 
Wk 
138 
Wk 
144a 
Wk 
150 
Wk 
156a 
Wk 
162 
Wk 
174 
Wk 
180a 
Wk 
186 
Wk 
198 
Wk 
204a 
Wk 
210 
Wk 
222 
Wk 
228 
Wk  
234 
Wk  
246 
Wk 
252 
EOT/ 
ETa,b 
Wk 
260/ 
EOSa,c UVd 
Telehealth Visite 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Vital signsf 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
AEs/SAEsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationh 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
ECGi 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Resting TTEj 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Stress TTEj 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose adjustment up to 
targetk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP compliance checkl 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
PK samplem 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Chemistry 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Hematology 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
NT-proBNPn 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Pregnancy test 
(β-hCG)o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NYHA class, KCCQ 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Abbreviations: β-hCG, beta−human chorionic gonadotropin; AE, adverse event; BP, blood pressure; ECG, electrocardiogram; eCRF, electronic case report form; 
EOS, end of study; EOT, end of treatment; ET, early termination; IMP, investigational medical product; KCCQ, Kansas City Cardiomyopathy Questionnaire; 
LVOT, left ventricular outflow tract; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; PK, pharmacokinetic; 
SAE, serious adverse event; TTE, transthoracic echocardiography; UV, unscheduled visit; Wk, week. 
Note: The Week 4 visit has a visit window of ± 4 days; all remaining visits from Week 6 to Week 260/EOS have visit windows of ± 7 days. 
a Stress TTE assessment must be performed at site. 
b  Participants who prematurely discontinue the study will attend an ET visit and return to the study site 8 weeks later for an EOS visit. 
 
 
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Table 3 
Schedule of Assessments – Year 3 Through End of Study (Continued) 
c Participants who complete 252 weeks of mavacamten treatment and do not rollover onto commercially available mavacamten will attend an EOT visit and 
return to the study site 8 weeks later for an EOS visit. Participants who rollover onto commercially available mavacamten at any time will be contacted 8 weeks 
later by telephone or other technology for an EOS follow-up to assess AEs, concomitant medications, and pregnancy. 
d At the Investigator’s discretion, unscheduled visits may be conducted at the investigational site for the assessment of AEs, physical examinations, vital signs, 
laboratory tests, drug dispensing, ECGs, and/or TTEs. Unscheduled safety assessments will be conducted for participants who temporarily discontinue study 
drug prior to resuming dosing, as outlined in Appendix 4. Study drug will be dispensed at the unscheduled visit; however, participants will not resume dosing 
until notified by the study site. All information collected from unscheduled visits will be recorded on the eCRF and included in the clinical database. 
e Assessments as part of telehealth visits are to be conducted via telephone or other technology based on standard at institution. 
f Vital signs will be taken in the sitting position prior to dosing and will include heart rate and BP after resting for at least 5 minutes. BP should be taken via an 
automated recorder. Respiratory rate will be obtained at the Week 260/EOS visit after resting for at least 5 minutes. Temperature will be obtained at the 
Week 260/EOS visit. 
g  Any changes in baseline conditions that occur after the informed consent form is signed, but prior to the first dose of study medication, are recorded on the 
medical history eCRF, unless the change is related to a study procedure, in which case it is considered an AE. All changes that occur after administration of the 
first dose of study medication and meet the definition of an AE are recorded as AEs. 
h At the visits indicated, an abbreviated cardiopulmonary physical examination will be conducted, with other systems assessed as directed by interval history; 
weight will also be recorded at all physical examinations. 
i A 12-lead ECG will be performed after 10 minutes of rest. 
j Instantaneous peak LVOT gradient (baseline) and provoked peak LVOT gradient (Valsalva maneuver) will be assessed. Ejection fraction (2-dimensional), left 
ventricular fractional shortening, global longitudinal strain by speckle tracking, and velocity timing interval will be analyzed. Resting TTE should be performed 
prior to stress echocardiography. All stress echocardiograms should include a 4-hour fast prior to exercise. If the post-exercise LVOT gradient is measured 
≥ 50 mmHg, further dose adjustment may be considered and discussed with the MyoKardia Medical Monitor. If dose adjustment occurs after Week 24, a 
follow-up visit (to mirror Week 8 (Table 2) assessments) should be scheduled 4 weeks later (± 7 days) to include a TTE assessment. All stress 
echocardiography visits will be conducted in the clinic. 
k Dose adjustment is optional. Dose adjustments beyond the Target Dose may only be exceeded for each given participant following discussion between the 
Investigator and the MyoKardia Medical Monitor. Lower doses are permissible. 
l Compliance with study drug will be monitored by capsule count at each clinic visit. 
m A blood sample will be collected prior to dosing for assessment of trough study drug plasma concentrations. Study drug should be administered on site to 
facilitate collection of this sample. 
n The blood draw for NT-proBNP will occur prior to stress echocardiography. 
o Pregnancy test (serum or urine) for females of childbearing potential, based on standard at institution. A urine pregnancy test is performed at home every 
4 weeks when no clinic visit is scheduled. 
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5. 
SELECTION AND WITHDRAWAL OF STUDY POPULATION 
5.1. 
General Study Population and Clinical Sites 
Up to approximately 20 participants with symptomatic oHCM are expected to enroll in this study 
at up to 5 clinical sites in the United States (US). 
5.2. 
Inclusion Criteria 
Each participant must meet the following criteria to be enrolled in this study. 
1. Has completed Study MYK-461-004. Prior participation in a non-interventional 
observational study is allowed 
2. Able to understand and comply with the study procedures, understand the risks involved 
with participating in the study, and provide written informed consent according to 
federal, local, and institutional guidelines before the first study-specific procedure 
3. Body weight > 45 kg at Screening 
4. Has safety laboratory parameters (chemistry and hematology) within normal limits 
(according to the central laboratory reference range) at Screening; however, a participant 
with safety laboratory parameters outside normal limits may be included if he or she 
meets all of the following criteria: 
• The safety laboratory parameter outside normal limits is considered by the 
Investigator to be clinically unimportant 
• If there is an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
result, the value must be < 3 × the upper limit of the laboratory reference range 
• The body size–adjusted estimated glomerular filtration rate is ≥ 30 mL/min/1.73 m2 
5. Female participants must not be pregnant or lactating and, if sexually active, must use 
one of the following highly effective birth control methods from the Screening visit 
through 4 months after the last dose of investigational medicinal product (IMP). 
• combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation or progestogen-only hormonal contraception associated 
with inhibition of ovulation by oral, implantable, or injectable route of administration 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
• Female participant is surgically sterile for 6 months or postmenopausal for 1 year. 
Permanent sterilization includes hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy, and/or documented bilateral tubal occlusion at least 6 months prior to 
Screening. Females are considered postmenopausal if they have had amenorrhea for 
at least 1 year or more following cessation of all exogenous hormonal treatments and 
follicle-stimulating hormone (FSH) levels are in the postmenopausal range. 
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Male partners must also use a contraceptive (eg, barrier, condom, or vasectomy). 
5.3. 
Exclusion Criteria 
A participant who meets any of the following criteria will be excluded from the study. 
1. Has QTcF > 500 milliseconds or any other ECG abnormality considered by the 
Investigator to pose a risk to participant safety (eg, second-degree atrioventricular block 
type II) 
2. Since enrollment into Study MYK-461-004, has developed obstructive coronary artery 
disease (> 70% stenosis in one or more arteries) or known moderate or severe aortic 
valve stenosis 
3. Since enrollment into Study MYK-461-004, has developed any acute or serious comorbid 
condition (eg, major infection or hematologic, renal, metabolic, gastrointestinal, or 
endocrine dysfunction) that, in the opinion of the Investigator or Medical Monitor, would 
pose a risk to participant safety or interfere with the study evaluation, procedures, or 
completion 
4. Has a positive serologic test at Screening for infection with human immunodeficiency 
virus, hepatitis C virus, or hepatitis B virus 
5. Since enrollment into Study MYK-461-004 has developed clinically significant 
malignant disease 
6. Is taking prohibited concomitant medications (see Section 7.7.3); background therapy on 
beta blockers or calcium channel blockers is allowed as long as the participant has been 
on a stable dose for at least 14 days prior to Screening 
7. Has evidence of current abuse of drugs or alcohol or a history of abuse that, in the 
Investigator's opinion, would cause the participant to be noncompliant or would 
otherwise increase the risk to the participant 
8. Is unable to comply with the study requirements, including the number of required visits 
to the clinical site 
5.4. 
Screening and Enrollment 
Eligible individuals who completed Study MYK-461-004 may be enrolled. An informed consent 
form (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 Study MYK-461-004. Numbers do not include identifiable information. 
The identification number will be used to identify the participant throughout the study and 
should appear on all study-related documentation. Rescreening may be allowed at the discretion 
of the Investigator and the MyoKardia Medical Monitor. 
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5.5. 
Withdrawal of Participants 
5.5.1. 
Withdrawal from the Study 
The degree to which a study participant withdraws can vary. However, every effort should be 
made to collect important safety data if feasible and the study participant agrees. Study 
participants can: 
• Withdraw from treatment (permanent treatment discontinuation) and agree to 
participate in the early termination (ET) and EOS visits 
• Withdraw from treatment (permanent treatment discontinuation) and agree to 
participate in the ET visit 
• Withdraw from treatment (permanent treatment discontinuation) and all follow-up 
Participants may withdraw from the study before study completion if they decide to do so, at any 
time, for any reason. Withdrawal of consent for treatment (permanent treatment discontinuation) 
should be distinguished from withdrawal of consent for ongoing study participation with 
scheduled visits and from withdrawal of consent for non-participant contact follow-up (eg, 
medical records check). 
If possible, and prior to the withdrawal of consent for ongoing study participation, the 
participants will be assessed using the procedures normally planned for the ET visit. 
Participants who withdraw from the study should be explicitly asked about the reason and the 
contribution of any possible AE(s) that led to their decision, and all 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 electronic case 
report form (eCRF) and in the participant’s medical records when considered as confirmed. The 
date of the withdrawal and the reason should be documented. 
For participants who do not withdraw consent for ongoing study participation but fail to return to 
the site, the Investigator should make every effort to contact the participant (eg, contacting 
participant’s family or private physician, reviewing available registries or health care databases) 
and to determine the participant’s health status, particularly vital status. Attempts to contact such 
participants must be documented in the participant’s records (eg, number of attempts and dates 
of attempted telephone contact and receipt for sending a registered letter). 
Participants who have withdrawn from the study cannot be treated further in the study. Their 
study identification numbers must not be reused. 
Treatment Discontinuation 
The Investigator should discontinue a participant’s study treatment permanently for any of the 
following reasons: 
• Pregnancy 
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• Heart failure related to systolic dysfunction 
• Study termination 
• Study site termination by MyoKardia (eg, in the case of major, noncorrectable 
protocol deviations) 
• Undergoing septal reduction therapy 
• Participant withdrawal from treatment or withdrawal from study 
Study treatment will be discontinued in the case of exaggerated pharmacologic effect (systolic 
dysfunction), higher than expected plasma concentration, or excessive QT prolongation (see 
Section 7.5). 
In addition, study treatment may be temporarily discontinued in the case of an AE or SAE at the 
Investigator’s discretion if there is a safety concern. 
In all cases, the reason(s) for permanent treatment discontinuation or study withdrawal will be 
recorded in the source document and on the appropriate eCRF. 
5.5.2. 
Handling of Participants After Permanent Treatment Discontinuation 
After permanent discontinuation of treatment, participants will be followed according to the 
study procedures as specified in this protocol through the scheduled date of study completion, or 
through the recovery or stabilization of any AE to be followed as specified in this protocol, 
whichever comes last. 
After permanent discontinuation of treatment, the participants will be assessed using the 
procedures planned for the ET and EOS visits. 
6. 
RANDOMIZATION AND BLINDING PROCEDURES 
6.1. 
Randomization 
Participants will not be randomized to treatment in this study. 
6.2. 
Study Blinding 
Treatment will not be blinded in this study. 
7. 
STUDY TREATMENT 
All participants will receive mavacamten in an open-label manner. 
7.1. 
Formulation, Packaging, and Labeling of Study Drug 
Mavacamten presentation is size 2, blue opaque capsules printed with a yellow band on the body 
and black band on the cap. Each capsule contains white to off-white powder. The active capsules 
are supplied in 3 strengths: 5, 10, and 15 mg. 
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Mavacamten capsules have been manufactured according to current Good Manufacturing 
Practice (cGMP) regulations. They will be supplied in high-density polyethylene bottles with 
induction seals and child-resistant caps at 30 count per bottle. All study drug will be labeled 
according to applicable local regulatory guidelines. 
Mavacamten capsules must be stored at 2°C to 25°C (36°F to 77°F) in the packaging supplied by 
MyoKardia. Study medication at the investigational site will be stored in a secure area with 
access limited to authorized study personnel. 
7.2. 
Administration and Schedule of Study Drug 
Study drug will be supplied to participants in 30-count high-density polyethylene bottles that are 
appropriately labeled. The participants will be instructed to store their supply of study drug 
capsules and bottles in a cool, dry place. 
Participants will take study drug as directed by the 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 of water. If the dosing window is missed, the participant 
should not take study drug that day. Participants should never take 2 doses of study drug within 
an 8-hour period. At Week 4, dosing should occur in the clinic after a blood draw for a plasma 
PK sample. 
7.3. 
Treatment Compliance 
Compliance with study drug will be monitored by capsule count at each clinic visit (Table 2 and 
Table 3). 
7.4. 
Hepatotoxicity Stopping and Rechallenge Rules 
Participants with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin [TBL], or international normalized ratio) or signs/symptoms of hepatitis may 
meet the criteria for withholding study medication or other protocol-required therapies. 
Withholding is either permanent or conditional depending on the clinical circumstances 
discussed below (as specified in the US Food and Drug Administration Guidance for Industry: 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 2009). 
7.4.1. 
Criteria for Permanent Withholding of Mavacamten Due to Potential 
Hepatotoxicity 
Mavacamten should be discontinued permanently and the participant should be followed 
according to the recommendations in Appendix 3 for possible drug-induced liver injury (DILI) if 
all the criteria below are met: 
• TBL > 2 × upper limit of normal (ULN) or international normalized ratio > 1.5 
• AND increased AST or ALT if the baseline value was < ULN and AST or ALT 
elevation is > 3 × ULN 
• AND no other cause for the combination of laboratory abnormalities is immediately 
apparent. Important potential causes for abnormal AST/ALT or TBL values include, 
but are not limited to, the following: 
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− Obstructive gall bladder or bile duct disease 
− Viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella) 
− Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right-sided heart failure 
− Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or 
dietary supplements 
− Heritable disorders causing impaired glucuronidation (eg, Gilbert syndrome); 
α-1 antitrypsin deficiency 
− Autoimmune hepatitis 
− Nonalcoholic steatohepatitis or other fatty liver disease 
If an alternative cause for hepatotoxicity is identified or less stringent conditions developed than 
what is noted above, the Investigator will determine whether study drug and other protocol-
required therapies should be permanently or temporarily discontinued based on participant 
population and/or severity of the hepatotoxicity or event, as deemed appropriate for the safety of 
the participant. 
7.4.2. 
Criteria for Conditional Withholding of Mavacamten Due to Potential 
Hepatotoxicity 
For participants who do not meet the criteria for permanent withholding of study medication 
outlined above, mavacamten should be withheld if ANY of the following criteria are met, and 
the participant should be evaluated for DILI: 
• Elevation of either AST or ALT, regardless of baseline AST or ALT value, if: 
− > 8 × ULN at any time 
− > 5 × ULN and < 8 × ULN for ≥ 2 weeks 
− >5 × ULN and < 8 × ULN and unable to adhere to enhanced monitoring schedule 
• OR: clinical signs or symptoms that are, in the opinion of the Investigator, consistent 
with hepatitis (such as right upper quadrant pain/tenderness, fever, nausea, vomiting, 
jaundice, rash, or eosinophilia > 5%). If such signs or symptoms are coupled with 
ALT or AST elevations > 3 × ULN, study medication should be withheld 
• OR: TBL > 3 × ULN at any time 
• OR: ALP > 8 × ULN at any time 
Mavacamten should be withheld pending an investigation into alternative causes of DILI. If 
study medication is withheld, the participant should be followed according to recommendations 
in Appendix 3 for possible DILI. Rechallenge may be considered if an alternative cause, such as 
acute hepatitis B infection, is discovered and the laboratory abnormalities resolve to normal or 
baseline (Section 7.4.3). 
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7.4.3. 
Criteria for Rechallenge of Mavacamten After Potential Hepatotoxicity 
The decision to rechallenge the participant should be discussed and unanimously agreed upon by 
the Investigator and Sponsor. 
If signs or symptoms recur with rechallenge, then mavacamten will be permanently discontinued. 
Participants who clearly meet the criteria for permanent discontinuation (as described in 
Section 7.4.1) should never be rechallenged. 
7.5. 
Guidelines for the Management of Exaggerated Pharmacologic 
Effect (Systolic Dysfunction), Excessive QT Prolongation, or Higher 
Than Expected Plasma Concentration 
If results, as reported by the central laboratories from any visit, show mavacamten plasma 
concentration is ≥ 1000 ng/mL, or LVEF < 50% (as read by site), or QTcF meets the following 
criteria, the participant will be notified by the study site/Investigator for further instructions. 
• If QRS is narrow (< 120 milliseconds), then temporary discontinuation criteria are the 
smaller of: 15% increase from baseline QTcF OR QTcF ≥ 520 milliseconds. 
• If QRS is wide (≥ 120 milliseconds), then temporary discontinuation criteria are the 
smaller of: a 15% increase from baseline QTcF OR QTcF ≥ 550 milliseconds. 
It will be communicated to the Investigator and Sponsor that a stopping criterion has been met 
and the procedures outlined in Section 4 will be implemented. If a participant discontinues study 
drug permanently, the participant will be encouraged to undergo ET and EOS assessments. 
Any participant who experiences heart failure related to systolic dysfunction will be managed as 
per site-specific standard of care. 
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. Reporting and follow-up of overdose are described below in 
Section 7.6.1. 
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 contact 
the MyoKardia Medical Monitor, and no further study drug should be administered until further 
notice. 
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 ACCF/AHA Guideline for the Management of 
Heart Failure (Yancy et al, 2013) and in the 2016 ESC Guidelines for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure (Ponikowski et al, 2016) should be implemented. 
Based on its almost exclusive hepatic metabolism through the CYP 2C19 and CYP 3A4 
enzymes, avoidance of inhibitors of these enzymes (eg, omeprazole) is important and 
administration of inducers of CYP 2C19 and CYP 3A4 may be helpful. The efficacy of other 
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measures of elimination has not been established. Reintroduction of study drug must be approved 
by the MyoKardia Medical Monitor. 
7.6.1. 
Reporting and Follow-up of Overdose 
If a participant should experience an overdose, the Investigator will report the overdose within 
24 hours, even if there are no signs or symptoms associated with the overdose in the participant. 
Follow-up on the participant’s condition will be conducted. 
7.7. 
Prior and Concomitant Treatment 
7.7.1. 
Prior Therapy 
At the time of signing the ICF, participants will be asked about their medication history over the 
previous 30 days, including prescription and nonprescription medications, herbal medications, 
vitamins, and minerals. 
If participants have not taken any prohibited medications in the past 14 days they may proceed to 
Screening. Participants taking prohibited medications must discontinue treatment for 14 days 
before proceeding to the Screening assessments. 
7.7.2. 
Concomitant Therapy 
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 (eg, biopsy). Include start/stop dates, route, and indication. 
Background therapy with either beta blockers or calcium channel blockers is permitted if the 
dose has been stable for 4 weeks at the time of enrollment. 
Background cardiomyopathy therapy (eg, beta-blocker, verapamil, or diltiazem) may be adjusted 
or stopped after a participant has received 24 weeks of mavacamten treatment in this study as 
determined by the Investigator in conjunction with the MyoKardia Medical Monitor. 
The occurrence of concomitant diagnostic/surgical/therapeutic procedures and available details 
will also be documented on the appropriate eCRF. 
7.7.3. 
Prohibited Therapy 
Prior or concomitant treatment with cardiotoxic agents such as doxorubicin or similar is 
prohibited, as is prior or concomitant treatment with antiarrhythmic drugs with negative 
inotropic activity (eg, flecainide or propafenone). 
The use of disopyramide or ranolazine is prohibited from 14 days before Screening to EOS. 
Additional prohibited medications are listed in Appendix 2. 
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8. 
RISKS AND PRECAUTIONS 
8.1. 
General 
Based on nonclinical data and the available clinical data, the most likely risks are those 
associated with higher exposures potentially resulting in dizziness or an excessive decrease in 
LVEF. This could result in the development or worsening of signs or symptoms of systolic heart 
failure or reduced cardiac output. 
Safety testing in other mammalian species has demonstrated that dose-limiting toxicity is related 
to exaggerated pharmacologic effect and not to off-target adverse effects. For overdose, see 
Section 7.6. 
8.2. 
Pregnancy 
8.2.1. 
Avoidance of Pregnancy 
Females of childbearing potential must use appropriate methods of birth control as listed in 
Section 8.2.2. Females of nonchildbearing potential are defined as females 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. Females 
are considered postmenopausal if they have had amenorrhea for at least 1 year or more following 
cessation of all exogenous hormonal treatments and follicle-stimulating hormone levels are in the 
postmenopausal range. 
8.2.2. 
Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those that result in a low failure rate 
(< 1% per year) when used consistently and correctly. From the time of Screening through 
4 months after the last dose of study drug, female participants should practice true abstinence or 
use effective means of contraception as follows: 
• combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation or progestogen-only hormonal contraception associated 
with inhibition of ovulation by oral, implantable, or injectable route of administration 
• IUD 
• hormone-releasing IUS 
• bilateral tubal occlusion 
• Female participant 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 levels are in the postmenopausal range. 
Male partners must also use a contraceptive (eg, barrier, condom, or vasectomy). 
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8.2.3. 
Reporting and Follow-up of Pregnancies 
All pregnancies in female participants and female partners of male participants receiving at least 
1 dose of study drug will be reported if they occur anytime from first dose to 4 months after the 
last dose of study drug. The Investigator is responsible for informing MyoKardia within 24 hours 
of knowledge of the pregnancy, even if no AE has occurred, per the reporting guidelines in 
Section 10.1.4 . 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. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
The Investigator is responsible for ensuring that all staff involved in the study are familiar and 
comply with the content of this section. 
The following describes the study procedures to be performed during the study. Additional 
details are provided in Table 2. When several assessments are to be conducted at the same time 
point, the preferred order of assessments is ECG, vital signs, PK, and then TTE. The order of 
assessments may vary slightly at specific time points (eg, 1-hour postdose) to facilitate the most 
contemporaneous performance of the required assessments. Unscheduled or additional safety 
assessments may be performed if necessary in the opinion of the Investigator. 
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 and Pharmacodynamic Assessments 
9.1.1. 
Echocardiography 
Details are provided in the Study Reference Manual. Echocardiography should be performed 
prior to dosing. Echocardiograms will be site-read and not blinded to the Investigator or the site. 
All echocardiography data will be sent to the interactive response system (IXRS) for LVEF 
stopping criterion (LVEF < 50% by local site-read). Echocardiograms will also be sent to a 
central imaging laboratory for possible future assessment. If necessary, contrast may be 
administered to ensure that high quality echocardiogram images are obtained. 
9.1.1.1. 
Resting Transthoracic Echocardiography 
Resting TTE will be assessed throughout the study, as indicated in Table 2 and Table 3. 
Instantaneous peak LVOT gradient at rest and provoked peak LVOT gradient (Valsalva 
maneuver) will be assessed. LVEF and other parameters will be obtained (see Study Reference 
Manual). 
Resting TTE should be performed prior to stress echocardiography. 
9.1.1.2. 
Stress Echocardiography 
Participants will undergo a standard symptom-limited exercise test (stress echocardiography), 
after a 4-hour fast, at the visits indicated in Table 2 and Table 3. The instantaneous peak LVOT 
gradient will be assessed immediately post-exercise by TTE. Any concomitant medication or 
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standard therapies for the treatment of HCM should be taken, as prescribed, on the day of the 
exercise test. 
9.1.2. 
New York Heart Association Functional Class 
The NYHA Functional Classification of heart failure assigns participants to 1 of 4 categories 
based on the participant’s symptoms (Table 4). Heart failure classification will be assessed at 
every clinical site study visit indicated in Table 2. 
Table 4 
New York Heart Association Functional Classification of Heart Failure 
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. 
Source: American Heart Association’s Classes of Heart Failure, 2015. 
9.1.3. 
Kansas City Cardiomyopathy Questionnaire 
The KCCQ is a self-administered 23-item questionnaire that quantifies physical limitation, 
symptoms, quality of life (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 
clinical summary score 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. The KCCQ will be administered to participants as indicated in Table 2. 
9.2. 
Pharmacokinetic Assessments 
9.2.1. 
Pharmacokinetic Assessments 
Blood samples will be collected for mavacamten plasma concentration assessments throughout 
the treatment period as indicated in Table 2. At all time points, a blood draw for drug 
concentration must be obtained prior to dosing. 
9.2.2. 
NT-proBNP 
Blood samples will be collected for NT-proBNP concentrations throughout the study, as 
indicated in Table 2 and Table 3. Unscheduled or additional blood samples may be collected if 
appropriate in the opinion of the Investigator and/or Sponsor. At all visits in which a stress 
echocardiography is performed, the blood draw for NT-proBNP will occur prior to stress 
echocardiography. 
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9.3. 
Safety Assessments 
Safety will be assessed throughout the study. Safety assessments include medical history, 
physical examinations, ECGs, vital signs, observed and participant-reported AEs, and safety 
laboratory results. Any abnormal findings judged by the Investigator to be clinically important 
will be recorded as an AE. 
9.3.1. 
Medical History 
A complete medical history will be recorded at the Screening visit, which will include evaluation 
(past or present) of the following: general, head and neck, eyes, ears, nose, throat, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, gynecological/urogenital, 
musculoskeletal/extremities, skin, neurological/psychiatric, endocrine/metabolic, 
hematologic/lymphatic, allergies/drug sensitivities, past surgeries, substance abuse, or any other 
diseases or disorders as well as participation in clinical studies (study medication and/or device 
or other therapy). Specific history related to a participant’s HCM diagnosis will also be collected. 
9.3.2. 
Physical Examination 
At the Screening visit, a complete physical examination will be conducted including a 
neurological examination (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, cardiovascular, neurological, and respiratory systems. At all 
other visits, an abbreviated cardiopulmonary physical examination will be conducted, with other 
systems assessed as directed by interval history; weight will also be recorded. 
Height (cm) and body weight (kg) will be measured at Screening, and body mass index (kg/m2) 
will be calculated. Participants will be required to remove their shoes and wear clothing as 
specified by the clinical site. Weight will also be collected at all subsequent onsite visits. 
9.3.3. 
12-lead ECG 
Twelve-lead ECG evaluations will be performed after 10 minutes of rest throughout the study, as 
indicated in Table 2 and Table 3. All ECG data will be sent to a central cardiac laboratory. 
On Day 1, ECG will be performed predose. At all other visits, ECGs may be obtained at any time. 
The Investigator will judge the overall interpretation as normal or abnormal with clinical 
significance. The Investigator will review the ECG and correlate abnormal findings with any 
other clinical findings, participant’s medical history, and laboratory data to determine the clinical 
importance of the finding. 
The Investigator may add extra 12-lead ECG safety assessments if there are any abnormal 
findings or if the Investigator considers it is required for any other safety reason. These 
assessments should be recorded as an unscheduled assessment. 
9.3.4. 
Vital Signs 
Vital signs are to be assessed throughout the study as indicated in Table 2, including 
temperature, heart rate (HR), respiratory rate, and blood pressure (BP) after resting for at least 
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5 minutes. Vital signs will be obtained with the participant in the same position; BP will be taken 
via an automated recorder. 
Vital signs will be taken prior to dosing. Refer to the Study Reference Manual for additional details. 
9.3.5. 
Other Safety Assessments 
Refer to Section 10 for information on AE assessment and Section 7.7.2 for concomitant therapy 
assessments. 
Safety laboratory results will be assessed in an ongoing manner. A central safety laboratory will 
be used. Laboratory parameters are provided in Appendix 1. 
9.4. 
Participant Restrictions During this Study 
The following restrictions apply for the specified times during the study period. If a participant 
does not comply with these restrictions or tests positive in any laboratory tests (eg, pregnancy), 
he or she may be excluded or withdrawn from the study. 
• Starting at Screening, participants will be required to abstain from blood or plasma 
donation until 4 months after the final study visit 
• Starting on Day 1 until the final follow-up visit, participants will be asked to abstain 
from grapefruit or grapefruit juice, Seville oranges, and quinine (eg, tonic water) 
• Contraception requirements are discussed in Section 8.2 
9.5. 
Study Procedures by Visit 
Study procedures are presented by visit in Table 2 and Table 3. Every effort should be made to 
avoid protocol deviations. 
At the Investigator’s discretion, unscheduled visits may be conducted for the assessment of AEs, 
physical examinations, vital signs, laboratory tests, drug dispensing, ECGs, and/or TTEs. All 
information collected from unscheduled visits will be recorded on the eCRF and included in the 
clinical database. 
9.6. 
Visit Scheduling 
All visits should occur within the visit window (± 4 days for Week 4; ± 7 days for all remaining 
visits from Week 6 to Week 260/EOS). If an evaluation is missed, reschedule and perform it as 
close as possible to the original date. 
10. 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS, SERIOUS ADVERSE EVENTS, AND ADVERSE 
EVENTS OF SPECIAL INTEREST 
Safety assessments will consist of monitoring and recording of AEs, including SAEs and adverse 
events of special interest (AESIs), performing protocol-specified safety laboratory assessments, 
measuring protocol-specified vital signs, and conducting other protocol-specified tests that are 
deemed critical to the safety evaluation of the study. 
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Hospitalization or procedural intervention for endpoint events (myectomy, septal ablation) will 
not be captured as SAEs, but will be recorded on specialized eCRFs. 
10.1. 
Definitions of Pretreatment Adverse Events, Adverse Events, Serious 
Adverse Events, and Adverse Events of Special Interest 
10.1.1. 
Pretreatment Adverse Events 
A pretreatment adverse event (PTAE) is an AE that occurs in a participant who has signed 
informed consent to participate in a study but has not received any study drug. A PTAE may 
result from a protocol-mandated procedure (eg, phlebotomy, invasive procedure, such as biopsy) 
but does not necessarily have to have a causal relationship with study participation. 
10.1.2. 
Adverse Events 
• According to the International Council for Harmonisation (ICH) guideline for GCP, 
an AE is defined as any untoward medical occurrence in a clinical investigation 
participant administered a pharmaceutical product; it does not necessarily have to 
have a causal relationship with this treatment. 
• An AE can therefore be any unfavorable and unintended sign (eg, tachycardia, 
enlarged liver, clinically important or abnormal laboratory finding), symptom 
(eg, nausea, chest pain), or evidence of disease activity temporally associated with the 
use of a study medication, whether or not related to the study medication.  
• Each AE should be recorded as a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should not be recorded as 
additional AEs. If a diagnosis is unknown, signs or symptoms should be recorded 
appropriately as a PTAE or AE.  
• Any new disease or exacerbation of an existing disease (eg, a worsening in the character, 
frequency, or severity of a known condition) is an AE except as described below: 
− Preexisting medical conditions (present at the time of signing of informed 
consent) are considered concurrent medical conditions and should not be recorded 
as PTAEs or AEs. However, if the participant experiences a worsening or 
complication of such a concurrent condition, the worsening or complication 
should be recorded appropriately as a PTAE (worsening or complication occurs 
before the first dose of study drug) or an AE (worsening or complication occurs 
after the first dose of study drug). Investigators should ensure that the event term 
recorded captures the change in the condition (eg, “worsening of ….”). 
• Recurrence of an intermittent medical condition (eg, headache) not present prior to 
the first dose of study drug 
• Any deterioration in a laboratory value or other clinical test (eg, ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
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The following additional points should be considered for PTAEs and AEs: 
• Preplanned medical or surgeries or procedures  
− Preplanned surgeries or procedures that were scheduled prior to signing of 
informed consent are not considered PTAEs or AEs. However, if a planned 
procedure is performed early (eg, as an emergency) due to worsening of a 
preexisting condition, the worsening of the condition should be captured 
appropriately as a PTAE or 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 PTAEs or 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 PTAEs and AEs. 
• Insufficient clinical response (lack of efficacy) 
− Insufficient clinical response, lack of efficacy, or pharmacologic action should not 
be recorded as an AE. The Investigator must make the distinction between 
exacerbation of preexisting medical condition and lack of therapeutic efficacy.  
• Overdose 
− Cases of overdose with any medication without manifested side effects are not 
considered PTAEs or AEs.  
The following should not be recorded as PTAEs or AEs: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the disease/disorder being studied, unless judged 
by the Investigator to be more severe than expected for the participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of a preexisting disease or condition present or 
detected at the start of the study that do not worsen 
10.1.3. 
Serious Adverse Event 
An SAE is defined as any untoward medical occurrence at any dose that:  
• Results in death 
• Is immediately life-threatening (places the participant at immediate risk of death from 
the event as it occurred) 
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• Requires inpatient 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 any of 
the outcomes listed above 
PTAEs that fulfill any of the criteria above are also to be considered SAEs and should be reported 
and followed up in the same manner. 
• The terms "severe" and "serious" are not synonymous. Severity refers to the intensity 
of an AE (eg, rated as mild, moderate, or severe); the event itself may be of relatively 
minor medical significance (such as severe headache without any further findings). 
• 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. 
• Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
• SAEs are required to be reported by the Investigator to the Sponsor within 24 hours 
after learning of the event. 
10.1.4. 
Adverse Events of Special Interest 
Symptomatic overdose, outcomes of a pregnancy, and LVEF ≤ 30% are considered AESIs.  
AESIs are required to be reported by the Investigator to the Sponsor within 24 hours, irrespective 
of regulatory seriousness criteria.  
10.2. 
Collection and Reporting of Adverse Events  
10.2.1. 
Pretreatment Adverse Events and Adverse Events Collection Periods 
Collection of PTAEs will commence from the time the participant signs the informed consent to 
participate in the study and continue until the participant receives the first dose of study drug. 
For participants who discontinue prior to study drug administration, PTAEs are collected until 
the participant discontinues study participation. 
Collection of treatment-emergent adverse events (TEAEs) (as defined in Section 10.1.2) will 
commence at the time the participant receives the first dose of study drug. Routine collection of 
TEAEs will continue until the end of the study. Assessments of the relationship of AEs to study 
drug will be captured for TEAEs and not PTAEs. 
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10.2.2. 
Pretreatment Adverse Events and Adverse Events Reporting Periods 
At each study visit, the Investigator will assess whether any subjective AEs have occurred. 
A neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Participants may report AEs occurring at any other time during the study.  
All participants experiencing PTAEs or TEAEs, whether considered associated with the use of 
the study drug or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to screening levels or until there is a satisfactory 
explanation for the changes observed. All PTAEs and TEAEs will be documented in the 
PTAE/AE page of the eCRF, whether or not the Investigator concluded that the event was related 
to the study drug. The information to be documented for each event is described in the following 
sections.  
10.2.2.1. Event description 
When collecting PTAEs and TEAEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms (eg, anemia, not low hemoglobin). However, if a 
diagnosis is known and there are other signs or symptoms that are not generally part of the 
diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
Death is an outcome and not the name of the event. In this situation, the event that led to the 
death is the name of the event.  
10.2.2.2. Start Date/Time and Stop Date/Time 
The date (and time during the period of residency) that the PTAE or TEAE started and the date 
(and time during the period of residency) that the event ended will be recorded. For events that 
continue for long periods of time, recording the end date as the day the event stabilized will be 
acceptable. 
10.2.2.3. Relationship to Study Drug (Suspected Adverse Reactions) 
The Investigator will assess causality by answering either “related” or “not related” 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 
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10.2.2.4. Severity/Intensity 
The intensity or severity of the PTAE or TEAE will be recorded using the following guidance: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
• Life-threatening (urgent intervention indicated) 
• Fatal (event led to death) 
10.2.2.5. Seriousness 
A PTAE or TEAE that meets any of the criteria for an SAE outlined in Section 10.1.3 will be 
recorded as an SAE, along with the criteria that were met.  
It is important to distinguish between seriousness (PTAE or AE compared with SAE) and 
severity/intensity (mild, moderate, severe, life-threatening, or fatal) of AEs as outlined in 
Section 10.2.2.4. 
10.2.2.6. Outcome 
The outcome of a PTAE or TEAE will be recorded according to the options provided on the eCRF. 
10.2.3. 
Reporting of Serious Adverse Events  
All SAEs occurring during the treatment-emergent period (defined as the period from the first 
dose of study drug to the last dose of study drug + 56 days), regardless of causality, will be 
reported by the Investigator or designee to MyoKardia/designee within 24 hours of knowledge of 
the event or sequelae. Deaths and SAEs occurring after the treatment-emergent period and 
considered related to study drug or study procedure must also be reported. SAE reporting 
instructions are provided in the Study Reference Manual. 
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 updating the SAE eCRF with this 
information.  
MyoKardia retains the right to request additional information for any participant with any 
ongoing AEs/SAEs at the end of the study, if judged necessary. 
Spontaneously reported SAEs after completion of the study should be promptly reported by the 
Investigator to the Sponsor. 
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. 
10.2.4. 
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 
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resolution, stabilization, the event is otherwise explained, or the participant is considered lost to 
follow-up at the end of the study. 
10.3. 
Suspected Unexpected Serious Adverse Event Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that qualify for mandatory 
expedited reporting to regulatory authorities where the SAE is suspected to be caused by the 
study treatment and is considered unexpected (ie, not defined as expected in the current IB, 
clinical protocol, or approved labeling for marketed products). In this case, MyoKardia or its 
designee will report the SUSAR to the relevant regulatory authority(ies). A report describing the 
SUSAR will be sent to all Investigators. Each Investigator must then notify his/her ethics 
committee (EC) of the SUSAR, as required by local regulatory authorities and in accordance 
with their EC policy. 
11. 
STATISTICAL METHODS 
11.1. 
Determination of Sample Size 
No statistical hypothesis testing will be performed in this long-term extension study. Up to 
20 individuals with symptomatic oHCM who completed Study MYK-461-004 will be enrolled. 
11.2. 
Study Endpoints 
11.2.1. 
Safety Endpoints 
• Frequency and severity of treatment-emergent AEs and SAEs 
• Frequency of cardiovascular (CV) death 
• Frequency of sudden death 
• Frequency of CV hospitalization 
• Frequency of heart failure due to systolic dysfunction, defined as a symptomatic 
LVEF < 50% 
• Frequency of myocardial infarction 
• Frequency of ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation, 
ventricular flutter, torsade de pointe) 
• Frequency of syncope 
• Frequency of seizures 
• Frequency of stroke 
• Frequency of LVEF < 50% as measured by echocardiography 
• QT and QTcF intervals over time 
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11.2.2. 
Efficacy and Pharmacodynamic Endpoints 
• Post-exercise, post-Valsalva, and resting LVOT gradient over time 
• NYHA functional class over time 
• KCCQ scores over time 
• NT-proBNP over time 
• Frequency of septal reduction therapy 
11.2.3. 
Pharmacokinetic Endpoints 
• Mavacamten plasma concentration over time 
• Population PK 
11.3. 
Statistical Analysis 
The analyses presented here represent an outline of the intended methodology. 
11.3.1. 
Analysis Populations 
Three analysis populations are defined in this study: 
• Safety Analysis Population: all participants who receive at least 1 dose of study drug 
• PK Analysis Population: all participants who receive at least 1 dose of study drug and 
have at least 1 evaluable mavacamten plasma drug concentration 
• PK/PD Analysis Population: all participants who receive at least 1 dose of study drug, 
have at least 1 evaluable mavacamten plasma drug concentration, and have 
post-baseline PD data; at least one 1 post-baseline PD data point must coincide 
temporally with an evaluable mavacamten plasma drug concentration 
11.3.2. 
General Considerations 
Data will be summarized in tabular format and concentration response plots may be constructed 
for selected variables. The sparse PK data will be combined with that of other studies to 
construct a population PK model across all studies. 
Descriptive summary statistics for continuous variables will include the number of participants, 
mean, standard deviation (SD) or standard error, median, minimum, and maximum. Nominal 
categorical variables will be summarized using counts and percentages. Ordinal variables may be 
tabulated but no formal statistical test will be conducted. 
11.3.3. 
Participant Disposition 
The number and percentage of participants who complete and discontinue, as well as reasons for 
early discontinuation, will be presented. 
11.3.4. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
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11.3.5. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
The duration of study drug exposure is defined as last dose date – first dose date + 1 day, 
regardless of intermittent discontinuations. 
A given administration will be considered noncompliant if the participant did not take the 
planned dose of treatment as required by the protocol. No imputation will be performed for 
participants with missing or incomplete data. 
Treatment compliance will be summarized descriptively (number [n], mean, SD, median, 
minimum, and maximum). Participants with compliance < 80% will be fully described and 
summarized. In addition, number and percentage of participants with at least 1 dosing 
administration will be given. 
11.3.6. 
Efficacy and Pharmacodynamic Analyses 
All efficacy and PD analyses will be performed on the safety population. 
11.3.7. 
Pharmacokinetic Analyses 
Plasma concentrations of mavacamten will be determined and summarized using descriptive 
statistics. In addition, a PK analysis, as well as PK/PD analysis, will be performed using 
nonlinear mixed effect modeling. Both analyses will be reported in separate reports. Data from 
previously conducted studies might be added for model development for PK and PK/PD. 
11.3.8. 
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 
• For quantitative safety parameters based on central laboratory measurements, 
descriptive statistics will be used to summarize results and change from baseline 
values by visit and treatment group; said changes may be presented in shift tables or 
scattergrams 
• The analysis of the safety variables will be descriptive, and no hypothesis testing is 
planned 
The safety analysis will focus on the treatment-emergent period, which is defined as the time 
from the first administration of study drug to the last administration of study drug + 56 days. 
11.3.8.1. Adverse Events 
AEs will be mapped to system organ classes (SOCs) 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 
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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 (n) and percentage (%) of participants 
experiencing at least 1 TEAE by SOC and PT. Multiple occurrences of the same event in the 
same participant will be counted only once in the tables. The denominator for computation of 
percentages is the safety population within each treatment group. 
AE incidence tables will be provided by treatment group for all types of TEAEs: all TEAEs, all 
treatment-emergent SAEs, and all TEAEs leading to permanent treatment discontinuation. 
Potential Drug-induced Liver Injury 
The incidence of liver-related AEs will be summarized by treatment group. The selection of PTs 
will be based on standardized MedDRA query hepatic disorder. 
Deaths 
• Deaths will be summarized and listed. 
Pregnancy 
• Participants who became pregnant during the study will be listed. 
Overdose 
• Onstudy overdoses will be listed. 
11.3.8.2. 12-Lead Electrocardiogram 
Twelve-lead ECGs will be obtained in the resting supine position. The RR, PR, QRS, and QT 
intervals will be measured and read by a central laboratory. Heart rate will be calculated as 
60/(RR × 1000) (with RR expressed in milliseconds) and rounded to the nearest integer. 
Correction for Heart Rate 
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. Each 
individual ECG QT value will be corrected for HR. The measured QT data will be corrected for 
HR using QTcF, as per the following formulae/method (with QT, RR, and QTc expressed in 
milliseconds): 
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. 
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Categorical Analysis 
The incidence count and percentage of participants with any postdose QTcF values of 
> 450 milliseconds, > 480 milliseconds, and > 500 milliseconds will be tabulated for all 
participants. Participants with QTc values > 500 milliseconds 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 milliseconds and > 60 milliseconds will 
be tabulated. 
Morphology Findings 
New ECG morphologies for each participant not present on any ECG at baseline for that 
participant will be summarized for all observation time points combined. 
The number and percentage of participants having T-wave morphology changes and/or the 
occurrence of abnormal U-waves that represent the appearance or worsening of the morphological 
abnormality from baseline will be reported. 
Concentration-QTc Analyses 
A concentration-QTc regression analysis, based on data collected from the ECG recordings after 
drug administration and concentration values for each participant at each matching time point, 
will be performed. The concentration-ECG relationship will be first evaluated by some 
descriptive plots to investigate any potential delayed or sustained effects and explore the shape of 
the relationship. Then, linear or nonlinear models will be implemented to estimate the slope and 
95% confidence intervals of the relationship. Predictions at selected concentration values will be 
computed within the model. 
11.3.8.3. Laboratory Data 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
laboratory variables (laboratory values and changes from baseline) may be calculated for each 
visit (baseline and post-baseline time points) and presented by treatment group. 
Listings of participants with laboratory values that are out of the reference range will be 
produced. Shift tables reflecting changes from baseline may be presented in lieu of descriptive 
statistics of changes from baseline. 
Potential Drug-induced Liver Injury 
The liver function tests, namely ALT, AST, ALP, and TBL, are used to assess possible 
drug-induced liver toxicity. 
A graph of distribution of peak values of ALT versus peak values of TBL will be presented. Note 
that the ALT and TBL values are presented on a logarithmic scale. The graph will be divided 
into 4 quadrants with a vertical line corresponding to 3 × ULN for ALT and a horizontal line 
corresponding to 2 × ULN for TBL. 
The normalization (to ≤ 1 × ULN or return to baseline if baseline > ULN) of elevated liver 
function tests will be summarized by categories of elevation (3 × ULN, 5 × ULN, 10 × ULN, 
20 × ULN for ALT and AST, 1.5 × ULN for ALP, and 1.5 × ULN and 2 × ULN for TBL), with 
the following categories of normalization: never normalized or normalized after permanent 
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discontinuation of study drug. Note that a participant will be counted only under the maximum 
elevation category (1-3 × ULN, 3-5 × ULN, 5-10 × ULN, 10-20 × ULN, > 20 × ULN). 
11.3.8.4. Vital Signs Data 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
vital signs’ variables (values and changes from baseline) may be calculated for each visit 
(baseline and post-baseline time points) and presented by treatment group. 
Shift tables reflecting changes from baseline may be presented in lieu of descriptive statistics of 
changes from baseline. 
11.3.8.5. Other Safety Analyses 
Abnormal physical examination results will be listed. Concomitant medications will be 
summarized. 
11.3.9. 
Interim Analyses 
Interim analyses may be conducted. No multiplicity adjustment will be done for these interim 
analyses. 
11.3.10. 
Exploratory Analyses 
Exploratory analyses may be performed. 
12. 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
12.1. 
Compliance Statement 
This study will be conducted in accordance with the ICH GCP guidelines; US Title 21 Code of 
Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312; European Union GCP; cGMP; the 
principles enunciated in the Declaration of Helsinki; and all human clinical research regulations 
in the countries where the study is to be conducted. 
12.2. 
Informed Consent 
The ICFs used for the study must comply with the Declaration of Helsinki, US 21 CFR Part 50, 
ICH GCP guidelines, and any other local regulations. The Investigator, or a person delegated by 
the Investigator, must explain the medical aspects of the study including the nature of the study 
and the treatment, orally and in writing, in such a manner that the potential participant is aware 
of potential benefits and risks. Potential participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. 
Participants, or a legal guardian if the participant is unable to, must give informed consent in 
writing. 
Prior to participation in any study-related procedures, participants must sign and date an 
EC-approved written ICF in a language the participant can understand. The informed consent 
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. 
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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. 
12.3. 
Ethics Committee 
The term EC used in this document refers to an Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) or equivalent. The EC must review and, if appropriate, approve the 
following documents, as applicable: 
• Study protocol and amendment(s) 
• Written ICF(s) and consent form updates 
• Participant recruitment procedures/documents (eg, advertisements) 
• Written information to be provided to participants 
• IB and available safety information (Note: ECs do not approve IBs but are 
responsible for acknowledging receipt) 
• Information about payments and compensation available to participants 
The EC approval must be in writing, clearly identifying the study (by protocol date and/or 
version), the documents reviewed, including informed consent, and date of the review. The 
Investigator has the responsibility to provide MyoKardia with the written EC approval prior to 
initiating any study-related procedures. 
The Investigator also has the responsibility to inform the EC of the following, according to the 
EC’s policy: 
• All SUSARs (as described in Section 10.3) 
• Any new information that may affect adversely the safety of the participants or the 
conduct of the trial 
• Protocol deviations 
• A synopsis of the study report upon study completion 
Documentation of subsequent reviews of the study must also be forwarded to MyoKardia. 
13. 
ADMINISTRATIVE PROCEDURES 
13.1. 
Sponsor’s Responsibilities 
MyoKardia reserves the right to terminate the study at any time. MyoKardia and the 
Investigators will assure that adequate consideration is given to the protection of the participants’ 
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interests. MyoKardia retains the right to terminate the study and remove all study materials from 
a clinical site at any time. Specific circumstances that may precipitate such termination are: 
• Request by Health Authority to terminate the study 
• Unsatisfactory participant enrollment with regard to quality or quantity 
• Significant or numerous deviations from study protocol requirements, such as failures 
to perform required evaluations on participants, maintain adequate study records or 
inaccurate, incomplete, or late data recording on a recurrent basis 
• The incident or severity of AEs in this or other studies indicating potential health 
hazard caused by the study treatment 
13.1.1. 
Participant Confidentiality 
The processing of personal data in pursuit of this study will be limited to those data that are 
reasonably necessary to investigate the utility of the study medications used in this study. These 
data will be processed with adequate precautions to ensure confidentiality according to 
applicable laws. 
MyoKardia ensures that the personal data are: 
• Collected for a specified and legitimate purpose 
• Processed fairly and lawfully 
• Accurate and up to date 
Explicit consent for the processing of personal data will be obtained prospectively from the 
participating participant. 
MyoKardia, whose responsibilities require access to personal data, agrees to keep the identity of 
participants confidential. This confidentiality will be maintained throughout the complete data 
processing. 
Participants will be entitled to request confirmation of the existence of personal data held by 
MyoKardia and will have the right to rectify erroneous or inaccurate data up until database lock. 
13.1.2. 
Study Supplies 
MyoKardia will supply or ensure the coordination of sufficient quantities of the following 
materials to each clinical site: 
• Mavacamten active capsules in 3 strengths (5, 10, and 15 mg) in 30-count bottles 
• Supplies for laboratory assessments 
• Study Reference Manual 
• Pharmacy Manual 
• IXRS Manual 
• IB 
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13.1.3. 
Investigator Training 
All clinical sites will have a center-specific study initiation meeting to ensure the center staff 
understands the protocol, study requirements and procedures, and data capture processes. This 
training will take place before the first participant is enrolled. Each clinical site will be provided 
with information regarding GCP and regulations specific to the conduct of the clinical studies. 
Each clinical site will be responsible for ensuring that new team members are adequately trained, 
and the training is documented. 
13.1.4. 
Ongoing Communication of Safety Information During the Study 
MyoKardia will provide the Investigator(s) with documentation of SAEs from this study and 
other studies that are related to mavacamten study medication and are unexpected (refer to 
Section 10.3), as appropriate. The Investigator(s) must forward this documentation to the EC as 
described in Section 10.3. 
MyoKardia will also notify the Investigator(s) about any other significant safety findings that 
could alter the safety profile of the IMP from what is described in the protocol and significantly 
affect the safety of participants, affect the conduct of the study, or alter the EC’s opinion about 
the continuation of the study. 
13.1.5. 
Study Monitoring 
MyoKardia will monitor this clinical study through remote data checks and monitoring visits to 
check the adequacy of clinical site staff and facilities, and to ensure adherence to the protocol, 
study procedures, and applicable regulations. The clinical site monitor will also assess proper 
eCRF completion and source document retention. The Investigator(s) and clinical site staff are 
expected to provide adequate space for monitoring visits and to allocate sufficient time to permit 
adequate review of the study’s progress. The Investigator(s) will permit study-related 
monitoring, audits, EC review, and regulatory inspection(s), providing direct access to source 
data/documents and study-related facilities (eg, pharmacy, diagnostic laboratories). 
13.1.6. 
Study Auditing and Inspecting 
MyoKardia may audit the study conduct, compliance with the protocol, and accuracy of the data 
in 1 or more clinical sites. 
The Investigator(s)/institution(s) will permit study-related monitoring, audits, and inspections by 
MyoKardia, EC, government regulatory authority(ies), and MyoKardia’s quality assurance 
personnel or its designees by providing direct access to source data/documents after appropriate 
notification from MyoKardia. 
13.2. 
Investigator’s Responsibilities 
13.2.1. 
Screening Log 
The Investigator must keep a record that lists all participants who signed an informed consent and 
the reason for noninclusion if the potential participant does not ultimately enroll and receive IMP. 
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13.2.2. 
Mavacamten Accountability 
The Investigator must ensure that the study drug at the investigational site is kept secured and 
accounted for with access limited to only those individuals authorized by the Investigator. The 
Investigator, his/her designee, or pharmacist must also maintain adequate records of distribution, 
dispensing, and destruction of all study drug at the end of the study. The study drug records must 
be readily available for inspection by the site monitor and/or auditor. Only those sites with 
institutional, local, state, or federal restrictions in the destruction of material will be allowed to 
return study drug to the depot. No study drug can be destroyed or returned to depot until the 
clinical site monitor has verified the accuracy of the study drug records at the clinical site. 
13.2.3. 
Reporting and Recording of Study Data 
Data will be captured and compiled using procedures developed by MyoKardia or designee. 
Electronic data capture (EDC) technology will be used for this study. Clearly record all 
requested study data on the eCRF and other forms as required. Whenever possible, record the 
reason for missing data in the source document. Only individuals who are identified on the study 
personnel responsibility/signature log and who have received appropriate training on the EDC 
system may enter or correct data in the eCRF. Incomplete or inconsistent data on the eCRF will 
result in data queries that require resolution by the Investigator or designee. Corrections to the 
eCRF, including the reason for the change, will be automatically documented through the EDC 
system’s audit trail. 
Participant source data must be maintained as original records or a certified copy (ie, copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original). The Investigator and affiliated 
institution should take measures to prevent the accidental or premature destruction of documents. 
Data collected on the eCRF must match the source documents. 
An eCRF must be completed for each participant who signs an ICF. 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. 
13.2.4. 
Source Data and Source Documents 
The nature and location of all source documents will be identified to ensure that all sources of 
original data required to complete the eCRF are known to the company and clinical site staff. 
The source documents are to be accessible for verification by the clinical site monitor. 
Source documents should at minimum include the following information for each participant: 
• Participant identification and contact information (name, date of birth, sex, address, 
phone) 
• Documentation verifying participant eligibility (ie, medical history, physical 
examination) 
• Informed consent process documentation and ICF 
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• 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 the 
clinical site’s policy does not permit direct access to the electronic medical records. 
13.2.5. 
Participant Identification Information 
To permit easy identification of the individual participant during and after the study, the 
Investigator is responsible for keeping an updated log that contains the participant identification 
information. This document will be reviewed by the clinical site monitor for completeness. 
However, to ensure the participant’s confidentiality, the document will be maintained at the 
clinical site and no copy will be made. 
13.2.6. 
Records Retention 
MyoKardia will inform the Investigator in writing when it is acceptable to dispose of any study 
records. To enable evaluation and/or audits from regulatory authorities or MyoKardia, the 
Investigator agrees to keep records, including the identity of all participants (eg, participant 
identification code list and all source documents), all original signed ICFs, copies of all eCRFs, 
original laboratory reports, detailed records of study medication disposition, and all essential 
documents for the conduct of a clinical study. To comply with international regulations, the 
records should be retained by the Investigator for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP. However, the Investigator may need to 
retain these documents for a longer period if required by the local regulatory requirements or by 
an agreement with MyoKardia. 
13.2.7. 
Protocol Deviations 
Unless there is a safety concern, there should be no deviations from the study protocol. In the 
event of a safety concern, the Investigator or designee must document and explain the reason for 
any deviation from the approved protocol. The Investigator may implement a deviation from, or 
a change to, the protocol to eliminate an immediate hazard to participants without prior EC 
approval. Immediately after the implemented deviation or change, the Investigator must submit a 
report explaining the reasons for the protocol deviation to the EC and MyoKardia, if required. 
The Medical Monitor will notify the study monitor of the decision. 
13.2.8. 
Blood Sample Collection/Storage 
Blood samples that are collected as part of routine medical care or as part of protocol procedures 
may be stored and analyzed for PK or PD analyses. 
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After the study, samples may be used for additional investigation to help identify factors that 
may influence response to therapy. Such samples will be used in compliance with guidelines 
defined by US Food and Drug administration Guidance on Informed Consent for In Vitro 
Diagnostic Device Studies Using Leftover Human Specimens That Are Not Individually 
Identifiable (issued 25Apr2006) and European Medicines Agency’s Reflection Paper on 
Pharmacogenomic Samples, Testing and Data Handling. 
13.3. 
Clinical Trial Insurance 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating 
clinical sites upon request. 
13.4. 
Protocol Amendments and Study Administrative Letters 
Study procedures will not be changed without the mutual agreement of the Investigator and 
MyoKardia. 
If there are any substantial changes to the study protocol, then these changes will be documented 
in a study protocol amendment and, where required, in a new version of the study protocol. 
The amendment should be approved by the EC and the appropriate regulatory authority(ies) 
before implementation, as appropriate. Local requirements should be followed for revised 
protocols. 
If a protocol amendment requires a change to the ICF, the EC will need to approve the revised 
ICF before the revised form is used. 
If there are nonsubstantial changes, such as clarification of statement or corrections to obvious 
errors/typos/inconsistencies in the protocol, or changes to logistical or administrative aspects, 
then MyoKardia may issue an Administrative Letter. If local regulations require any 
administrative change, it will be communicated to or approved by the EC. 
14. 
DATA QUALITY ASSURANCE 
Quality assurance and quality control systems will be implemented and maintained per Standard 
Operating Procedures by MyoKardia, as appropriate, to ensure that this clinical study is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, ICH E6 GCP: consolidated guidance and the applicable regulatory requirements. 
15. 
ADMINISTRATIVE CONSIDERATIONS 
15.1. 
Use of Computerized Systems 
This study will require the use of the following electronic data collection methods: 
• EDC system to capture protocol-required participant data: clinical sites will enter data 
from source documents onto eCRFs for each study visit using a web-based interface. 
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Study monitors and data management personnel will use this system to review data 
and generate queries and reports as needed 
• Cardiac clinical data management systems will be used to analyze ECG and 
echocardiographic data from digital equipment used by clinical site personnel to 
collect participant data 
• IXRS to facilitate drug distribution 
In addition, other central data management systems/databases and software may be used to 
collect and analyze study data: 
• Laboratory Information Systems or proprietary systems will be used by laboratories 
for storing and/or analyzing bioanalytical laboratory data collected throughout the 
study 
• Statistical software will be used for the statistical analysis of the study data 
Information on the above systems will be provided to the Investigator, clinical site personnel, 
and other personnel as appropriate. Measures will be taken to ensure data security and accuracy, 
including but not limited to user training, granting of user accounts and privileges to trained and 
authorized personnel in a role-based manner, username/password/electronic signature 
requirements enforcement, programmed and manual edit checks as outlined in data validation 
specifications, computer generated audit trails, centralized data management, and routine study 
monitoring. The systems used will be compliant with US 21 CFR Part 11 and Annex 11 to the 
Rule Governing Medicinal Products in the European Union and the data collected will be 
archived (at minimum) for the period specified by applicable regulatory requirements. 
15.2. 
Study Records 
The Investigator and affiliated institution shall maintain the study documents and records as 
specified in “Essential Documents for the Conduct of a Clinical Trial” (ICH E6 Section 8), and 
as required by the applicable regulatory requirement(s). This includes, but is not limited to, the 
protocol, eCRFs, AE reports, participant source data (original records or certified 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. 
16. 
PUBLICATION 
The data and results of the study will be owned solely by MyoKardia and shall be confidential 
information of MyoKardia, participant to the Investigator’s publication rights, all as outlined in 
the agreement between the Investigator/institution and MyoKardia regarding the conduct of the 
clinical study (the “Clinical Study Agreement”). It is understood by the Investigator that 
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MyoKardia may use the information developed in this study in connection with the development 
of MyoKardia’s proprietary IMP and, therefore, may disclose such information as necessary or 
useful to other clinical Investigators or regulatory agencies. To allow for the use of the 
information derived from the study, the Investigator understands that he/she has an obligation to 
provide and disclose all study results and all data developed during this study to MyoKardia. 
Any publication or presentation of the results or data of this clinical study by the Investigator 
may only be made in strict compliance with the provision of the Clinical Study Agreement. The 
Investigator understands that it is not MyoKardia’s intention to prevent publication of the data 
generated in the study; rather, MyoKardia reserves the right to control the form and timing of 
such publication for commercial reasons and desires to confirm the scientific accuracy of such 
information prior to such publication or presentation. 
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17. 
REFERENCE LIST 
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http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jsp#.VrtuzPkrKUl. 
Chuan P, Sivaramakrishnan S, Ashley EA, Spudich JA. Cell-intrinsic functional effects of the α-
cardiac myosin Arg-403-Gln mutation in familial hypertrophic cardiomyopathy. Biophys J. 
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EMA/CHMP (European Medicines Agency/Committee for Medicinal Products for Human Use). 
Reflection Paper on Pharmacogenomic Samples, Testing and Data Handling. 15 Nov 2007. 
Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC 
500003864.pdf. 
Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, 
Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW; American College 
of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; 
American Association for Thoracic Surgery; American Society of Echocardiography; American 
Society of Nuclear Cardiology; Heart Failure Society of America; Heart Rhythm Society; 
Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons. 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. Developed in collaboration with the American Association for Thoracic 
Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, 
Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular 
Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 
2011 Dec 13;58(25):e212-60. 
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 Apr;35(5):1245-55. 
International Council for Harmonisation (ICH). E6(R2) Good Clinical Practice: Integrated 
Addendum to ICH E6(R1) Guidance for Industry. March 2018. Available at: 
http://www.fda.gov/downloads/Drugs/Guidances/ucm464506.pdf. 
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-
Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, 
Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; 
Authors/Task Force Members; Document Reviewers. 2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of 
acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the 
special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 
14 Jul 2016;37(27):2129-2200. 
Sommese RF, Sung J, Nag S, Sutton S, Deacon JC, Choe E, Leinwand LA, Ruppel K, Spudich 
JA. Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human 
β-cardiac myosin motor function. Proc Natl Acad Sci USA. 2013 Jul 30;110(31):12607-12. 
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Stern, JA, Markova S, Ueda Y, Kim JB, Pascoe PJ, Evanchik MJ, Green EM, Harris SP. A small 
molecule inhibitor of sarcomere contractility relieves left ventricular outflow tract obstruction in 
feline hypertrophic cardiomyopathy. PLoS One. 2016 Dec 14;11(12):e0168407. 
Sung J, Choe E, Elting M, Nag S, Sutton S, Deacon J, Leinwand L. Ruppel K, Spudich J. Single 
molecule studies of recombinant human α- and β-cardiac myosin to elucidate molecular 
mechanism of familial hypertrophic and dilated cardiomyopathies. Biophysical J. 2012;102(3 
suppl 1):613a-614a. 
US Department of Health and Human Services Food and Drug Administration. Guidance for 
industry. Drug-induced liver injury: premarketing clinical evaluation. Jul 2009. Available from: 
https://www.fda.gov/downloads/Drugs/.../guidances/UCM174090.pdf. 
US Department of Health and Human Services Food and Drug Administration. Guidance on 
informed consent for in vitro diagnostic device studies using leftover human specimens that are 
not individually identifiable. 25 Apr 2006. Available from: 
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocu
ments/ucm071265.pdf. 
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, 
Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, 
McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, 
Wilkoff BL; American College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a 
report of the American College of Cardiology Foundation/American Heart Association Task 
Force on practice guidelines. Circulation. 2013 Oct 15;128(16):e240-327. 
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APPENDIX 1. LABORATORY ASSESSMENTS 
The following safety laboratory parameters will be measured by the central laboratory: 
Hematology/Coagulation 
Serum Chemistry 
• 
CBC, including differential count 
• 
Sodium 
• 
Platelet count 
• 
Potassium 
• 
INR 
• 
Chloride 
• 
aPTT 
• 
Bicarbonate 
 
• 
Calcium 
 
• 
Magnesium 
 
• 
BUN 
 
• 
Creatinine 
 
• 
ALP 
 
• 
ALT 
 
• 
AST 
 
• 
Total bilirubin 
 
• 
CPKa 
 
• 
Glucose 
 
• 
Protein 
 
• 
Albumin 
Abbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; aPTT, activated partial thromboplastin 
time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; CPK, creatine 
phosphokinase; INR, international normalized ratio. 
a If CPK is high, troponin I will be performed and reported. 
At the Investigator’s discretion, safety laboratory assessments may be repeated on Day 1 to 
confirm study eligibility before dosing of study medication. 
The following non-safety laboratory parameters will be measured at Screening: 
• Hepatitis panel (hepatitis B virus and hepatitis C virus) 
• Human immunodeficiency virus test 
• Follicle-stimulating hormone 
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APPENDIX 2. PROHIBITED MEDICATIONS 
Cardiotoxic Agents 
Prior or concomitant treatment with cardiotoxic agents, such as doxorubicin or similar, is 
prohibited. Prior or concomitant treatment with antiarrhythmic drugs with negative inotropic 
activity, such as flecainide or propafenone, is also prohibited. 
Disopyramide and Ranolazine 
Use of disopyramide or ranolazine is prohibited from 14 days before Screening to EOS. 
Moderate and Potent CYP 2C19 Inhibitors and Potent CYP 3A4 Inhibitors 
Potent and moderate CYP 2C19 inhibitors and potent CYP 3A4 inhibitors are prohibited from 
14 days before Screening through the end of study. Examples are listed below. 
• Efavirenz 
• Etravirine 
• Fluconazole 
• Fluvoxamine 
• Fluoxetine 
• Moclobemide 
• Omeprazole 
• Ticlopidine 
• Voriconazole 
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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 aminotransferase (AST/ALT) and total bilirubin (TBL) elevation 
according to the criteria specified in Section 7.4 (3 × upper limit of normal [ULN] for AST/ALT 
and 2 × ULN for TBL in participants with no underlying liver disease and eligibility criteria 
requiring normal liver function at baseline) require the following: 
• The event is to be reported to MyoKardia as a serious adverse event (SAE) within 
24 hours of discovery or notification of the event (ie, before additional etiologic 
investigations have been concluded) 
• The appropriate case report form (CRF) (eg, Adverse Event CRF) that captures 
information necessary to facilitate the evaluation of treatment-emergent liver 
abnormalities are to be completed and sent to MyoKardia 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Section 10.1.3. 
Additional Clinical Assessments and Observation 
All participants for whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI or who experience 
AST/ALT elevations > 3 × ULN are to undergo a period of “close observation” until 
abnormalities return to normal or to the participant’s baseline levels. Assessments that are to be 
performed during this period include the following: 
• Repeat liver chemistries within 24-48 hours (ALT, AST, alkaline phosphatase [ALP], 
TBL); in cases of TBL > 2 × ULN or AST/ALT much greater than 3 × ULN, 
retesting is to be performed within 24 hours. 
− For participants that are far away from the trial site, it may be difficult for the 
participants to return to the trial site promptly. In this case, the participants should 
be retested locally, but normal laboratory ranges should be recorded, results 
should be made available to trial Investigators immediately, and the data should 
be included in the case reports. 
− Participants are to be monitored at least twice weekly; testing frequency may 
decrease to once per week or less if laboratory abnormalities stabilize or the 
investigational product(s) or protocol-required therapies have been discontinued 
AND the participant is asymptomatic. 
• Obtain prothrombin time/international normalized ratio, fractionated bilirubin, and 
any other potentially relevant laboratory evaluations of liver function or disease 
• Obtain complete blood count with differential to assess for eosinophilia 
• Obtain appropriate blood sampling for pharmacokinetic analysis, if it has not already 
been collected 
• Obtain a more detailed history of the following: 
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− Prior and/or concurrent diseases or illness 
− Exposure to environmental and/or industrial chemical agents 
− Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 
− Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
− Concomitant medications (including nonprescription medicines and herbal and 
dietary supplements) 
• Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A, B, 
C, D, E, Epstein-Barr virus, herpes simplex virus, etc); evaluate for other potential 
causes of DILI, including but not limited to nonalcoholic steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease 
• Obtain gastroenterology or hepatology consult 
• Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider 
these tests in cases of concurrent transaminase and TBL elevation, as specified in 
Section 7.4 
• Follow the participant until all laboratory abnormalities return to baseline or normal. 
The “close observation period” is to continue for a minimum of 4 weeks after 
investigational product(s) or protocol-required therapies discontinuation 
The potential DILI event and additional information, such as medical history, concomitant 
medications, and laboratory results must be captured in corresponding CRFs. 
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APPENDIX 4. MANAGEMENT OF PARTICIPANTS WHO ARE 
UNABLE TO ATTEND ONSITE STUDY VISITS FOR 
PROTOCOL-SPECIFIED ASSESSMENTS AND 
MAVACAMTEN DOSE ADJUSTMENTS (EG, COVID-19 
OR OTHER PANDEMICS, NATURAL DISASTERS, OR 
MAJOR DISRUPTIONS) 
The following provisions may be made to accommodate participants who are unable to attend 
onsite study visits for scheduled assessments and dispensation of mavacamten:  
• Participants who are unable to be seen at the clinic may be required to temporarily 
discontinue mavacamten. 
• Participants may be tested for COVID-19 at the discretion of the Investigator and/or 
Sponsor. 
• Mavacamten may be shipped directly from the study site to the participant, as 
necessary. 
Temporary Discontinuation of Mavacamten 
If the participant does not complete a visit within 4 weeks of the expected visit date, the 
participant will be contacted by the site at the end of the 4-week period and will be instructed to 
stop taking mavacamten. 
Participants who temporarily discontinue from mavacamten should be contacted by the site every 
2 weeks from the time of discontinuing mavacamten to assess for AEs and to document 
concomitant medications until the next study visit. 
Resumption of Mavacamten Dosing 
Participants who temporarily discontinue mavacamten may resume mavacamten dosing as 
follows: 
• Resume mavacamten at the dose they were taking when they temporarily 
discontinued, following completion of an unscheduled safety visit 
• Resume study visits at T + x weeks (where T is the study week at discontinuation and 
x is the number of weeks discontinued) 
Participants who have discontinued and resumed treatment according to these guidelines may 
repeat the discontinuation/resumption cycle as often as necessary. 
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Schema for Dose Discontinuation and Resumption for Participants Who Are Unable to 
Attend Onsite Study Visits for Protocol-Specified Assessments and Mavacamten Dose 
Adjustments (eg, COVID-19 or Other Pandemics, Natural Disasters, or Major Disruptions) 
 
 
 
 
 
 
Participant does not complete a visit 
within 4 weeks of expected visit date 
Study site notifies participant to discontinue dosing 
•
Resume mavacamten at the dose they were taking when 
they temporarily discontinued, following completion of an 
unscheduled safety visit 
•
Resume study visits at T + x weeks (where T is the study 
week at discontinuation and x is the number of weeks 
discontinued) 
Participants Who Temporarily Discontinue Mavacamten 
Process for 
Resuming 
Mavacamten 
Dosing 
Criterion for 
Discontinuation 
of Mavacamten 
PIONEER-OLE Study 
Note: Unscheduled safety assessments will be conducted for participants who temporarily 
discontinue study drug prior to resuming dosing, as outlined in Table 2. Study drug will be 
dispensed at the unscheduled visit; however, participants will not resume dosing until notified 
by the study site. 
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APPENDIX 5. INVESTIGATOR’S SIGNATURE 
I have read and understood the contents of the clinical protocol, MYK-461-008 Amendment 4, 
An Open-label Extension Study of Mavacamten (MYK-461) in Adults with Symptomatic 
Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in Study MYK-461-004 
(PIONEER-HCM), and I agree to the following: 
• To assume responsibility for the proper conduct of this clinical study at this clinical 
site and to conduct the study in compliance with this protocol, any future 
amendments, and with any other study conduct procedures provided by 
MyoKardia/designee 
• That I am aware of, and will comply with, the internationally recognized code of 
Good Clinical Practices (GCP) and all other applicable regulatory requirements to 
obtain written and dated approval for the Ethics Committee (EC; eg, Institutional or 
Central Review Board [IRB] or Independent Ethics Committee [IEC]) for the study 
protocol, written informed consents, consent form updates, study participant 
recruitment procedures, and any other written information to be provided to the study 
participants before initiating this clinical study 
• Not to implement any changes to, or deviations from, the protocol without prior 
agreement from MyoKardia and review and documented approval from the EC, 
except to eliminate an immediate hazard to the study participants, or when change(s) 
involves only logistical or administrative aspects of the clinical study 
• To permit direct monitoring and auditing by MyoKardia or MyoKardia’s 
representatives and inspection by the appropriate regulatory authority(ies) 
• That I am thoroughly familiar with the appropriate use of the Investigational 
Medicinal Product (IMP) and other study medication(s) (if applicable), as described 
in this protocol, and any other information provided by MyoKardia or designee, 
including, but not limited to the current Investigator’s Brochure (IB) or equivalent 
document and marketed prescription information (if applicable) 
• To provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically, and safely 
• To ensure that all persons assisting in this study are adequately informed about the 
protocol, IMP/study medication(s), and their clinical study-related duties and functions 
 
Signed: ____________________________________ 
Date: ___________________ 
(sign name with credentials) 
 
Printed Name: ______________________________ 
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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES TABLE 
Protocol Amendment 3: 22 January 2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary objectives of this amendment are to: 
• Extend the duration of the study to 5 years 
• Add guidance for COVID-19 and other disruptions of clinical conduct 
• Adjust echocardiogram core laboratory assessments to be site-read and not blinded to 
the Investigator or site in addition to sending to a central imaging laboratory for 
possible future assessment 
• Update text regarding the evaluation, recording, and reporting of adverse events, 
serious adverse events, and adverse events of special interest to be consistent with 
global changes that have been made across the mavacamten program 
Changes are summarized in the table below. Additional changes were made for clarity, 
consistency, and accuracy throughout the document. 
Summary of Changes 
Section(s) 
Summary of Change 
Reason(s) for Change 
Title Page 
MyoKardia, Inc. 
333 Allerton Avenue 
South San Francisco, CA 94080 
1000 Sierra Point Parkway 
Brisbane, CA 94005 
MyoKardia address was updated. 
Synopsis/ 
Section 7.7.2 Concomitant 
Therapy 
Background cardiomyopathy 
therapy (eg, beta-blocker, 
verapamil, or diltiazem) may be 
adjusted or stopped after a 
participant has received 
24 weeks of mavacamten 
treatment in this study as 
determined by the Investigator 
in conjunction with the 
MyoKardia Medical Monitor. 
Investigator in conjunction with 
MyoKardia Medical Monitor may 
adjust background cardiomyopathy 
therapy. Clarification was 
provided regarding monitoring 
subjects following reduction of 
doses of mavacamten and 
background cardiomyopathy 
therapy. 
Synopsis/ 
Section 4 Overall Study 
Design and Plan/ 
Section 4.1 Study Duration/ 
Figure 1 Study Schema 
The study duration is 172264 
weeks (up to 4 weeks Screening, 
156252 weeks treatment [5 years], 
and 12 8 weeks posttreatment 
follow-up) unless the development 
of mavacamten is stoppedThe 
Overall study duration was 
extended to be up to 260 weeks, 
with treatment duration extended 
to up to approximately 5 years. 
Circumstances for 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Table 2 Schedule of 
Assessments 
Table 3 Schedule of 
Assessments 
protocol may be amended to allow 
an extension beyond 3 years 
should or until mavacamten 
remain in clinical development but 
not yet be available becomes 
commercially available (at the 
discretion of MyoKardia). 
participant/study termination were 
clarified. 
Treatment duration and study 
duration were updated throughout 
the document as appropriate and 
the schedule of assessments was 
updated and divided into 2 tables. 
Synopsis/ 
Section 9.1.1 
Echocardiography 
Echocardiograms will be site-
read and not blinded to the 
Investigator or the site. All 
echocardiography data will be sent 
to the IXRS for LVEF stopping 
criterion (LVEF < 50% by local 
site read). Echocardiograms will 
also be sent to a central imaging 
laboratory for possible future 
assessment. If necessary, 
contrast may be administered to 
ensure that high quality ECHO 
images are obtained. 
Echocardiograms will be site-read 
and not blinded to the Investigator 
or the site and will be sent to the 
IXRS for LVEF stopping criterion.  
Echocardiograms will also be sent 
to a central imaging laboratory for 
possible future assessment. 
Synopsis/  
Figure 1 Study Schema/ 
Table 2 Schedule of 
Assessments/ 
Table 3 Schedule of 
Assessments 
Telehealth assessments 
(conducted via telephone or 
other technology based on 
standard at institution) will be 
conducted at Weeks 18, 30, 42, 
54, 66, 78, 90, 102, 114, 126, 138, 
150, 162, 174, 186, 198, 210, 234, 
and 246 to assess AEs, 
concomitant medications, and 
pregnancy. 
Telehealth visits added for 
assessment of AEs, concomitant 
medications, and pregnancy. 
Table 2, Schedule of 
Assessments 
e All changes that occur after the 
administration of the study 
medication and meet the 
definition of an AE are 
recorded as AEs. 
Updated footnote to specify that 
the definition of AE has been met 
to be recorded as AE. 
Table 2, Schedule of 
Assessments 
h …All stress echocardiography 
visits will be conducted in the 
clinic and not in the home 
health setting. 
Updated footnote to clarify that 
stress echocardiography visits need 
to occur in the clinic. 
Table 3, Schedule of 
Assessments 
a  Visit may be conducted by 
properly trained home health 
agency if appropriate 
delegation of authority is 
documented at study site; 
however, if scheduled, stress 
Clarified that with the exception of 
stress TTE assessments, other 
assessments scheduled to be 
conducted on-site may be 
conducted by properly trained 
home health agency if appropriate 
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Section(s) 
Summary of Change 
Reason(s) for Change 
TTE assessment must be 
performed at site. 
delegation of authority is 
documented at study site. 
Global 
Women Females 
Changed “women” to “females” 
throughout protocol to be more 
consistent with regulatory practice. 
Synopsis/ 
Section 5.2 Inclusion 
Criteria  
1. Has completed Study MYK-
461-004. Prior participation in a 
non-interventional observational 
study is allowed. 
Text was added to clarify that 
participants who had previously 
participated in a non-interventional 
study were included. 
Synopsis/ 
Section 11.2.1 Safety 
Endpoints 
 
Frequency of heart failure 
requiring the initiation of oral loop 
diuretics or the administration of 
intravenous loop diuretics due to 
systolic dysfunction, defined as a 
symptomatic LVEF <50% 
Previous heart failure endpoint 
replaced with heart failure due to 
systolic function 
Section 1.2 Clinical Studies 
Details provided in Section 1.2 
Updated the status of the 
completed and ongoing studies in 
the mavacamten clinical program. 
Section 7.2 Administration  
and Schedule of Study 
Drug 
Participants should be instructed to 
take the study drug under fasting 
conditions (≥ 8 hours) at 
approximately the same time every 
day (±8 hours). 
Requirement for mavacamten 
dosing under fasting conditions 
was removed in accordance with 
the results of a recent food effect 
study. 
Section 7.7.2 Concomitant 
Therapy 
The occurrence of concomitant 
diagnostic/surgical/therapeutic 
procedures and available details 
will also be documented on the 
appropriate eCRF. 
Added language regarding the 
collection of data regarding 
concomitant 
diagnostic/surgical/therapeutic 
procedures. 
Synopsis/ 
Section 4 Overall Study 
Design and Plan/ 
Appendix 4 
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 
participant management in these 
situations is outlined in 
Appendix 4. 
Text was added to introduce 
provisions in study conduct for 
participants who may be affected 
in the context of a pandemic (eg, 
COVID-19) or other pandemics, 
natural disasters, or major 
disruptions.   
Abbreviations: AE, adverse event; COVID-19, corona virus disease; CYP, cytochrome P450; eCRF, electronic case 
report form; ECHO, echocardiogram; HCM, hypertrophic cardiomyopathy; IXRS, interactive response system; 
LVEF, left ventricular ejection fraction; TTE, transthoracic echocardiogram. 
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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES TABLE 
Protocol Amendment 2: 11 April 2019 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
This protocol amendment is being submitted in order to update text based on the 
Investigator’s Brochure (IB) version 6, to change the Medical Monitor, to allow for increases 
in dose beyond Week 6, to allow for increments in dosing beyond the previous Maximum 
Target Dose, to provide updated language on overdose, to provide updated listing of 
contraception requirements, to include an additional stress echocardiogram at Week 72, and 
to extend the study duration from 2 to 3 years. 
Section(s) 
Summary of Change 
Reason(s) for Change 
Title page 
Removed clinical operations contact 
Replaced the name and contact 
information for 
 
with that of
 
Clinical operations contact no 
longer accurate 
 
To change the Medical Monitor 
Section 1.2 
Revised to reflect updated 
Investigator’s Brochure (IB) 
including additional studies, 
enrollment data, and clinical study 
report completion status 
New IB version 6 was released 
Synopsis, Figure 1, 
Table 2, Section 2.2, 
Section 4 
Added stress echocardiography at 
Week 72 
To further evaluate left ventricular 
outflow tract (LVOT) gradient and 
to subsequently be able to dose 
adjust the participants accordingly if 
required 
Synopsis, Figure 1, 
Section 4 
Added text to indicate that 
participants can be dose 
adjusted/uptitrated beyond Week 6 
To allow Investigators the flexibility 
to dose adjust the participants based 
on the results of transthoracic 
echocardiography (TTE)/stress 
echocardiography beyond Week 6 
Section 7.4.3 
Removed reference to Independent 
Data Monitoring Committee 
There is no Independent Data 
Monitoring Committee for this 
study 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Synopsis, Section 5.2 
Inclusion Criteria #5 (contraception) 
updated 
Updated listing of appropriate birth 
control methods for participants 
who are women of childbearing 
potential, in this case, a requirement 
for at least one “highly effective” 
form per the Clinical Trial 
Facilitation Group (CTFG) 
guidance on contraception in 
clinical trials. The previously 
described option of the use of the 
“double barrier” method with the 
male using a condom and female 
using a diaphragm or cervical cap 
has been removed as neither of 
these methods is considered “highly 
effective” by CTFG. 
In addition, with data from Study 
MYK-461-010 now available, the 
statement warning about 
mavacamten potentially reducing 
the effectiveness of hormonal 
contraceptives has been removed. 
Section 8 
Pregnancy and contraception 
guidance updated 
To harmonize with updated 
eligibility criteria on highly 
effective contraception based on 
new available information from 
MyoKardia drug-drug interaction 
studies 
Section 11.3.9 
Allowed for the possibility of an 
interim analysis 
To allow the flexibility for an 
interim analysis, if needed 
Synopsis, Section 4 
Added text to allow for dose 
increments above the previous 
Maximum Target Dose upon 
discussion between the Investigator 
and the MyoKardia Medical 
Monitor 
To allow flexibility to the 
Investigator to be able to dose adjust 
a participant beyond the Target 
Dose for participants who were 
noted to have a subtherapeutic 
pharmacokinetic (PK) or 
pharmacodynamic (PD) response. 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Synopsis, Section 4 
Participants on 5 mg who have met 
the stopping criteria will be 
temporarily discontinued on 
treatment. 
Based on clinical evaluation, these 
participants can be considered for 
dose reintroduction at 5 mg 
following discussion between the 
Investigator and the MyoKardia 
Medical Monitor. 
To allow for careful clinical 
consideration of treatment 
discontinuation or study retention 
for a participant on 5 mg who meets 
the stopping criteria 
Synopsis, Section 4 
Updated language to Fridericia-
corrected QT interval (QTcF) 
stopping criteria 
Rules were changed from static 
single QTcF value to take into 
consideration QRS width and 
percent change in QTcF from 
baseline. These rules are more 
reflective of the expected variances 
in QT interval and conduction 
abnormalities prevalent in 
hypertrophic cardiomyopathy 
(HCM) patients. 
Table 2 
Respiratory rate should be recorded 
at Screening and end of study (EOS) 
Clarification that respiratory rate in 
addition to other protocol stipulated 
vital signs will be taken at 
Screening and EOS 
Table 2 
Added language clarifying that vital 
signs are to be measured prior to 
dosing and respiratory rate should 
be obtained after at least 5 minutes 
of resting 
To clarify instructions for when to 
obtain vital signs 
Table 2 
Added additional PK samples to be 
taken at Weeks 36 and 60 
In view of optionality to dose titrate 
beyond Week 6, additional PK 
samples are required at these 2 time 
points. 
Section 7.5 
Instructions for managing a 
participant experiencing heart 
failure related to systolic 
dysfunction were updated to 
site-specific standard of care. 
To accommodate potential 
variances in the way heart failure 
related to systolic dysfunction may 
be managed across sites, as well as 
changes that might take place in 
management guidelines 
Section 7.6 
New language on overdose 
To clarify clinical threshold when 
participants are to be dose 
discontinued following a drug 
overdose 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Throughout document 
Style changes 
To make document more consistent 
with the American Medical 
Association (AMA) Manual of Style 
or with MyoKardia preference 
Throughout document 
The treatment period was extended 
by 52 weeks, from 104 weeks 
(2 years) to 156 weeks (3 years), 
with study duration extending from 
120 weeks to 172 weeks. Study 
assessments were accordingly 
extended, with additional time 
points added throughout. 
To allow more time to provide 
participants treatment access until 
MYK-461 receives marketing 
approval 
Throughout document 
Maximum Target Dose wording 
changed to Target Dose 
To clarify that the Target Dose is a 
dose obtained from the parent 
MYK-461-004 study that is no 
longer a maximum dose as 
participants in the current study can 
be given a dose higher than the 
Target Dose 
Section 5.5.1 
“Participant withdrawal from 
treatment or withdrawal from study” 
was added as a reason the 
Investigator should discontinue a 
participant’s study treatment 
permanently. 
To allow for study treatment 
discontinuation with participant 
withdrawal from the study. 
Synopsis, Table 2, 
Section 4, Section 9.1.4, 
Section 11.2.2 
“Frequency of angina burden” and 
Canadian Cardiovascular Society 
chest pain grading scale were 
removed as endpoints and 
assessment. 
The study did not require this 
assessment for evaluation of chest 
pain. 
Synopsis, Section 2.2, 
Section 4 
Allowance was added for 
participants on a stable dose of 
10 or 15 mg (for 24 weeks or 
longer) to be dose reduced by the 
Investigator in conjunction with the 
Medical Monitor. 
This addition is to allow participants 
on stable treatment who are deemed 
to have achieved clinical benefit in 
the opinion of the Investigator and 
Medical Monitor, based on clinical 
assessments demonstrating 
symptomatic and functional 
improvement, to be dose reduced to 
a dose considered appropriate by 
both the Investigator and Medical 
Monitor. 
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Amendment 2 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Synopsis, Table 2, 
Section 9.2.1 
All PK blood draws after Week 4 
were specified to be predose draws. 
Due to the option to be able to dose 
adjust the participant beyond 
Week 6, trough PK measures are 
required to be able to accurately 
conduct dose adjustments. 
Section 11.3, 
Section 11.3.6, 
Section 11.3.10, 
Section 15.1 
References to a statistical analysis 
plan (SAP) were removed. 
For an open-label single arm 
extension study, analyses may be 
documented in an abbreviated 
document instead of a full SAP. 
Abbreviations: CTFG, Clinical Trial Facilitation Group; EOS, end of study; IB, Investigator’s Brochure; PK, 
pharmacokinetics; QTcF, Fridericia-corrected QT interval; SAP=statistical analysis plan. 
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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES TABLE 
Protocol Amendment 1: 03 April 2018 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
This protocol amendment is being submitted in order to clarify items, ensure consistency, 
and change the medical monitor. 
Section(s) 
Summary of Change 
Reason(s) for Change 
Title page 
• Changed the title of clinical 
operations contact to 
 
 
• Replaced the name and contact 
information for 
 
 with that of 
 
 
• To update the title of the clinical 
operations contact 
 
• To change the medical monitor 
Synopsis (Study Design); 
Section 7.7.2 
Changed “and/or” to “or”; added 
“either” in conjunction with the “or” 
To be consistent with the 
requirement that a participant cannot 
be on both beta blockers and 
calcium channel blockers 
simultaneously 
Synopsis (Study Design) Changed “individualized to target a 
steady-state trough plasma 
concentration” to “individualized to 
obtain a steady-state trough plasma 
concentration” 
To eliminate repeating words 
Synopsis (Study Design); 
Section 4 
Inserted “PK” in “plasma sample” 
To improve clarity and to be 
consistent throughout the protocol 
Synopsis (Study Design) Changed visit window at Week 6 to 
± 7 days (from ± 4 days) 
To be consistent with study visit 
windows in Table 1 Schedule of 
Study Procedures 
Synopsis (Study Design); 
Section 4 
Added and deleted text in dose 
reduction rule, including adding an 
electrocardiogram in addition to the 
echocardiogram (TTE) at the 
unscheduled visit and allowing the 
unscheduled visit to be within 
2-4 weeks instead of within 
2-3 weeks 
To clarify the dose reduction rule 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Synopsis (Study Design); 
Figure 1 Study Schema, 
footnote b; Section 4 
• Added Week 116 to any mention 
of EOS visit 
• Added ET to any mention of 
Week 104 visit 
To improve clarity and consistency 
Synopsis (Study Design) 
• Replaced “standard 
echocardiogram” with “standard 
TTE” 
• Added standard TTE at 
Week 116/EOS 
• To clarify that echocardiogram 
means TTE 
• To clarify that the TTE should be 
conducted at EOS, consistent with 
Section 4 
Synopsis (Study Design); 
Figure 1 Study Schema; 
Table 1 Schedule of 
Study Procedures, 
footnote h (old); 
Section 4; Section 9.1.1.2 
• Deleted language about the 
post-exercise stress TTE needing 
to be within 4 weeks prior to the 
last dose of study drug and 
replaced with “Week 104/ET” in 
Synopsis (Study Design), 
Section 4, and Section 9.1.1.2; also 
changed Figure 1 (including 
footnote b) so the TTE is at 
Week 104/ET; deleted Table 1, 
footnote h 
• Added post-exercise TTEs at 
Weeks 4 and 48 in Figure 1 and at 
Week 48 in Section 9.1.1.2 
• Because there is no CPET in the 
study, there is no need to have the 
post-exercise TTE within 4 weeks 
prior to last dose of study drug at 
Week 104/ET; the post-exercise 
TTE should be conducted at the 
Week 104/ET visit 
 
• To be consistent with Table 1 and 
text in Synopsis (Study Design) 
and Section 4 
Synopsis (Study Design); 
Figure 1 Study Schema; 
Table 1 Schedule of 
Study Procedures, table 
and footnote k; Section 4 
• Changed “premenopausal women” 
to “women of childbearing 
potential” 
• Changed frequency of pregnancy 
tests from every 4-6 weeks 
(Figure 1) or 6 weeks (Synopsis 
[Study Design],Table 1 footnote k, 
and Section 4) to every 4 weeks; in 
Table 1 Schedule of Study 
Procedures, added a pregnancy test 
at Week 8 to ensure a pregnancy 
test is taken every 4 weeks 
• Added “urine” to Table 1, 
footnote k 
• To be consistent with other 
mavacamten protocols 
 
• To be consistent regarding the 
frequency of at-home pregnancy 
tests for women of childbearing 
potential (every 4 weeks) 
 
 
 
 
 
• To clarify that it is a urine 
pregnancy test 
Synopsis (Study 
Duration); Section 4.1 
• In Synopsis (Study Duration): 
Changed the study duration from 
116 weeks to 120 weeks in 
Synopsis (Study Duration) 
• In Section 4.1: Changed the study 
duration from 116 weeks to 
120 weeks and posttreatment 
duration from 8 weeks to 12 weeks 
• To correct an arithmetic error in 
the previous protocol’s Synopsis 
(Study Duration) 
 
• To correct study duration and 
posttreatment duration in 
Section 4.1 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Synopsis (Inclusion 
Criteria); Section 5.2 
Deleted urinalysis as a safety 
laboratory assessment in inclusion 
criterion 4 
To be consistent with the fact that 
urinalysis is not being done (per 
Table 1 Schedule of Study 
Procedures) 
Synopsis (Exclusion 
Criteria) item 5; 
Section 5.3 item 5 
Deleted “a history of” 
To eliminate extraneous words 
Synopsis (Exclusion 
Criteria) item 6; 
Section 4; Section 5.3 
item 6 
Changed “for at least 4 weeks” to 
“for at least 14 days prior to 
Screening” 
To clarify the criterion and to be 
consistent with other protocols 
Table 1 Schedule of 
Study Procedures 
Deleted rows for body height and 
body weight since they are already 
included in the physical 
examinations and described in 
footnote e 
To simplify the table 
Table 1 Schedule of 
Study Procedures (table 
and footnote h); 
Section 7.3 
Added row in Table 1 for IMP 
compliance and a footnote (h) 
indicating that compliance will be 
checked by capsule count; added 
“clinic” to “at each visit” in 
Section 7.3 
To clarify when compliance will be 
checked 
Table 1 Schedule of 
Study Procedures 
• In Table 1, changed “Plasma 
sample for drug level” to “PK 
sample” and added “PK” to the 
abbreviations 
• In footnote i, changed wording 
from “plasma sample” to “blood 
sample for PK” 
To be consistent with other 
mavacamten protocols 
Table 1 Schedule of 
Study Procedures 
Eliminated NYHA functional class, 
KCCQ, and CCS assessments at 
Weeks 12, 36, 60, 84, and 96 
To reduce the number of 
assessments 
Table 1 Schedule of 
Study Procedures, note 
Added a note that the visit window 
is ± 4 days at Week 4 and ± 7 days 
at all remaining visits from Week 6 
to Week 116/EOS 
To clarify the visit windows 
Table 1 Schedule of 
Study Procedures, 
footnote b; Section 9.3.1 
Added that a participant’s HCM 
history will be collected 
To record participants’ HCM 
histories as part of their medical 
histories 
Table 1 Schedule of 
Study Procedures, 
footnote c 
Changed timing of body temperature 
assessment from every clinic visit to 
only Day 1 and Week 116/EOS 
visits 
To reduce the number of body 
temperature assessments 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Table 1 Schedule of 
Study Procedures, 
footnote e 
Added “at all physical 
examinations” 
To clarify when weight will be 
collected 
Table 1 Schedule of 
Study Procedures, 
footnote f; Section 9.3.3; 
Section 11.3.8.2 
• Deleted triplicate 12-lead ECG 
language 
• Deleted “within 2 hours” (Table 1 
and Section 9.3.3) 
• To eliminate the need for 
triplicate 12-lead ECGs 
• To eliminate the 2-hour restriction 
Table 1 Schedule of 
Study Procedures, 
footnote g 
Added sentence “All post-exercise 
stress echocardiograms should 
include a 4-hour fast prior to 
exercise.” 
To clarify the procedure in the table 
and to be consistent with 
Section 9.1.1.2 
Table 1 Schedule of 
Study Procedures, 
footnote i 
Deleted “≤ 2 hours” 
To eliminate the requirement that 
PK blood sample needs to be 
collected within 2 hours prior to 
dosing 
Section 2.2; Section 4 
Added that an eligible participant’s 
dose may be increased to the 
maximum target dose after Week 6 
if it is first discussed with and 
approved by the MyoKardia medical 
monitor 
To allow the possibility of 
increasing the dose after Week 6 in 
this 2-year study in participants who 
were eligible for a dose increase at 
Week 6 but whose dose was not 
increased at that time due to 
investigator judgment 
Section 4 
Changed “Dose adjustment will 
occur at Week 6” to “Dose 
adjustment may occur at Week 6” 
and “The dose will be increased at 
Week 6” to “The dose may be 
increased at Week 6” 
To clarify that a principal 
investigator does not need to 
increase the dose at Week 6 if he or 
she does not think a dose increase is 
justified in his or her clinical 
judgment 
Section 4 
Changed the final sentence in the 
third paragraph 
To clarify the criterion for not 
increasing the dose 
Section 4 
• Changed visit windows at Week 8 
and Week 12 from ± 4 days to 
± 7 days 
• Inserted “functional” into “NYHA 
class” 
• Replaced “symptom assessments” 
with KCCQ score and CCS chest 
pain grading scale 
• To correct an error in the text and 
to be consistent with the Synopsis  
 
• To be more precise and to be 
consistent with the Synopsis 
• To provide more detail and to be 
consistent with the Synopsis 
Section 5.4 
Added sentence “Rescreening may 
be allowed at the discretion of the 
investigator and the sponsor’s 
medical monitor.” 
To clarify that rescreening is 
permitted 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Section 7.2 
• Changed the drug administration 
window from ± 4 hours to 
± 8 hours 
• Deleted “immediately” 
 
• Changed “drug blood level is 
obtained” to “a plasma PK sample” 
• To be consistent with 
MYK-461-005 
EXPLORER-HCM 
• To be consistent with Table 1, 
footnote i 
• To be consistent with other 
plasma PK sample language 
throughout the protocol 
Section 7.5 
Added “…and the procedures 
outlined in Section 4 will be 
implemented”, deleted a sentence, 
and changed “After the participant” 
to “If a participant” 
To clarify what procedures will 
happen and to be consistent with 
Section 4 
Section 7.7.3; 
Appendix 2 
Updated both sections, including 
adding ranolazine as a prohibited 
therapy in Appendix 2 
To be internally consistent without 
being repetitive and to be consistent 
with prohibited therapy in 
MYK-461-005 EXPLORER-HCM 
Section 8.2.4 
Added text regarding reporting 
guidelines and extending reporting 
outcomes to 6 months after birth 
To update language after 
pharmacovigilance review 
Section 9.1.1.1 
Deleted “or cardiopulmonary 
exercise testing (CPET)” 
To be consistent with the fact that 
CPET is not being performed in this 
study 
Section 9.1.1.2 
Changed “baseline” to “Screening” 
To be consistent with usage 
throughout the protocol 
Section 9.2.2 
• Deleted sentence that plasma 
concentrations of NT-proBNP 
will be evaluated in a blinded 
manner 
• Added Weeks 4, 48, 104, and 116 
to NT-proBNP blood draw time 
points 
• Deleted sentence that on Day 1 
and at Week 16, blood draws for 
NT-proBNP will be performed 
before and immediately after 
CPET 
• To be consistent with the fact that 
NT-proBNP is not being 
evaluated in a blinded manner in 
this open-label study 
• To be consistent with sequence of 
NT-proBNP blood draw before 
stress echo 
• To be consistent with the fact that 
CPET is not being performed in 
this study (see item above) 
Section 10 
Reorganized and updated section 
To follow recommendations made 
after pharmacovigilance team 
review 
Appendix 1 
Deleted thyroid-simulating hormone 
assessment 
To eliminate this assessment since it 
is not being conducted in this study 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Throughout document 
Replaced “β-blockers” with “beta 
blockers” 
To be consistent with other recent 
MyoKardia protocols 
Throughout document 
Style changes (eg, spaces around 
mathematical operators) (Note: these 
are not shown in track changes since 
they do not affect clinical operations 
or patient safety) 
To make document more consistent 
with the AMA Manual of Style or 
with client preference 
Abbreviations: AMA, American Medical Association; CCS, Canadian Cardiovascular Society; 
CPET, cardiopulmonary exercise test; ECG, electrocardiogram; EOS, end of study; ET, early termination; 
HCM, hypertrophic cardiomyopathy; IMP, investigational medicinal product; KCCQ, Kansas City 
Cardiomyopathy Questionnaire; NYHA, New York Heart Association; NT-proBNP, N-terminal pro b-type 
natriuretic peptide; PK, pharmacokinetics; TTE, transthoracic echocardiogram. 
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