Clinical trial NCT04766892
Conditions: Heart Failure With Preserved Ejection Fraction
Keywords: HFpEF NT-proBNP Cardiac troponin T
Sponsor: Bristol-Myers Squibb
Start date: 2021-03-30; Completion date: 2024-02-26
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2a proof-of-concept study to assess safety, tolerability, and preliminary efficacy of mavacamten treatment on biomarker levels in participants with heart failure with preserved ejection fraction (HFpEF) and elevation of NT-proBNP with or without elevation of cTnT. Data from this study will inform future study designs of mavacamten in patients with HFpEF.

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 Exploratory, Open-label, Proof-of-concept, Phase 2a Study of Mavacamten (MYK-461) in 
Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Chronic Elevation of 
Cardiac Biomarkers 
 
 
NCT Number: NCT04766892 
Document Date (Date in which document was last revised): 01 Sep 2021 
 
 
 


Mavacamten: Protocol 
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CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
AN EXPLORATORY, OPEN-LABEL, PROOF-OF-CONCEPT, 
PHASE 2A STUDY OF MAVACAMTEN (MYK-461) IN 
PARTICIPANTS WITH HEART FAILURE WITH 
PRESERVED EJECTION FRACTION (HFpEF) AND 
CHRONIC ELEVATION OF CARDIAC BIOMARKERS  
Protocol Number: 
MYK-461-019 
Amendment Number: 
1 
Compound: 
Mavacamten (MYK-461) 
Study Phase: 
2a 
Acronym: 
EMBARK-HFpEF 
Sponsor Name 
MyoKardia, Inc. (a Wholly-Owned Subsidiary of Bristol Myers 
Squibb) 
Legal Registered 
Address: 
1000 Sierra Point Parkway 
Brisbane, CA 94005 
Medical Monitor: 
 Clinical Trial Physician 
Clinical Operations 
Contact: 
 Global Trial Manager 
Original Protocol 
Approval Date: 
06 August 2020 
Amendment 1 
01 September 2021 
Confidentiality Statement 
This document contains trade secrets or otherwise confidential and/or proprietary information of 
MyoKardia, Inc, a wholly-owned subsidiary of Bristol Myers Squibb. 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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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Schema ........................................................................................................................22 
1.3. 
Schedule of Study Procedures ....................................................................................23 
2. 
INTRODUCTION ......................................................................................................27 
2.1. 
Study Rationale ...........................................................................................................27 
2.2. 
Background .................................................................................................................27 
2.2.1. 
Clinical Studies ...........................................................................................................28 
2.3. 
Benefit/Risk Assessment ............................................................................................30 
2.3.1. 
Risk Assessment .........................................................................................................31 
2.3.2. 
Benefit Assessment .....................................................................................................33 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................34 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
4. 
STUDY DESIGN .......................................................................................................36 
4.1. 
Overall Design ............................................................................................................36 
4.2. 
Scientific Rationale for Study Design ........................................................................36 
4.3. 
Justification for Dose ..................................................................................................37 
4.4. 
End of Study Definition ..............................................................................................37 
5. 
STUDY POPULATION .............................................................................................37 
5.1. 
Inclusion Criteria ........................................................................................................37 
5.2. 
Exclusion Criteria .......................................................................................................39 
5.3. 
Lifestyle Considerations .............................................................................................41 
5.4. 
Screen Failures ............................................................................................................41 
5.5. 
Criteria for Temporarily Delaying ..............................................................................42 
6. 
STUDY DRUG ...........................................................................................................42 
6.1. 
Study Drug Administered ...........................................................................................42 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................43 
6.2.1. 
Formulation, Packaging, and Labeling of Study Drug ...............................................43 
6.2.2. 
Direct-to-Participant Study Drug Shipment (At Selected Sites) ................................43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................44 
6.4. 
Study Drug Compliance .............................................................................................44 
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.............................................................................................................44 
6.6. 
Continued Access to Study Drug After the End of the Study ....................................44 
6.7. 
Treatment of Overdose ...............................................................................................44 
6.7.1. 
Reporting and Follow-up of Overdose .......................................................................44 
6.8. 
Prior and Concomitant Therapy ..................................................................................45 
6.8.1. 
Prior Medication .........................................................................................................45 
6.8.2. 
Background HFpEF Medication .................................................................................45 
6.8.3. 
Prohibited Medication ................................................................................................45 
6.8.4. 
COVID-19 Vaccine Considerations ...........................................................................45 
7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................46 
7.1. 
Discontinuation of Study Drug ...................................................................................46 
7.1.1. 
Liver Chemistry Stopping Criteria .............................................................................46 
7.1.1.1. 
Criteria for Permanent Withholding of Mavacamten Due to Potential 
Hepatotoxicity .............................................................................................................46 
7.1.1.2. 
Criteria for Conditional Withholding of Mavacamten Due to Potential 
Hepatotoxicity .............................................................................................................47 
7.1.1.3. 
Criteria for Rechallenge of Mavacamten After Potential Hepatotoxicity ..................47 
 
 ...........................................................48 
 
 .................................................................................49 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................49 
7.3. 
Lost to Follow-up .......................................................................................................49 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................50 
8.1. 
Pharmacodynamic Assessments .................................................................................50 
8.1.1. 
Cardiac Biomarkers ....................................................................................................50 
 
 ....................................................................51 
 
 ...................................................................51 
 
 ......................................................................51 
 
 .........................................................................................51 
 
 ..........................................................51 
 
 .........................................................................................52 
 
 ..............................................................52 
 
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8.2. 
Safety Assessments .....................................................................................................52 
8.2.1. 
Medical History ..........................................................................................................53 
8.2.2. 
Physical Examinations ................................................................................................53 
8.2.3. 
Vital Signs ..................................................................................................................53 
8.2.4. 
12-Lead Electrocardiograms .......................................................................................53 
8.2.5. 
Clinical Safety Laboratory Assessments ....................................................................53 
8.2.6. 
Pregnancy Testing ......................................................................................................54 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................54 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................54 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................55 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................55 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................55 
8.3.5. 
Pregnancy ...................................................................................................................56 
8.3.6. 
Adverse Events of Special Interest .............................................................................57 
 
 ........................................................................................................57 
 
 ..........................................................................57 
 
......................................................................................57 
 
 ...................................................................................58 
9. 
STATISTICAL CONSIDERATIONS .......................................................................58 
9.1. 
Statistical Hypotheses .................................................................................................58 
9.2. 
Sample Size Determination ........................................................................................58 
9.3. 
Analysis Sets ...............................................................................................................58 
9.4. 
Statistical Analyses .....................................................................................................58 
9.4.1. 
General Considerations ...............................................................................................59 
9.4.2. 
Primary Pharmacodynamic Endpoints .......................................................................59 
 
 ................................................................................................59 
9.4.4. 
Safety Endpoints .........................................................................................................60 
9.4.4.1. 
Adverse Events ...........................................................................................................60 
9.4.4.2. 
12-Lead Electrocardiogram ........................................................................................61 
9.4.4.3. 
Laboratory Data ..........................................................................................................62 
9.4.4.4. 
Vital Signs Data ..........................................................................................................62 
9.4.4.5. 
Other Safety Analyses ................................................................................................62 
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 ..........................................................................................63 
 
 ..........................................................................................................63 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................63 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Consideration ......................63 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................63 
10.1.2. 
Financial Disclosure ...................................................................................................64 
10.1.3. 
Informed Consent Process ..........................................................................................64 
10.1.4. 
Data Protection ...........................................................................................................65 
10.1.5. 
Committees Structure .................................................................................................65 
10.1.5.1. 
Independent Data Monitoring Committee ..................................................................65 
10.1.6. 
Data Quality Assurance ..............................................................................................65 
10.1.7. 
Source Documents ......................................................................................................66 
10.1.8. 
Study and Site Start and Closure ................................................................................66 
10.1.9. 
Sponsor’s Responsibilities ..........................................................................................67 
10.1.9.1. 
Participant Confidentiality ..........................................................................................67 
10.1.9.2. 
Study Supplies ............................................................................................................68 
10.1.9.3. 
Investigator Training ..................................................................................................68 
10.1.9.4. 
Ongoing Communication of Safety Information During the Study ...........................68 
10.1.9.5. 
Study Monitoring ........................................................................................................69 
10.1.9.6. 
Study Auditing and Inspecting ...................................................................................69 
10.1.10. 
Publication Policy .......................................................................................................69 
10.2. 
Appendix 2: Prohibited Medications ..........................................................................69 
10.3. 
Appendix 3: Safety Laboratory Tests .........................................................................70 
10.4. 
Appendix 4: Evaluation, Recording, and Reporting of Adverse Events, 
Serious Adverse Events, and Adverse Events of Special Interest ..............................73 
10.4.1. 
Definitions of Pretreatment Adverse Events, Adverse Events, Serious 
Adverse Events, and Adverse Events of Special Interest ...........................................73 
10.4.1.1. 
Pretreatment Adverse Events ......................................................................................73 
10.4.1.2. 
Adverse Events ...........................................................................................................73 
10.4.1.3. 
Serious Adverse Event ................................................................................................74 
10.4.1.4. 
Adverse Events of Special Interest .............................................................................75 
10.4.2. 
Collection and Reporting of Adverse Events .............................................................75 
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10.4.2.1. 
Pretreatment Adverse Events and Adverse Events Collection Periods ......................75 
10.4.2.2. 
Pretreatment Adverse Events and Adverse Events Reporting Periods .......................76 
10.4.2.3. 
Reporting of Serious Adverse Events .........................................................................77 
10.4.2.4. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................77 
10.4.3. 
Safety Reporting to Investigators, Institutional Review Boards, Independent 
Ethics Committees, and Regulatory Authorities ........................................................77 
10.4.4. 
Pregnancy ...................................................................................................................78 
10.4.4.1. 
Avoidance of Pregnancy .............................................................................................78 
10.4.4.2. 
Reporting and Follow-up of Pregnancies ...................................................................78 
10.5. 
Appendix 5: Potential Drug-induced Liver Injury Reporting and Additional 
Assessments Reporting ...............................................................................................79 
10.6. 
Appendix 6: Abbreviations and Definitions ...............................................................81 
11. 
REFERENCES ...........................................................................................................83 
12. 
PROTOCOL ACCEPTANCE PAGE.........................................................................85 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................23 
Table 2: 
Study Drug ..................................................................................................................42 
 
 ..................52 
Table 4: 
Analysis Populations Definitions ...............................................................................58 
Table 5: 
Protocol-required Safety Laboratory Tests .................................................................71 
 
LIST OF FIGURES 
Figure 1: 
MYK-461-019 Study Schema ....................................................................................22 
 
 
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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES TABLE 
Protocol Amendment 1: 01 September 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: 
• Update the eligibility criteria for participants 
• Change the primary endpoint from cardiac troponin I to cardiac troponin T 
 
 
• Streamline the Screening Visit (reduce from 3 visits to 1 visit) and make the Prescreening 
Visit optional 
• Update the assessments to be completed at Prescreening, Screening, Day 1, and Weeks 
18, 20, and 22 
 
 
• Update the pregnancy language to align with Investigator Brochure (IB) Edition 8.1 
• Eliminate home visit options for study assessments 
• Allow echocardiographic contrast agents 
Changes are summarized in the table below. Additional changes were made for clarity, 
consistency, and accuracy throughout the document. Minor administrative and editorial changes 
were also made. 
Location of 
Change 
Summary of Change 
Rationale for Change 
Title Page  
Section 1.1.  
Section 12. 
Updated title 
Cardiac Troponin I and/or NT-proBNP 
Biomarkers 
Title was changed to 
reflect the change in 
eligibility criteria 
Title Page 
Updated Medical Monitor and Clinical 
Operations Manager  
To reflect organizational 
staffing changes 
Section 1.1. 
Updated number of sites 
Approximately 320 study sites 
To support recruitment 
Section 1.2. 
Section 1.3. 
Initial Biomarker Assessment changed to 
Optional Prescreening Up to D -49  
To streamline the 
screening process 
Section 1.2. 
Section 1.3. 
Screening Period Up to D -28  
To align with change from 
3 to 1 Screening Visit  
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Location of 
Change 
Summary of Change 
Rationale for Change 
Section 1.1. 
Section 1.2. 
Section 1.3. 
Section 4.1. 
• Cardiac troponins and NT-proBNP 
measured during Enrollment 
 
 
 
 
 
 
To simplify the 
acquisition of pre-dose 
blood and imaging 
biomarkers 
Section 1.3. 
Adverse events, height, weight, and 12-lead 
ECG to be recorded during Optional 
Prescreening Up to Day -49 
To increase the flexibility 
for acquiring eligibility 
data 
Section 1.3. 
Section 10.3. 
Added collection of SPEP  
IMP compliance deleted from Wk 2, 4, 8, 10, 
16, 18, 22, 24 (TC) columns. 
 
Changed per the protocol 
clarification letter 
Removed since cannot be 
completed remotely via 
telephone call 
 
Section 1.3. 
Updated the footnotes for Table 1 
To align with the changes 
made to the number of 
screening visits and 
changes in the 
assessments 
Section 1.1. 
Section 2.1. 
Order of cardiac biomarkers was updated in 
the study rationale 
To align with the new 
eligibility criteria. All 
participants will have a 
degree of NT-proBNP 
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Location of 
Change 
Summary of Change 
Rationale for Change 
elevation with or without 
elevation of hs-cTnT. 
Section 1.1. 
Section 2.2. 
Section 4.1. 
Section 5.1. 
Section 8.1.1. 
Section 9.4.1. 
Additional text to describe change in assessment
from 
 to hs-cTnT with supporting 
rationale from the literature 
hs-cTnT is a more 
sensitive prognostic 
biomarker than 
. 
Section 2.3.1 
Section 6.8.4 
Appendix 10.2. 
Added information related to COVID-19 
vaccines 
To provide clarity on 
COVID-19 vaccination 
administration 
Section 1.1. 
Section 3. 
Section 9.4.2. 
The order of the primary objectives was 
rearranged and 
 was changed to cTnT 
To align with the overall 
rationale of the study 
(evaluate safety of 
mavacamten and impact 
of mavacamten on levels 
of NT-proBNP and cTnT) 
and to replace 
 
with the more sensitive 
prognostic biomarker hs-
cTnT 
Section 1.1. 
Section 3. 
Section 9.4.4. 
The safety endpoint for vital sign was changed 
to vital sign abnormalities 
To ensure consistency for 
the primary safety 
endpoints, data on vital 
sign abnormalities (not all 
vital signs) will be 
recorded 
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Location of 
Change 
Summary of Change 
Rationale for Change 
Section 1.1. 
Section 5.1. 
• Inclusion Criteria 5 for biomarker 
criteria clarified and participant 
restriction removed 
• Inclusion Criteria 6 to include 
LVEF ≤ 45% if not consistent with 
recovered HFrEF at discretion of study 
medical monitor 
• Inclusion Criteria 8 to include option to 
use echocardiographic contrast agents 
 
To focus on elevated NT-
proBNP; to prevent 
subject exclusion due to a 
spurious low LVEF; to 
correct an inconsistency, 
and interim review 
removed because 
enrollment will be almost 
complete 
 
; to 
enhance study eligibility. 
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Location of 
Change 
Summary of Change 
Rationale for Change 
Section 1.1. 
Section 5.1. 
Section 8.3.5. 
Section 10.4.4.2. 
Updated the timing that contraception methods 
must be used from 3 to 4 months after the last 
dose of study drug 
To align with updated 
pregnancy language in IB 
Edition 8.1 
Section 1.1. 
Section 5.2. 
• Exclusion Criteria 4 updated to further 
clarify positive serum immunofixation 
result  
• Exclusion Criteria 12 updated to define 
coronary artery disease as obstructive 
• Exclusion Criteria 27 updated to 
exclude acute decompensated heart 
failure events requiring treatment 
within 30 days prior to Screening 
• Exclusion Criteria 29 added to exclude 
subjects with hypersensitivity to or 
contraindication to intravenous 
electrocardiography contrast agents 
To enable recruitment of 
subjects with positive 
results that do not 
represent a safety concern 
for entry into the study; to 
focus on significant 
coronary disease; to 
eliminate patients at 
increased risk of 
cardiovascular events 
during the study; to permit 
subjects to safely receive 
echocardiographic 
contrast agents 
Section 5.4. 
Individuals who do not meet the criteria for 
participation in this study (prescreen or 
screen failure) may be rescreened  
To enhance the eligibility 
of subjects to enter the 
study 
Section 8. 
Added text to describe that prescreening 
evaluations are optional and when they may be 
performed 
To simplify the screening 
process 
Footnotes to 
Schedule of Study 
Procedures 
Section 1.1. 
Section 5.1. 
. 
Updated text on use of contrast 
echocardiograms 
 
 
To reduce screen failures 
due to poor image quality 
Section 8.2.2. 
Height (cm) and body weight (kg) will be 
measured at Prescreening and/or Screening, 
and body mass index (kg/m2) will be 
calculated. 
To increase the flexibility 
for acquiring eligibility 
data 
Section 8.2.3. 
Vital signs to be obtained with the participant 
at rest 
To ensure consistency 
throughout the text, vital 
signs will be taken with 
participants at rest 
Section 8.2.6. 
Pregnancy tests to be conducted in clinic only 
Home visit options are 
being removed 
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Location of 
Change 
Summary of Change 
Rationale for Change 
Section 9.4.4.1. 
AEs will be mapped to SOCs and PTs using 
version 23.0 of theMedical Dictionary for 
Regulatory Activities (MedDRA). 
To clarify that the same 
version number (23.0) of 
MedDRA will be used for 
the entire study 
Section 9.4.4.1.1. 
Updated text on data collected and listing 
provided for participant deaths during the 
study period 
Clarify the analysis on 
death  
Section 9.4.4.1.2. 
Updated the pregnancy summaries that will be 
generated 
Clarify the analysis on 
pregnancy summaries 
Section 9.4.4.1.3. 
Updated the summaries for reports of 
symptomatic overdose that will be generated 
Clarify the analysis on 
symptomatic overdose 
Section 9.4.4.3.1. 
Deletion of normalization criteria for DILI and 
cross referenced to SAP 
Simplify detailed text 
Section 11. 
Gohar A, et al. Eur J Heart Fail. 2017 
Hoffmann J, et al. Ann Clin Biochem. 2019 
 
 
 
 
 
 
References in bold added 
to support the rationale for 
focusing on hs-cTnT in 
this study. 
 
 
 
 
 
 
 
Abbreviations: 
; BMI = body mass index; D = Day; DIL = drug-induced liver injury; 
ECG = electrocardiogram; EOS = End of Study; 
; hs-cTnT = high 
sensitivity cardiac troponin T; 
; IMP = investigational medicinal 
product; LVEF = left ventricular ejection fraction; LVMI = left ventricular mass index; NT-proBNP = N terminal 
pro b type natriuretic peptide; 
; PT = preferred term; SAP = statistical analysis plan; 
SOC = system organ class; SPEP = serum protein electrophoresis; TC = telephone call; 
 
; Wk = week. 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
AN EXPLORATORY, OPEN-LABEL, PROOF-OF-CONCEPT, 
PHASE 2A STUDY OF MAVACAMTEN (MYK-461) IN 
PARTICIPANTS WITH HEART FAILURE WITH PRESERVED 
EJECTION FRACTION (HFPEF) AND CHRONIC ELEVATION 
OF CARDIAC BIOMARKERS 
Rationale: 
This is a Phase 2a proof-of-concept study to assess safety, tolerability, and preliminary efficacy of 
mavacamten treatment on N-terminal pro b-type natriuretic peptide (NT-proBNP) levels and high-
sensitivity cardiac troponin T (hs-cTnT) levels in participants with heart failure with preserved ejection 
fraction (HFpEF) and chronic elevation of cardiac biomarkers. Data from this study will inform future 
study designs of mavacamten in participants with HFpEF. 
Objectives and Endpoints: The primary, 
 objectives and 
endpoints of the study are as follows: 
Objectives 
Endpoints 
Primary 
 
• To evaluate the safety and tolerability of a 26-week 
course of mavacamten 
• Frequency and severity of treatment-
emergent adverse events (TEAEs), adverse 
events of special interest (AESIs) 
[symptomatic overdose, outcomes of 
pregnancy, left ventricular ejection fraction 
(LVEF) ≤30%], and serious adverse events 
(SAEs); laboratory abnormalities; vital sign 
abnormalities; and cardiac rhythm 
abnormalities 
• To evaluate the effect of a 26-week course of 
mavacamten on N-terminal pro b-type natriuretic 
peptide (NT-proBNP) levels (at rest) 
• Change from baseline to Week 26 in 
NT-proBNP (at rest) 
• To evaluate the effect of a 26-week course of 
mavacamten on cardiac troponin T (cTnT) levels 
(at rest) 
• Change from baseline to Week 26 in cTnT 
(at rest), as assessed by a high-sensitivity 
assay 
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Overall Design: This is a multicenter, exploratory, open-label Phase 2a study to explore the safety, 
efficacy and/or pharmacodynamic effect, 
, and tolerability of mavacamten in approximately 
35 ambulatory participants with symptomatic HFpEF and elevated NT-proBNP with or without 
elevation in hs-cTnT as defined in the inclusion/exclusion criteria. The study will include an up to 
7-week screening period, a 26-week treatment period, and an 8-week posttreatment follow-up period. 
Participants will receive a 26-week course of mavacamten followed by an 8-week washout period. All 
participants will initially receive 2.5 mg orally each day. At Week 14, the dose for some participants 
may be 
 5 mg orally each day as defined in the Study Procedures and Treatment section 
below. 
 
 
 
 
 
Inclusion Criteria: 
1. Able to understand and comply with the study procedures, understand 
the risks involved in the study, and provide written informed consent 
according to federal, local, and institutional guidelines before the first 
study-specific procedure. 
2. Is at least 50 years old at Screening. 
3. Body weight is greater than 45 kg at Screening. 
4. Documented prior objective evidence of heart failure as shown by 1 or 
more of the following criteria: 
a. Previous hospitalization for heart failure with documented 
radiographic evidence of pulmonary congestion. 
b. Elevated left ventricular (LV) end-diastolic pressure or 
pulmonary capillary wedge pressure at rest (≥15 mm Hg) or 
with exercise (≥ 25 mm Hg). 
c. Elevated level of NT-proBNP (> 400 pg/mL) or brain 
natriuretic peptide (BNP) (> 200 pg/mL). In the absence of 
qualifying historical NT-proBNP or BNP levels meeting this 
threshold, screening NT-proBNP meeting the threshold in 
inclusion criterion 5 will satisfy inclusion criterion 4. 
d. Echocardiographic evidence of medial E/e' ratio ≥15 or left 
atrial enlargement (left atrial volume index >34 mL/m2) 
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together with chronic treatment with spironolactone, 
eplerenone, or a loop diuretic. 
5. Meets 1 or both of the following criteria: 
a. A screening hs-cTnT ≥ 99th percentile AND a screening NT-
proBNP > 200 pg/mL (if not in atrial fibrillation or atrial 
flutter) or > 500 pg/mL (if in atrial fibrillation or atrial flutter) 
OR if the screened participant is of African descent or has a 
body mass index (BMI) ≥ 30.0 kg/m2, a screening hs-cTnT 
≥ 99th percentile, AND a screening NT-proBNP > 160 pg/mL 
(if not in atrial fibrillation or atrial flutter) or > 400 pg/mL (if 
in atrial fibrillation or atrial flutter).  
b. A screening NT-proBNP > 300 pg/mL (if not in atrial 
fibrillation or atrial flutter) or > 750 pg/mL (if in atrial 
fibrillation or atrial flutter) OR if the screened participant is of 
African descent or has a BMI ≥ 30.0 kg/m2, a screening NT-
proBNP > 240 pg/mL (if not in atrial fibrillation or atrial 
flutter) or > 600 pg/mL (if in atrial fibrillation or atrial flutter). 
6. Has documented LVEF ≥60% at the Screening visit as determined by 
the echocardiography central laboratory and no history of prior 
LVEF ≤ 45% under stable conditions. If historical LVEF ≤ 45% is not 
consistent with recovered HFrEF medical history, the participant may 
be included after review of previous echocardiographic images and 
discussion with the study medical monitor. 
7. Has maximal left ventricular wall thickness ≥ 12 mm OR documented 
elevated left ventricular mass index (LVMI) by 2-dimensional 
imaging (> 95 g/m2 if female and > 115 g/m2 if male) as determined 
by the echocardiography central laboratory.  
8. Has adequate acoustic windows on screening resting TTE as 
determined by echocardiography central laboratory, to enable high 
likelihood of acquisition of high-quality TTEs throughout the study. 
Echocardiographic contrast agents may be used if the image quality of 
unenhanced echocardiographic images is deemed inadequate and there 
are no contraindications to the use of contrast agents 
 
. 
9. Has NYHA class II or III symptoms at Screening. 
10. Has safety laboratory parameters (chemistry, hematology, coagulation, 
and urinalysis) 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/she meets all of the following criteria: 
a. The safety laboratory parameter outside normal limits is 
considered by the investigator to be clinically unimportant. In 
this case, the investigator should discuss the result in question 
with the study medical monitor prior to enrollment. 
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b. If there is an alanine aminotransferase or aspartate 
aminotransferase result, the value must be <3 × the upper limit 
of the laboratory reference range. 
c. The body size-adjusted estimated glomerular filtration rate is 
≥ 30 mL/min/1.73 m2. 
11. Female participants must not be pregnant or lactating and, if sexually 
active (and not postmenopausal or surgically sterile per the definition 
below), must be using one of the following highly effective birth 
control methods from the Screening visit through 4 months after the 
last dose of study drug. Male partners of female participants must also 
use a contraceptive (eg, barrier, condom, or vasectomy). 
a. 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. 
b. Intrauterine device. 
c. Intrauterine hormone-releasing system. 
d. Female is surgically sterile or postmenopausal for 1 year. 
Permanent sterilization includes hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, and/or documented 
bilateral tubal occlusion 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. 
Exclusion Criteria: 
1. Previously participated in a clinical study in which mavacamten was 
received. 
2. Hypersensitivity to any of the components of the mavacamten 
formulation. 
3. Participated in a clinical trial where the participant received any 
investigational drug (or is currently using an investigational device) 
within 30 days prior to Screening or 5 times the respective elimination 
half-life (whichever is longer). 
4. Has a prior diagnosis of hypertrophic cardiomyopathy OR a known 
infiltrative or storage disorder which could cause HFpEF and/or 
cardiac hypertrophy, such as amyloidosis, Fabry disease, or Noonan 
syndrome with LV hypertrophy OR a positive serum immunofixation 
result unless a hematologist confirms the patient does not have 
amyloidosis or multiple myeloma. 
5. Has any medical condition that precludes exercise stress testing (for 
stress echocardiogram). 
6. Has a history of syncope within the last 6 months or sustained 
ventricular tachycardia with exercise within the past 6 months. 
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7. Has a history of resuscitated sudden cardiac arrest at any time or 
known appropriate implantable cardioverter defibrillator discharge 
within 6 months prior to Screening. 
8. Has persistent or permanent atrial fibrillation not on anticoagulation 
for at least 4 weeks prior to Screening and/or is not adequately rate 
controlled within 6 months prior to Screening (note: participants with 
persistent or permanent atrial fibrillation who are anticoagulated and 
adequately rate-controlled are allowed). 
9. For participants on beta blocker, verapamil, or diltiazem, any dose 
adjustment < 14 days before Screening. 
10. Currently treated or planned treatment during the study with either: 
(a) a combination of beta blocker and verapamil or a combination of 
beta blocker and diltiazem, (b) disopyramide, or (c) biotin or biotin-
containing supplements/multivitamins. 
11. Has any electrocardiogram (ECG) abnormality considered by the 
investigator to pose a risk to participant safety (eg, second-degree 
atrioventricular block type II). 
12. Has either: (a) known unrevascularized obstructive coronary artery 
disease OR (b) acute coronary syndrome in the last 3 months. 
13. Has known moderate or severe aortic valve stenosis, 
hemodynamically significant mitral stenosis, or severe mitral or 
tricuspid regurgitation at Screening (all in the investigator’s 
judgment). 
14. Has any acute or serious comorbid condition (eg, major infection or 
hematologic, renal, metabolic, gastrointestinal, or endocrine 
dysfunction) that, in the judgment of the investigator, could lead to 
premature termination of study participation or interfere with the 
measurement or interpretation of the efficacy and safety assessments 
in the study. 
15. Has severe chronic obstructive pulmonary disease, or other severe 
pulmonary disease, requiring home oxygen, chronic nebulizer therapy, 
chronic oral steroid therapy or hospitalized for pulmonary 
decompensation within 12 months. 
16. Hemoglobin < 10.0 g/dL. 
17. Body mass index (BMI) ≥ 45.0 kg/m2. 
18. Positive serologic test at Screening for infection with human 
immunodeficiency virus, hepatitis C virus, or hepatitis B virus. 
Positive hepatitis BsAb participants are allowed as this positive 
serologic test denotes presence of neutralizing, protective antibodies 
and does not denote chronic infection. 
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19. Active coronavirus disease 2019 (COVID-19) infection and/or other 
acute respiratory infection at time of Screening or randomization. 
20. History of clinically significant malignant disease within 5 years of 
Screening: 
a. Participants who have been successfully treated for 
nonmetastatic cutaneous squamous cell or basal cell 
carcinoma or have been adequately treated for cervical 
carcinoma in situ can be included in the study. 
21. History or evidence of any other clinically significant disorder, 
condition, or disease (with the exception of those outlined above) that, 
in the opinion of the investigator or study medical monitor, would 
pose a risk to participant safety or interfere with the study evaluation, 
procedures, or completion. 
22. Currently taking, or has taken within 14 days prior to Screening, a 
prohibited medication (including over-the-counter medications) such 
as a cytochrome P450 (CYP) 2C19 inhibitor (eg, omeprazole, 
esomeprazole), a strong CYP3A4 inhibitor, or St. John’s Wort. 
23. Prior or concomitant treatment with cardiotoxic agents such as 
doxorubicin or similar. 
24. Unable to comply with the study requirements, including the number 
of required visits to the clinical site. 
25. Employed by, or a relative of someone employed by MyoKardia, the 
investigator, or his/her staff or family. 
26. Left ventricular global longitudinal strain by TTE in the range from 
0 to -12.0 (assessed by central TTE reader). 
27. Acute decompensated heart failure events requiring intravenous (IV) 
diuretics, IV inotropes, IV vasodilators, or a left ventricular assist 
device within 30 days prior to Screening. 
28. NT-proBNP at Screening > 2000 pg/mL. 
29. Known hypersensitivity or contraindication to the IV 
echocardiography contrast agent, if contrast echocardiography is 
required due to inadequate quality of unenhanced echocardiographic 
images. 
Disclosure Statement: This is a single-arm, open-label, exploratory study. 
Number of Sites: Approximately 30 study sites within or outside the United States 
Number of Participants: Approximately 35 participants 
Study Procedures and Treatment: 
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Doses of mavacamten used in this study will be 2.5 and 5 mg. Dose adjustments at Week 14 (described 
in greater detail below) will be based upon NT-proBNP and LVEF measured at the Week 12 visit. 
Study visits will occur at Prescreening (optional), Screening, Day 1, Week 6, Week 12, Week 14, 
Week 
, Week 
, Week 26, and the End of Study (EOS) visit at Week 34. 
 
 Assessments during the 
treatment period will include vital signs, AEs, concomitant medications, abbreviated physical 
examination, weight, 12-lead ECG, 
, 
, safety laboratory assessments 
(chemistry, hematology, coagulation panel, and urinalysis), 
, hs-cTnT, NT-proBNP, urine 
pregnancy test (for women of childbearing potential only), 
 
 
 
 
. In addition, participants will be contacted via telephone call at Weeks 2, 
4, 8, 10, 16, 
, and 24 to collect information about AEs and concomitant medications. Participants 
who prematurely discontinue study drug at any time will attend an early drug discontinuation visit 
within 14 days of study drug discontinuation and the EOS visit at Week 34. 
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The dose may be 
 for safety at any time. 
Safety will be monitored throughout the study. 
Criteria for Evaluation: 
Efficacy: The primary endpoint is change from baseline to Week 26 in NT-proBNP (at rest) and cTnT 
(at rest). 
Safety: Safety assessments include monitoring of AEs and concomitant medications, safety laboratory 
assessments, physical examinations, vital sign measurements, TTEs, cardiac/activity monitoring, and 
ECGs. 
Statistical Methods: 
This exploratory study will include a total of approximately 35 participants. 
In general, descriptive summaries will be presented at each visit. The descriptive summary for 
continuous variables will also be provided for the change from baseline. Summaries of continuous 
variables will include the number of participants, mean, standard deviation, median, first quartile, third 
quartile, minimum, and maximum. For variables with highly skewed distribution (eg, log-normal 
distribution), such as hs-cTnT and NT-proBNP, geometric mean and percent coefficient of variation 
will also be reported in descriptive summaries. Descriptive summaries for categorical variables will 
include the number and percentage of participants. Unless otherwise stated, denominators for 
percentages will be the number of participants in the analysis population. 
Study Committees: Independent Data Monitoring Committee 
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1.2. 
Schema 
Figure 1: 
MYK-461-019 Study Schema 
 
Abbreviations: D = Day; EOS = End of Study; EOT = End of Treatment;  
NT-proBNP = N-terminal pro b-type natriuretic peptide; QD = once daily; 
; 
wks = weeks. 
 
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1.3. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures 
Assessment 
Optional 
Prescreening: Up to 
Day -49a 
Screening: Up 
to Day -28  
D1b 
Wk 2, 4, 8, 10, 
16, 
, 24 
(TC)c 
Wk  
6c 
Wk  
12c 
Wk  
14c 
Wk 
 
Wk 
 
Wk  
26/ 
EOTc, e 
Early 
Discont. 
Visitf 
Wk 34/ 
EOSc 
Informed consent 
Xg 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical examination 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Abbreviated physical 
examinationh 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
Height 
X 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures (Continued) 
Assessment 
Optional 
Prescreening: Up
to 
Day -49a 
Screening: Up 
to Day -28  
D1b 
Wk 2, 4, 8, 10, 
16, 
, 24 
(TC)c 
Wk  
6c 
Wk  
12c 
Wk  
14c 
Wk 
  
Wk 
 
Wk  
26/ 
EOTc,e 
Early 
Discont. 
Visitf 
Wk 34/ 
EOSc 
Hepatitis panel, HIV testl 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum free light chain ratio 
and SPEP w/immunofixationl 
 
X 
 
 
 
 
 
 
 
 
 
 
Chemistryl 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyl 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panell 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisl 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
HbA1cl 
 
X 
 
 
 
 
 
 
 
 
 
 
NT-proBNPl 
X 
X 
Xm,n 
 
X 
X 
X 
X 
X 
Xn 
X 
Xn 
hs-cTnTl 
X 
X 
Xm,n 
 
X 
X 
X 
X 
X 
Xn 
X 
Xn 
TSHl 
 
X 
 
 
 
 
 
 
 
 
 
 
FSH and serum pregnancy 
test (females)l 
 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(females)l 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures (Continued) 
Assessment 
Optional 
Prescreening: Up 
to 
Day -49a 
Screening: Up 
to Day -28 
D1b 
Wk 2, 4, 8, 10, 
16, 
, 24 
(TC)c 
Wk  
6c 
Wk  
12c 
Wk  
14c 
Wk 
 
Wk 
 
Wk  
26/ 
EOTc,e 
Early 
Discont. 
Visitf 
Wk 34/ 
EOSc 
IMP QD 
 
 
 
 
 
 
 
 
 
 
 
 
Adjust dose 
 
 
 
 
 
 
X 
 
 
 
 
 
IMP dosing at site 
 
 
X 
 
 
 
 
 
 
X 
 
 
IMP compliance 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
D = Day; ECG = electrocardiogram; Discont. = discontinuation; eCRF = electronic case report form; EOS = End of Study; EOT = End of Treatment; 
FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HIV = human immunodeficiency virus; 
; 
hs-cTnT = high-sensitivity cardiac troponin T; 
; IMP = investigational medicinal product;  
; NT-proBNP = N-terminal pro b-type natriuretic peptide; 
; 
; QD = once daily; 
; SPEP = serum protein electrophoresis; TC = telephone call;  
TSH = thyroid-stimulating hormone; 
; Wk = Week. 
a Although encouraged for all potential participants, the prescreen for initial biomarker data is not required to be performed at the investigator’s discretion if 
prior NT-proBNP and/or cardiac troponin results from the ambulatory/outpatient setting indicate that the participant is likely to qualify for the study. In this 
case, the prior biomarker results should be documented in the eCRF (including assay type [high-sensitivity or not] and laboratory-specific upper limit of 
normal). 
 
. 
c Visit may be conducted in a window of ±3 days from the timepoint. 
  
 
 
  
e EOT visit assessments may be performed over up to 3 consecutive days if needed for scheduling purposes given the number of assessments. 
f The Early Discontinuation Visit may be utilized for the purposes of either permanent study drug discontinuation (without withdrawal from the study) or 
discontinuation/withdrawal from the study. In the former case, the EOS visit will still be conducted approximately 8 weeks after the Early Discontinuation Visit 
(and without functional testing 
 
). 
g There is a separate consent for the assessments completed at the optional prescreening visit. 
h Abbreviated physical examination is an abbreviated cardiopulmonary physical examination, with other systems assessed as appropriate based on interval 
history at the investigator’s discretion. 
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Table 1: 
Schedule of Study Procedures (Continued) 
l Refer to the Study Laboratory Manual for details on how to complete the procedures. 
m Sampling for
, NT-proBNP, and hs-cTnT should be drawn predose.  
n Sampling for 
, NT-proBNP, and hs-cTnT must be drawn prior to exercise 
 
 
 
 
 
 
 
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2. 
INTRODUCTION 
Mavacamten is a targeted cardiac-specific myosin inhibitor being developed for once-daily 
treatment of hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection 
fraction (HFpEF) and chronic elevation of N-terminal pro b-type natriuretic peptide (NT-
proBNP). 
2.1. 
Study Rationale 
This is a Phase 2a proof-of-concept study to assess safety, tolerability, and preliminary efficacy 
of mavacamten treatment on NT-proBNP levels and high-sensitivity cardiac troponin T 
(hs-cTnT) levels in participants with HFpEF and chronic elevation of cardiac biomarkers. The 
data from this study will complement results from the completed MYK-461-006 
MAVERICK-HCM study in symptomatic participants with the related condition nonobstructive 
hypertrophic cardiomyopathy (nHCM). Data from this study will inform future study designs of 
mavacamten in participants with HFpEF. 
2.2. 
Background 
Heart failure with preserved ejection fraction is a clinical syndrome defined by current or prior 
heart failure symptoms, evidence of cardiac dysfunction as a cause of the symptoms, and a left 
ventricular ejection fraction (LVEF) ≥50%. Although HFpEF is a complex syndrome with 
multiple causes, left ventricular (LV) diastolic dysfunction with elevated filling pressures and 
impaired exercise capacity play an important role in the pathophysiology of the condition. 
Mavacamten is a first-in-class, small molecule, selective allosteric inhibitor of cardiac myosin 
that reversibly inhibits its binding to actin. Mavacamten’s profile of myosin modulation is 
predicted to reduce ventricular filling pressures in participants with HFpEF and LV hypertrophy 
by improving ventricular compliance. 
A related condition, nHCM—which can present with the HFpEF phenotype (Pieske et al, 2019)—
is characterized clinically by unexplained 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, which is often caused by mutations in genes encoding cardiac sarcomere 
proteins, is myocardial hypercontractility accompanied by reduced LV compliance, often with 
reduced ventricular chamber size, often supranormal ejection fraction, and diastolic dysfunction. 
In the recent MAVERICK-HCM trial, mavacamten was shown to robustly reduce both 
NT-proBNP (an indicator of wall stress) and cardiac troponin I (cTnI) (an indicator of myocardial 
injury) in participants with symptomatic nHCM (Ho et al, 2020). Potentially beneficial effects of 
mavacamten were most pronounced in a combined subset of higher risk participants: those with 
either baseline cTnI greater than the 99th percentile (of a reference population) or with E/e'average 
(an echocardiogram surrogate for elevated LV filling pressures and ratio of early filling velocity of 
blood entering the left ventricle across the mitral valve during diastole to the velocity of motion of 
the myocardium in the region of the mitral annulus during the early filling portion of diastole) >14. 
As the pathophysiology underlying nHCM and HFpEF is similar, this proof-of-concept study 
tests the hypothesis that an adjacent population of participants with HFpEF will experience 
similar salutary biomarker changes to those seen in participants with nHCM in the 
MAVERICK-HCM study. Primary efficacy biomarkers in this study focus on NT-proBNP and 
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hs-cTnT 
. The focus on hs-cTnT 
is in light of published studies demonstrating several advantages of this cardiac troponin assay. 
First, hs-cTnT is a more sensitive prognostic marker 
 
 
. Secondly, hs-cTnT, but not 
, has been shown to be a reliable biomarker to 
reflect echocardiographic stages of diastolic dysfunction 
, a hallmark of 
HFpEF. Furthermore, the latter study demonstrated that hs-cTnT concentrations corresponded 
with LV wall thickness and left atrial chamber size. Therefore, this study focuses on a segment 
of HFpEF characterized by LV hypertrophy, LVEF >60%, and chronically elevated NT-proBNP 
(elevated wall stress) with or without elevated hs-cTnT (indicating ongoing myocardial injury).  
2.2.1. 
Clinical Studies 
As of 31 October 2019, clinical conduct has been completed for 9 studies as follows: 
• Study MYK-461-002, a single-ascending dose (SAD) study in 48 healthy participants 
• Study MYK-461-003, a multiple-ascending dose study in 60 healthy participants 
• Study MYK-461-009, a drug-interaction study with verapamil in 25 healthy 
participants 
• Study MYK-461-010, a drug-interaction study with an oral contraceptive in 
13 healthy women 
• Study MYK-461-011, an ethnobridging pharmacokinetics (PK) study in 20 Japanese 
and 8 Caucasian participants 
• Study MYK-461-012, an intrinsic factor PK study in 8 participants with cytochrome 
P450 (CYP) 2C19 poor metabolizers (PMs) and 8 participants identified as CYP2C19 
normal metabolizers (NMs). 
• Study MYK-461-013, a single-dose, mass balance study in 6 healthy participants 
• Study MYK-461-001, a SAD study in 15 participants with HCM 
• Study MYK-461-004 (PIONEER-HCM), a Phase 2 study in participants with 
obstructive hypertrophic cardiomyopathy (oHCM) 
In total, 210 participants with HCM or healthy participants were enrolled across the completed 
studies, 188 of whom were exposed to at least 1 dose of mavacamten. 
Additionally, more than 400 participants have been enrolled across 6 studies of mavacamten that 
were ongoing as of 31 October 2019: 
• Study MYK-461-005 (EXPLORER-HCM), a Phase 3, multinational, randomized, 
double-blind, placebo-controlled study in participants with symptomatic oHCM 
• Study MYK-461-006 (MAVERICK-HCM), a Phase 2 randomized, 
placebo-controlled, concentration-guided exploratory study in participants with 
symptomatic nHCM 
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• Study MYK-461-008 (PIONEER-OLE), an open-label extension study in participants 
with symptomatic oHCM who were previously enrolled in Study MYK-461 
PIONEER-HCM 
• Study MYK-461-007 (MAVA-LTE), an open-label extension study in participants 
with symptomatic HCM who were previously enrolled in Studies MYK-461-006 
(MAVERICK-HCM) or MYK-461-005 (EXPLORER-HCM) studies 
• Study MYK-461-014, a 3-period cross-over study in healthy participants to assess the 
relative bioavailability of the initial capsule formulation and the final commercial 
formulation of mavacamten, and the effect of food on the final commercial 
formulation 
• Study MYK-461-015, an intrinsic factor study to assess PK of mavacamten on 
participants with the mild and moderate hepatic impairment and healthy controls 
For a full list of studies, please reference the current Investigator’s Brochure (IB).  
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2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of mavacamten may be found in the IB. 
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2.3.1. 
Risk Assessment 
The safety profile of mavacamten treatment for participants with HCM is acceptable in the 
context of the observed clinical efficacy. Cumulatively (as of 30 October 2020), 97 total SAEs 
have been reported in 61 participants in the mavacamten clinical development program. Of these, 
69 SAEs occurred in 45 participants treated with mavacamten and 28 SAEs occurred in 17 
participants treated with placebo. Most serious and nonserious events reported for mavacamten-
treated participants across the program were outcomes or symptoms of the underlying disease. No 
clinically significant off-target treatment effects were identified for mavacamten. In the pivotal 
Phase 3 study (MYK-461-005), dizziness was the most frequently reported AE and was more 
frequent in mavacamten-treated participants than placebo-treated participants. In the integrated 
safety summary, dizziness occurred in 15.5% of mavacamten treated participants and 12.2% of 
placebo treated participants. Given the absence of clear alternative etiology in a high proportion 
of participants, dizziness is proposed as an adverse drug reaction for mavacamten. Other proposed 
adverse drug reactions for mavacamten include heart failure and systolic dysfunction, which 
occurred in <5% of participants administered mavacamten. Systolic dysfunction with 
mavacamten has been reversible and has not resulted in a picture of progressive cardiac failure 
(recurrent hospitalizations and progressive LVEF reduction) as described in the literature 
associated with progression of underlying HCM. 
Based on nonclinical data and the available clinical data, the most likely risks are those associated 
with higher exposures resulting in excessive decrease in cardiac contractility (decline in LVEF). 
Reduced tolerance might be reflected in nonspecific AEs such as fatigue or in reflex changes in 
resting heart rate (HR) or systolic blood pressure (BP). Higher exposures could result in the 
development of signs or symptoms of systolic heart failure, especially in the setting of 
simultaneous tachyarrhythmias or ischemia. 
Safety testing in other mammalian species has demonstrated that dose-limiting toxicity is related 
to excess pharmacologic effect and not to off-target adverse effects. Experiments with isolated 
adult rat ventricular myocytes in vitro and with anesthetized rats in vivo have established that the 
pharmacological effects of mavacamten can be counteracted by β-adrenergic agonists 
(isoproterenol and dobutamine, respectively) or the calcium sensitizer levosimendan. 
Teratogenicity is considered a potential risk due to findings in nonclinical studies conducted in 
2 species (rabbits and rats) that resulted in postimplantation loss, decreased mean fetal body 
weight, and fetal malformations (visceral and skeletal) at doses that overlap with doses used in 
humans. However, there are no clinical data available for pregnancy with exposure to 
mavacamten. No pregnancies have been reported in participants exposed to mavacamten due to 
use of stringent contraceptive measures in all trials including use of oral contraceptives. Study 
MYK-461-010, a DDI study, confirmed that oral contraceptives are safe to use while on 
mavacamten. 
Three important potential risks are described below. See the current IB for further details. 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Drug 
Systolic dysfunction 
Data across nonclinical 
toxicology studies have shown 
that plasma exposures 
associated with excess 
pharmacology likely to lead to 
reduced cardiac function, 
decreased blood pressure, and 
compensatory increases in heart 
rate. Clinical data have shown 
that dose-dependent on-target 
reductions in left ventricular 
ejection fraction (LVEF) have 
generally been well tolerated in 
healthy participants. Data from 
Study MYK-461-006, 
conducted in participants with 
nonobstructive hypertrophic 
cardiomyopathy (nHCM), 
demonstrated that those who 
experienced decreases in LVEF 
were returning to normal 
pretreatment levels after 
discontinuation of study 
treatment. 
As this risk is related to 
excessive on-target 
pharmacology, 
 
 
 
 
. 
Pharmacodynamic biomarkers 
(including N-terminal-pro B 
type natriuretic peptide, high 
sensitivity cardiac troponin and 
LVEF) by transthoracic 
echocardiography) will guide 
and should contribute to the 
safety 
. 
Additionally, LVEF is assessed 
serially throughout the study and 
will lead to temporary and/or 
permanent discontinuation of 
study drug if safety thresholds 
are met 
 
Prolonged QTc 
Consistent prolongation of 
corrected QT interval (QTc) 
with the typical QT 
measurements has been 
identified across all chronic dog 
studies. Clinical data from 
human exposure to mavacamten 
are mixed. Dose- and 
concentration-dependent QTc 
prolongation was observed in 
healthy participants in multiple 
ascending dose Study MYK-
461-003. However, no QTc 
prolongations were observed in 
the single-dose studies or in 
healthy participants, in the 
12-week study of participants 
with obstructive hypertrophic 
cardiomyopathy (Study 
MYK-461-004), or in the 
QTc prolongation, where 
observed in either animal studies 
or in healthy volunteers in the 
multiple ascending dose Study 
MYK-461-003, has been dose 
and concentration dependent. As 
the dosing strategy in this study 
is conservative, with a 
maximum dose of 5 mg in this 
protocol, this should mitigate 
any risk of QTc prolongation. 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
nHCM (Study MYK-461-006) 
participants at the 16-week (End 
of Treatment) analysis. 
Teratogenicity 
Oral administration of 
mavacamten in nonclinical 
studies conducted in 2 species 
(rabbits and rats) resulted in 
postimplantation loss, decreased 
mean body weight, skeletal 
malformations (rats) and 
visceral and skeletal 
malformations (rabbits), 
suggestive of a teratogenic 
potential of the compound. 
There are no clinical data on the 
safety of mavacamten during 
pregnancy, and highly effective 
contraception is required in the 
ongoing clinical studies. 
The risk of embryofetal toxicity 
due to paternal drug exposure in 
the semen was assessed based 
on preclinical data, actual semen 
concentrations of mavacamten 
in men dosed with mavacamten 
in Study MYK-461-003, and the 
potential for these concentration 
levels to cause maternal 
systemic exposures that could be 
teratogenic. It was concluded 
from the findings and estimates 
of maternal exposure by a man 
taking mavacamten that the risk 
of teratogenic effects caused by 
the drug transferred by semen or 
other body fluids is negligible. 
Effective forms of contraception 
to mitigate this risk are specified 
in this protocol. 
Nonlive COVID-19 vaccination is considered a simple concomitant medication within the study. 
However, the efficacy and safety of nonlive vaccines (including non-live COVID-19 vaccines) in 
participants receiving mavacamten is unknown. 
2.3.2. 
Benefit Assessment 
There is no currently known benefit of mavacamten to individuals with HFpEF; however, the 
results of the MAVERICK-HCM study of mavacamten in a high-risk subset of individuals with 
symptomatic nHCM suggest the potential for improvement of biomarkers related to LV wall 
stress (NT-proBNP) and myocardial injury (cardiac troponin) in HFpEF, in addition to E/e' as a 
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marker of diastolic function. Therefore, this study aims to test the hypothesis that mavacamten 
administration in HFpEF can improve biomarkers of cardiac wall stress and myocardial injury. 
The results have the potential to guide further development to more rigorously assess potential 
benefit in this segment of HFpEF patients. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to mitigate risk to participants in this study, the potential 
risks identified in association with mavacamten are justified by the anticipated potential benefits 
that may be afforded to participants with HFpEF. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To evaluate the safety and tolerability of a 
26-week course of mavacamten 
• Frequency and severity of treatment-emergent 
adverse events (TEAEs), adverse events of 
special interest (AESIs) [symptomatic overdose, 
outcomes of pregnancy, left ventricular ejection 
fraction (LVEF) ≤30%], and serious adverse 
events (SAEs); laboratory abnormalities; vital 
sign abnormalities; and cardiac rhythm 
abnormalities 
• To evaluate the effect of a 26-week course of 
mavacamten on N-terminal pro b-type 
natriuretic peptide (NT-proBNP) levels (at rest) 
• Change from baseline to Week 26 in 
NT-proBNP (at rest) 
• To evaluate the effect of a 26-week course of 
mavacamten on cardiac troponin T (cTnT) 
levels (at rest) 
• Change from baseline to Week 26 in cTnT (at 
rest), as assessed by a high-sensitivity assay 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a multicenter, exploratory, open-label, Phase 2a study to explore the safety, efficacy, 
pharmacodynamic effect, 
and tolerability of mavacamten in approximately 35 ambulatory 
participants with symptomatic HFpEF and elevated NT-proBNP with or without elevation in hs-
cTnT as defined in the inclusion/exclusion criteria.  
The study will include an up to 7-week screening period, a 26-week treatment period, and an 
8-week posttreatment follow-up period. 
Study visits will occur at Prescreening (optional), Screening, Day 1, Week 6, Week 12, Week 14, 
Week 18, Week 22, Week 26, and the End of Study (EOS) visit at Week 34 (Table 1). 
 
 
Assessments during the treatment period will include vital signs, AEs, concomitant medications, 
abbreviated physical examination, weight, 12-lead electrocardiogram (ECG), 
 
, 
, safety laboratory assessments (chemistry, 
hematology, coagulation panel, and urinalysis), 
, NT-proBNP, hs-cTnT, urine pregnancy 
test (for women of childbearing potential only), 
 
 
 
 
 
. In addition, participants will be 
contacted via telephone call at Weeks 2, 4, 8, 10, 16, 
, and 24 to collect information about AEs 
and concomitant medications. Participants who prematurely discontinue study drug at any time 
will attend an early drug discontinuation visit within 14 days of study drug discontinuation and 
the EOS visit at Week 34. 
All participants will initially receive 2.5 mg mavacamten orally QD. At Week 14, the dose for 
some participants may be 
 5 mg QD based on NT-proBNP and resting LVEF 
measured at the Week 12 visit. 
 
 
 
 
 
 
 
 
 
4.2. 
Scientific Rationale for Study Design 
This study will test the hypothesis that mavacamten treatment can reduce biomarkers of cardiac 
wall stress and myocardial injury in a targeted segment of HFpEF participants that shares similar 
features to a subset of MAVERICK-HCM participants with symptomatic nHCM who 
experienced similar improvements in wall stress and myocardial injury. Additionally, the study 
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will provide a preliminary assessment of the tolerability and safety of mavacamten 
administration in this targeted HFpEF segment. 
Assuming similar kinetics of NT-proBNP and troponin changes to those seen in nHCM, the 
open-label design will allow adequate assessment of biomarker reduction without a placebo 
group as individual and mean decreases in both NT-proBNP and troponin (if observed at 
Week 26) would be expected to return to approximately baseline by Week 34 (the end of the 
8-week washout period). 
The study additionally will explore several measures of symptoms and functioning in the 
participants with a goal of obtaining preliminary estimates of the effects of mavacamten on these 
parameters. These data may be useful in informing future study designs in HFpEF. 
4.3. 
Justification for Dose 
In the MAVERICK-HCM study, biomarker reductions (NT-proBNP and cardiac troponins) were 
noted in study participants at Week 4 of treatment when all participants were receiving 5 mg of 
mavacamten orally. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the EOS visit shown in the Schedule of Study Procedures (Table 1). 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Able to understand and comply with the study procedures, understand the risks involved 
in the study, and provide written informed consent according to federal, local, and 
institutional guidelines before the first study-specific procedure. 
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2. Is at least 50 years old at Screening. 
3. Body weight is greater than 45 kg at Screening. 
4. Documented prior objective evidence of heart failure as shown by 1 or more of the 
following criteria: 
a. Previous hospitalization for heart failure with documented radiographic evidence of 
pulmonary congestion. 
b. Elevated LV end-diastolic pressure or pulmonary capillary wedge pressure at rest 
(≥15 mm Hg) or with exercise (≥ 25 mm Hg). 
c. Elevated level of NT-proBNP (> 400 pg/mL) or brain natriuretic peptide (BNP) 
(>200 pg/mL). In the absence of qualifying historical NT-proBNP or BNP levels 
meeting this threshold, screening NT-proBNP meeting the threshold in inclusion 
criterion 5 will satisfy inclusion criterion 4. 
d. Echocardiographic evidence of medial E/e' ratio ≥ 15 or left atrial enlargement (left 
atrial volume index >34 mL/m2) together with chronic treatment with spironolactone, 
eplerenone, or a loop diuretic. 
5. Meets 1 or both of the following criteria: 
a. A screening hs-cTnT ≥ 99th percentile AND a screening NT-proBNP > 200 pg/mL (if 
not in atrial fibrillation or atrial flutter) or > 500 pg/mL (if in atrial fibrillation or 
atrial flutter) OR if the screened participant is of African descent or has a BMI 
≥ 30.0 kg/m2, a screening hs-cTnT ≥ 99th percentile, AND a screening NT-proBNP 
> 160 pg/mL (if not in atrial fibrillation or atrial flutter) or > 400 pg/mL (if in atrial 
fibrillation or atrial flutter). OR 
b. A screening NT-proBNP > 300 pg/mL (if not in atrial fibrillation or atrial flutter) or 
> 750 pg/mL (if in atrial fibrillation or atrial flutter) OR if the screened participant is 
of African descent or has a BMI ≥ 30.0 kg/m2, a screening NT-proBNP > 240 pg/mL 
(if not in atrial fibrillation or atrial flutter) or > 600 pg/mL (if in atrial fibrillation or 
atrial flutter). 
6. Has documented LVEF ≥ 60% at the Screening visit as determined by the 
echocardiography central laboratory and no history of prior LVEF ≤ 45% under stable 
conditions. If historical LVEF ≤ 45% is not consistent with recovered HFrEF medical 
history, the participant may be included after review of previous echocardiographic 
images and discussion with the study medical monitor. 
7. Has maximal left ventricular wall thickness ≥ 12 mm OR documented elevated left 
ventricular mass index (LVMI) by 2-dimensional imaging (>95 g/m2 if female and >115 
g/m2 if male) as determined by the echocardiography central laboratory.  
8. Has adequate acoustic windows on screening resting TTE as determined by 
echocardiography central laboratory, to enable high likelihood of acquisition of high 
quality TTEs throughout the study. Echocardiographic contrast agents may be used if the 
image quality of unenhanced echocardiographic images is deemed inadequate and there 
are no contraindications to the use of contrast agents 
. 
9. Has NYHA Class II or III symptoms at Screening. 
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10. Has safety laboratory parameters (chemistry, hematology, coagulation, and urinalysis) 
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/she meets all of the following criteria: 
a. The safety laboratory parameter outside normal limits is considered by the 
investigator to be clinically unimportant. In this case, the investigator should discuss 
the result in question with the study medical monitor prior to enrollment. 
b. 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. 
c. The body size-adjusted estimated glomerular filtration rate is ≥30 mL/min/1.73 m2. 
11. Female participants must not be pregnant or lactating and, if sexually active (and not 
postmenopausal or surgically sterile per the definition below), must be using one of the 
following highly effective birth control methods from the Screening visit through 
4 months after the last dose of study drug. Male partners must also use a contraceptive 
(eg, barrier, condom, or vasectomy). 
a. 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. 
b. Intrauterine device. 
c. Intrauterine hormone-releasing system. 
d. Female is surgically sterile or postmenopausal for 1 year. Permanent sterilization 
includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or 
documented bilateral tubal occlusion 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. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Previously participated in a clinical study in which mavacamten was received. 
2. Hypersensitivity to any of the components of the mavacamten formulation. 
3. Participated in a clinical trial where the participant received any investigational drug (or 
is currently using an investigational device) within 30 days prior to Screening or 5 times 
the respective elimination half-life (whichever is longer). 
4. Has a prior diagnosis of HCM OR a known infiltrative or storage disorder which could 
cause HFpEF and/or cardiac hypertrophy, such as amyloidosis, Fabry disease, or Noonan 
syndrome with LV hypertrophy OR a positive serum immunofixation result unless a 
hematologist confirms the patient does not have amyloidosis or multiple myeloma. 
5. Has any medical condition that precludes exercise stress testing (for stress 
echocardiogram). 
6. Has a history of syncope within the last 6 months or sustained ventricular tachycardia 
with exercise within the past 6 months. 
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7. Has a history of resuscitated sudden cardiac arrest at any time or known appropriate 
implantable cardioverter defibrillator discharge within 6 months prior to Screening. 
8. Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks 
prior to Screening and/or is not adequately rate controlled within 6 months prior to 
Screening (note: participants with persistent or permanent atrial fibrillation who are 
anticoagulated and adequately rate-controlled are allowed). 
9. For participants on beta blocker, verapamil, or diltiazem, any dose adjustment <14 days 
before Screening. 
10. Currently treated or planned treatment during the study with either: (a) a combination of 
beta blocker and verapamil or a combination of beta blocker and diltiazem, 
(b) disopyramide, or (c) biotin or biotin-containing supplements/multivitamins. 
11. Has any ECG abnormality considered by the investigator to pose a risk to participant 
safety (eg, second-degree atrioventricular block type II). 
12. Has either: (a) known unrevascularized obstructive coronary artery disease OR (b) acute 
coronary syndrome in the last 3 months. 
13. Has known moderate or severe aortic valve stenosis, hemodynamically significant mitral 
stenosis, or severe mitral or tricuspid regurgitation at Screening (all in the investigator’s 
judgment). 
14. Has any acute or serious comorbid condition (eg, major infection or hematologic, renal, 
metabolic, gastrointestinal, or endocrine dysfunction) that, in the judgment of the 
investigator, could lead to premature termination of study participation or interfere with 
the measurement or interpretation of the efficacy and safety assessments in the study. 
15. Has severe chronic obstructive pulmonary disease, or other severe pulmonary disease, 
requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy or 
hospitalized for pulmonary decompensation within 12 months. 
16. Hemoglobin < 10.0 g/dL. 
17. Body mass index (BMI) ≥ 45.0 kg/m2. 
18. Positive serologic test at Screening for infection with human immunodeficiency virus, 
hepatitis C virus, or hepatitis B virus. Positive hepatitis BsAb participants are allowed as 
this positive serologic test denotes presence of neutralizing, protective antibodies and 
does not denote chronic infection. 
19. Active COVID-19 infection and/or other acute respiratory infection at time of Screening 
or randomization. 
20. History of clinically significant malignant disease within 5 years of Screening: 
a. Participants who have been successfully treated for nonmetastatic cutaneous 
squamous cell or basal cell carcinoma or have been adequately treated for cervical 
carcinoma in situ can be included in the study. 
21. History or evidence of any other clinically significant disorder, condition, or disease 
(with the exception of those outlined above) that, in the opinion of the investigator or 
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study medical monitor, would pose a risk to participant safety or interfere with the study 
evaluation, procedures, or completion. 
22. Currently taking, or has taken within 14 days prior to Screening, a prohibited medication 
(including over-the-counter medications) such as CYP2C19 inhibitor (eg, omeprazole, 
esomeprazole), a strong CYP3A4 inhibitor, or St. John’s Wort. 
23. Prior or concomitant treatment with cardiotoxic agents such as doxorubicin or similar. 
24. Unable to comply with the study requirements, including the number of required visits to 
the clinical site. 
25. Employed by, or a relative of someone employed by MyoKardia, the investigator, or 
his/her staff or family. 
26. Left ventricular global longitudinal strain (GLS) by TTE in the range from 0 to -12.0 
(assessed by central TTE reader). 
27. Acute decompensated heart failure events requiring intravenous (IV) diuretics, IV 
inotropes, IV vasodilators, or a left ventricular assist device within 30 days prior to 
Screening. 
28. NT-proBNP at Screening > 2000 pg/mL. 
29. Known hypersensitivity or contraindication to the IV echocardiography contrast agent, if 
contrast echocardiography is required due to inadequate quality of unenhanced 
echocardiographic images. 
5.3. 
Lifestyle Considerations 
The following restrictions apply for the specified times during the study period. If a participant 
does not comply with these restrictions or tests positive in any laboratory tests (eg, drug, alcohol, 
pregnancy), he/she may be excluded or withdrawn from the study. 
• Starting 72 hours prior to the first dose of study drug until the final follow-up visit, 
participants should not engage in unaccustomed intensive exercise except during 
protocol-specified exercise tests. 
• Starting at Screening, participants will be required to abstain from blood or plasma 
donation until 3 months after the final study visit. 
• Starting on Day 1 until the final follow-up visit, participants will be asked to abstain 
from grapefruit or grapefruit juice, Seville oranges, and quinine (eg, tonic water). 
• Starting at the time of signing informed consent, participants must abstain from 
taking biotin and biotin-containing supplements/multivitamins. 
Contraception requirements are discussed in the inclusion criteria in Section 5.1. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
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Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 
Individuals who do not meet the criteria for participation in this study (prescreen or screen 
failure) may be rescreened. 
5.5. 
Criteria for Temporarily Delaying 
With consideration to unforeseen circumstances (including those related to the COVID-19 
pandemic), randomization and/or initial study drug administration may be delayed, if necessary, 
upon documented mutual agreement by the study physician and MyoKardia or their designee. 
6. 
STUDY DRUG 
Study drug is defined as any investigational intervention intended to be administered to a study 
participant according to the study protocol. 
6.1. 
Study Drug Administered 
The study drug administered in this study is mavacamten supplied as 2.5 and 5 mg capsules. 
Mavacamten capsules of both strengths are identical in appearance. 
Participants will receive a mavacamten capsule (either 2.5 or 5 mg) once daily for 26 weeks 
(Day 1 to Week 26). 
 
 
Study drug will be supplied to participants in 30-count high-density polyethylene bottles that are 
appropriately labeled. Participants will be instructed to store study drug in a cool, dry place. 
Participants will take study drug as directed by the investigator/designee. Participants should be 
instructed to take study drug at approximately the same time every day. Study drug should be 
taken with approximately 8 ounces of water. Participants should never take > 1 dose of study drug 
within an 8-hour period. On study visit days, study drug dosing should be delayed until after 
study assessments are complete and the study staff instruct the participant to take their daily dose. 
Table 2 provides an overview of the study drug. 
Table 2: 
Study Drug 
Intervention Name 
Mavacamten 
Type  
Drug 
Dose Formulation 
Capsule 
Unit Dose Strength(s) 
2.5 mg and 5 mg 
Dosage Level(s) 
2.5 mg or 5 mg once daily 
Route of Administration 
Oral 
Use 
Experimental 
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Table 2: 
Study Drug (Continued) 
Intervention Name 
Mavacamten 
Investigational Medicinal Product 
Mavacamten 
Sourcing 
Provided by the sponsor 
Packaging and Labeling 
See Section 6.2  
6.2. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported and 
resolved before use of the study drug. 
Only participants enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. At the study site and site pharmacy all study drug must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study drug are provided in 
the Pharmacy Manual. 
6.2.1. 
Formulation, Packaging, and Labeling of Study Drug 
Mavacamten capsules are provided as size 2, blue opaque capsules printed with a yellow band on 
the body and a black band on the cap. Each capsule contains white to off-white powder. 
Mavacamten capsules are supplied in 2.5 and 5 mg strengths. Mavacamten capsules of both 
strengths are identical in appearance. 
Mavacamten is manufactured according to current Good Manufacturing Practice regulations. It is 
supplied in high-density polyethylene bottles with induction seals and child-resistant caps with 
30 capsules in each bottle. All bottles are labeled according to applicable local regulatory 
guidelines. 
Mavacamten capsules must be stored at 36°F to 77°F (2°C to 25°C) in the packaging supplied by 
MyoKardia. 
6.2.2. 
Direct-to-Participant Study Drug Shipment (At Selected Sites) 
In certain circumstances, it may be necessary to ship study drug directly to a participant to 
accommodate the participant’s schedule through Week 26. Study sites should contact the 
participant by telephone to confirm study drug delivery. Refer to the Pharmacy Manual for 
details. 
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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. There will be no blinding at the site level. 
6.4. 
Study Drug Compliance 
Participant compliance with study drug dosing will be monitored by capsule count at all study 
visits from Week 2 through the end of study treatment. Refer to the Pharmacy Manual for details. 
6.6. 
Continued Access to Study Drug After the End of the Study 
Not applicable. Currently, there is no continued access to study drug after the end of the study. 
6.7. 
Treatment of 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. Only symptomatic overdoses should be reported as AEs/adverse 
events of special interest (AESI). 
In the event of symptomatic overdose or in the presence of significant symptoms and/or clinical 
compromise, the investigator should contact the study medical monitor, and the study drug 
should be temporarily discontinued. The participant should be closely monitored clinically for 
AEs/SAEs, with supportive measures undertaken as clinically indicated. If necessary, corrective 
measures, as described in the 2013 American College of Cardiology Foundation/American Heart 
Association Guideline for the Management of Heart Failure (Yancy et al, 2013) and in the 2016 
European Society of Cardiology Guidelines for the Diagnosis and Treatment of Acute and 
Chronic Heart Failure (Ponikowski et al, 2016), should be implemented. Resumption of study 
drug must be approved by the study medical monitor. 
6.7.1. 
Reporting and Follow-up of Overdose 
Symptomatic overdose is an AESI as defined in Section 8.3.6. If a participant should experience 
symptomatic overdose, the investigator will report the symptomatic overdose to the study 
medical monitor and complete the required information in the electronic data capture (EDC) 
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system within 24 hours of study staff becoming aware of the overdose. Follow-up on the 
participant's condition will be conducted by the investigator and study staff. 
6.8. 
Prior and Concomitant Therapy 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements a participant is taking will be monitored at all study visits from 
Screening until the end of the study and documented on the appropriate electronic case report 
form (eCRF), including start/stop dates, dose, route of administration, and indication. 
6.8.1. 
Prior Medication 
At the time of providing signed informed consent, participants will be asked about medication 
use during the previous 30 days, including prescription and nonprescription medications, herbal 
medications, vitamins, and minerals. Any prohibited medication and restricted food items must 
be discontinued for ≥14 days before screening may proceed. 
6.8.2. 
Background HFpEF Medication 
As results of clinical trials to date in HFpEF have generally been neutral, management of the 
condition is primarily focused on associated symptoms (eg, edema) and/or conditions 
(eg, hypertension and atrial fibrillation). Background medications for HFpEF and related 
conditions and symptoms (eg, antihypertensives and mineralocorticoid antagonists) are allowed 
during the study unless specifically excluded by eligibility criteria. The treatment should be well 
tolerated for at least 2 weeks prior to screening and should generally be maintained through the 
EOS visit. In this context, investigators are encouraged not to change background medications 
(including dose) from Day 1 to Week 34; however, investigators should manage participants 
appropriately using their clinical judgment. Any change in medications must be entered into the 
eCRF with the rationale for the change. 
6.8.3. 
Prohibited Medication 
Medications that are prohibited during the study are outlined in Section 10.2. Prior or 
concomitant treatment with cardiotoxic agents, such as doxorubicin or similar, is prohibited. 
The study medical monitor should be contacted for any questions regarding prior or concomitant 
medications. 
6.8.4. 
COVID-19 Vaccine Considerations 
Locally authorized or approved COVID-19 vaccines that are NOT live are allowed and should be 
handled in the same manner as other vaccines. Administration may occur during the study, 
including during the administration of mavacamten study treatment and after the last 
administration of mavacamten study treatment. 
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7. 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Drug 
Temporary treatment discontinuation: 
• Will be implemented when a predefined safety threshold 
 has been met. 
• May be considered by the investigator in the case of an AE/SAE or for another reason. 
As a general rule, any discontinuation of study drug should be initially considered temporary 
unless permanent treatment discontinuation is mandated. 
In rare instances, it may be necessary for a participant to permanently discontinue study drug. If 
study drug is permanently discontinued, the participant will be encouraged to remain in the study 
to be evaluated for safety and study endpoints as appropriate through the EOS visit. See the 
Schedule of Study Procedures (Table 1) for data to be collected at the time of discontinuation of 
study drug and follow-up and for any further evaluations that need to be completed. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Participants with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin [TBL], or international normalized ratio [INR]) or signs/symptoms of 
hepatitis may meet the criteria for withholding of study drug or other protocol-required therapies. 
Withholding is either permanent or conditional depending on the clinical circumstances 
discussed below as specified in the United States (US) Food and Drug Administration (FDA) 
Guidance for Industry–Drug Induced Liver Injury: Premarketing Clinical Evaluation, July 2009. 
7.1.1.1. 
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 Section 10.5 for possible drug-induced liver injury (DILI), 
if all the criteria below are met: 
• TBL > 2 × ULN or INR > 1.5. 
• AND increased AST or ALT, if the baseline value was <ULN and AST or ALT 
elevation is > 3 × ULN. 
• AND no other cause for the combination of laboratory abnormalities is immediately 
apparent. Important potential causes for abnormal AST/ALT or TBL values include, 
but are not limited to, the following: 
− Obstructive gall bladder or bile duct disease. 
− Viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella). 
− Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right sided heart failure. 
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− Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or 
dietary supplements. 
− Heritable disorders causing impaired glucuronidation (eg, Gilbert syndrome); 
α-1 antitrypsin deficiency. 
− Autoimmune hepatitis. 
− Nonalcoholic steatohepatitis (NASH) or other fatty liver disease. 
If an alternative cause for hepatotoxicity is identified, or less stringent conditions develop 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 the participant 
population and/or the severity of the hepatotoxicity or event, as deemed appropriate for the 
safety of the participant. 
7.1.1.2. 
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 in Section 7.1.1.1, mavacamten should be withheld if ANY of the following criteria are 
met, and the participant should be evaluated for DILI: 
• AST or ALT > 8 × ULN at any time. 
• AST or ALT > 5 × ULN and < 8 × ULN for ≥2 weeks. 
• AST or ALT > 5 × ULN and < 8 × ULN and unable to adhere to enhanced 
monitoring schedule. 
• ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR >1.5). 
• ALT or AST > 3 × ULN and 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%). 
• TBL > 3 × ULN at any time. 
• ALP > 8 × ULN at any time. 
Mavacamten should be withheld pending an investigation into alternative causes of DILI. If 
mavacamten is withheld, the participant should be followed according to recommendations for 
possible DILI (Section 10.5). 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 7.1.1.3). 
7.1.1.3. 
Criteria for Rechallenge of Mavacamten After Potential Hepatotoxicity 
The decision to rechallenge a participant should be discussed and unanimously agreed upon by 
the investigator, the study co-coordinating investigators, and MyoKardia or their designee. 
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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 7.1.1.1) should never be rechallenged. 
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7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator or MyoKardia or their designee for 
safety, behavioral, or compliance reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early drug discontinuation visit 
should be conducted, as shown in the Schedule of Study Procedures (Table 1). See the Schedule 
of Study Procedures for data to be collected at the time of study discontinuation. 
The participant will be permanently discontinued both from the study drug and from the study at 
that time. 
If the participant withdraws consent for disclosure of future information, MyoKardia or their 
designee may retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, at minimum 
3 telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Site personnel, or an independent third party, will attempt to collect the vital status of 
the participant within legal and ethical boundaries for all enrolled participants, 
including those who did not receive study drug. Public sources may be searched for 
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vital status information. If vital status is determined as deceased, this will be 
documented and the participant will not be considered lost to follow-up. Sponsor 
personnel will not be involved in any attempt to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 in 
Section 10.1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Study Procedures 
(Table 1). Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with MyoKardia or their designee immediately 
upon occurrence or awareness to determine if the participant should continue or discontinue 
study drug. 
Adherence to the study design requirements, including those specified in the Schedule of Study 
Procedures, is essential and required for study conduct. 
Prescreening evaluations are optional and may be performed to assess chronic values of cardiac 
biomarkers if no historical values of chronic NT-proBNP or cardiac troponins are available. All 
screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
At the investigator’s discretion or per the request of MyoKardia or their designee, unscheduled 
visits may be conducted for reasons including, but not limited to, assessment of AEs, new or 
worsening symptoms, physical examinations, vital signs, laboratory tests, ECGs, 
. 
ECGs 
 conducted at unscheduled visits will be sent to the respective core laboratory for 
central reading. 
8.1. 
Pharmacodynamic Assessments 
Planned time points for all pharmacodynamic assessments are provided in the Schedule of Study 
Procedures (Table 1). 
8.1.1. 
Cardiac Biomarkers 
Blood samples will be collected to evaluate NT-proBNP, hs-cTnT, 
 concentrations as 
outlined in Table 1. 
With the exception of post-exercise cardiac biomarker samples, where indicated in the Schedule 
of Study Procedures, all blood draws for cardiac biomarkers must be drawn at rest and prior to 
exercise. Unscheduled or additional blood samples may be collected if appropriate in the opinion 
of the investigator (eg, for medical management of heart failure) and/or MyoKardia or their 
designee. Whenever possible, discussion with the study medical monitor is encouraged. 
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8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of Study Procedures 
(Table 1). 
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8.2.1. 
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). 
8.2.2. 
Physical Examinations 
At selected visits, a complete physical examination will be conducted including a neurological 
examination (gross motor and deep tendon reflexes), height (Prescreening and/or Screening only) 
and weight, and assessment of the following: general appearance, skin, head and neck, mouth, 
lymph nodes, thyroid, abdomen, musculoskeletal, cardiovascular, and respiratory systems. At all 
other clinic visits, an abbreviated cardiopulmonary physical examination will be conducted, with 
other systems assessed as directed by interval history. 
Height (cm) and body weight (kg) will be measured at Prescreening and/or Screening, and body 
mass index (kg/m2) will be calculated. Participants will be required to remove their shoes and 
wear clothing as specified by the clinical site. 
Body weight will be recorded as indicated in Table 1. 
8.2.3. 
Vital Signs 
Complete vital signs including temperature, HR, respiratory rate (RR), and BP will be assessed 
as in indicated in Table 1. 
Vital signs will be obtained with the participant in the same position; BP will be taken after at 
least 5 minutes of rest via an automated recorder. 
At all visits, vital signs will be taken prior to dosing. Alert values will be flagged. Refer to the 
Study Laboratory Manual for additional details. 
8.2.4. 
12-Lead Electrocardiograms 
Central read, single 12-lead ECG evaluations will be performed after 10 minutes of rest as indicated 
in Table 1. At clinic visits during the treatment period, ECGs will be taken prior to dosing. 
The investigator may perform 12-lead ECG safety assessments if he/she considers it is required 
for any other safety reason. These assessments should be recorded as an unscheduled assessment. 
8.2.5. 
Clinical Safety Laboratory Assessments 
Safety laboratory results will be assessed in an ongoing manner. See Section 10.3 for the list of 
clinical laboratory tests to be performed and to the Schedule of Study Procedures (Table 1) for 
the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory 
reports must be filed with the source documents. 
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• Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant's condition. 
• All laboratory tests considered clinically significant abnormal values during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or study 
medical monitor. 
− If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified, and 
MyoKardia or their designee notified. 
− All protocol-required laboratory tests, as defined in Section 10.3, must be 
conducted in accordance with the laboratory manual and the Schedule of Study 
Procedures (Table 1). 
− If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded. 
8.2.6. 
Pregnancy Testing 
Serum pregnancy testing will be performed at Screening for all females of childbearing potential. 
In addition, urine pregnancy testing in clinic will be conducted every 4 to 6 weeks throughout the 
study. Confirmatory serum testing will be performed if any urine test is positive. 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The investigator should refer to Section 10.4 for detailed definitions of AEs and SAEs and 
additional information regarding AE reporting. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up on all AEs. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.4. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs, including SAEs, will be collected from the signing of the informed consent form (ICF) 
until 56 days after the last dose of study drug (Table 1). 
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be recorded as pretreatment adverse events (PTAEs), as detailed in Section 10.4. 
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All SAEs/AESIs will be recorded and reported to MyoKardia or their designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Section 10.4. The investigator 
will submit any updated SAE data to MyoKardia or their designee within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the investigator must promptly notify 
MyoKardia or their designee (via paper SAE form). 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, AESIs (as defined in Section 8.3.6), and AEs will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 7.3), including being considered lost to follow-up at the end 
of the study. Further information on follow-up procedures is provided in Section 10.4. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to MyoKardia or their designee of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants and the safety of 
a study drug under clinical investigation are met. 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 or 
their 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, and interventions) and for updating the SAE eCRF with 
this information. 
MyoKardia or their designee 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 that are considered related to study drug after completion of the 
study should be promptly reported by the investigator to MyoKardia or their designee. 
Prompt notification by the investigator to MyoKardia or their designee 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. MyoKardia or their designee has a legal 
responsibility to notify both the local regulatory authority and other regulatory agencies about 
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the safety of a study drug under clinical investigation. MyoKardia or their designee will comply 
with country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, institutional review boards (IRBs)/independent ethics committees (IECs), and 
investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from MyoKardia or their designee will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5. 
Pregnancy 
Female participants of childbearing potential must use appropriate methods of contraception as 
listed in the inclusion criteria (Section 5.1). Female participants of nonchildbearing potential are 
defined as those who are permanently (surgically) sterilized or are postmenopausal. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, and bilateral tubal occlusion or 
ligation. Female participants are considered postmenopausal if they have had amenorrhea for at 
least 1 year following cessation of all exogenous hormonal treatments and FSH levels are in the 
postmenopausal range. 
• All pregnancies in female participants and female partners of male participants who 
received at least one dose of study drug must be reported if they occur anytime from 
the first dose of study drug to 4 months after the last dose of study drug. 
• The investigator is responsible for informing MyoKardia or their designee within 24 
hours of knowledge of the pregnancy even if no AE has occurred. If a pregnancy is 
reported, the investigator will record pregnancy information on the appropriate form 
and submit it to MyoKardia or their designee within 24 hours of learning of the 
pregnancy of the female participant or the female partner of a male participant (after 
obtaining the necessary signed informed consent from the female partner). 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, or ectopic pregnancy) are considered SAEs and will be 
reported as such. 
• The participant or pregnant female partner of a male participant will be followed to 
determine the outcome of the pregnancy. The participant will be asked to provide 
information on the outcome of the pregnancy through 6 months after birth or details 
of premature termination of the pregnancy. The investigator will collect follow-up 
information on the participant or pregnant female partner of a male participant and 
the neonate for 6 months after birth and the information will be forwarded to 
MyoKardia or their designee 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
drug by the investigator will be reported to MyoKardia or their designee, as described 
in Section 8.3.4. While the investigator is not obligated to actively seek this 
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information in former study participants or pregnant female partners of male 
participants, he/she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study drug. 
8.3.6. 
Adverse Events of Special Interest 
Symptomatic overdose, teratogenicity, and LVEF ≤30% as determined by local site read or 
centrally read echocardiogram are considered AESIs. 
AESIs are required to be reported by the investigator to MyoKardia or their designee within 24 
hours, irrespective of regulatory seriousness criteria. If a participant should experience 
symptomatic overdose, LVEF ≤30%, or if pregnancy outcome becomes known, the investigator 
will report the information to the study medical monitor and complete the required information 
in the EDC system within 24 hours of study staff becoming aware of the AESI. 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
There is no formal statistical hypothesis testing in this exploratory Phase 2a study. 
9.2. 
Sample Size Determination 
Given the exploratory nature of the study, no formal sample size calculation was done. The 
sample size will be approximately 35 participants. 
9.3. 
Analysis Sets 
For the purpose of analysis, the following analysis populations are defined: 
Table 4: 
Analysis Populations Definitions 
Analysis Population 
Definition 
ITT 
All enrolled participants regardless of whether they receive study drug. 
Safety 
All enrolled participants who receive at least 1 dose of study drug, with 
analyses conducted by actual treatment received. 
ITT = intention-to-treat; 
. 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary 
 endpoints. 
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9.4.1. 
General Considerations 
In general, descriptive summaries will be presented at each visit. The descriptive summary for 
continuous variables will also be provided for the change from baseline. Summaries of 
continuous variables will include the number of participants, mean, standard deviation (SD), 
median, first quartile, third quartile, minimum, and maximum. For variables with a highly 
skewed distribution (eg, log-normal distribution), such as hs-cTnT and NT-proBNP, geometric 
mean and percent coefficient of variation will also be reported in descriptive summaries. 
Descriptive summaries for categorical variables will include the number and percentage of 
participants. Unless otherwise stated, denominators for percentages will be the number of 
participants in the analysis population. 
9.4.2. 
Primary Pharmacodynamic Endpoints 
The primary pharmacodynamic endpoints are the following: 
• Change from baseline to Week 26 in NT-proBNP (at rest) 
• Change from baseline to Week 26 in hs-cTnT (at rest), as assessed by a high-
sensitivity assay 
Further details for these analyses will be specified in the study SAP. 
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Further details for these analyses will be specified in the study SAP. 
9.4.4. 
Safety Endpoints 
The safety endpoints are the following: 
• Frequency and severity of treatment-emergent adverse events (TEAEs), AESIs 
(symptomatic overdose, teratogenicity, and LVEF ≤30% as determined by local site 
read or centrally read echocardiogram), and SAEs; laboratory abnormalities; vital 
sign abnormalities; and cardiac rhythm abnormalities 
All safety analyses will be performed for 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, unless specified otherwise.  
• 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; 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 dose of study drug to the last dose of study drug + 56 days. 
9.4.4.1. 
Adverse Events 
AEs will be mapped to system organ classes (SOC) and preferred terms (PTs) using the Medical 
Dictionary for Regulatory Activities (MedDRA) v23.0. 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 drug. AEs with onset during the treatment-emergent period (ie, 
TEAEs) or with an onset before the first dose of study drug that increase in severity or become 
serious during the treatment-emergent period will be considered TEAEs. 
AE incidence tables will present the number and percentage of participants experiencing at least 
one TEAE by SOC, high-level group term (HLGT), high-level term (HLT), and PT in 
alphabetical order for each treatment group. Multiple occurrences of the same event in the same 
participant will be counted only once within a treatment phase. The denominator for computation 
of percentages is the safety population within each treatment group. 
AE incidence tables will be provided for TEAEs, including all TEAEs, all treatment-emergent 
SAEs, all treatment-emergent treatment-related AEs, all treatment-emergent treatment-related 
SAEs, TEAEs by severity, and all TEAEs leading to permanent treatment discontinuation. 
9.4.4.1.1. Death 
The number and percent of participants who died by study period (TEAE, on-study) will be 
summarized for the safety population, and a listing will be provided for all events involving a 
participant death, if applicable.  
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9.4.4.1.2. Pregnancy 
The following pregnancy summaries will be generated, if applicable: 
• Number of female participants or female partners of male participants who become 
pregnant  
• Outcomes of the pregnancies and analysis of the outcomes 
• TEAEs experienced during the pregnancy by primary SOC, HGLT, HLT, and PT 
showing the number and percent of participants sorted by internationally agreed order 
of SOC and alphabetic order of HLGT, HLT, and PT 
9.4.4.1.3. Symptomatic Overdose 
The following summaries for reports of symptomatic overdose will be generated, if applicable: 
• Number of participants who experienced symptomatic overdose summarized by 
treatment received 
• Analysis of the cause and occurrence of the symptomatic overdose 
• TEAE experienced during the symptomatic overdose by primary SOC, HGLT, HLT, 
and PT showing the number and percent of participants sorted by internationally 
agreed order of SOC and alphabetic order of HLGT, HLT, and PT 
9.4.4.2. 
12-Lead Electrocardiogram 
The RR, pulse rate (PR), QRS, and QT intervals will be measured and read by a central 
laboratory. 
 
. 
9.4.4.2.1. Correction for Heart Rate 
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. Each 
individual ECG QT value will be corrected for HR. 
 
 
 
 
9.4.4.2.2. ECG Numeric Variables 
Heart rate, 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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9.4.4.2.3. Categorical Analysis 
The number and percentage of participants with any postdose QTcF values of >450 msec, 
>480 msec, and >500 msec will be summarized. Participants with QTc values >500 msec will be 
listed with corresponding baseline values, QTcF, and baseline and treatment HR. The incidence 
count and percentage of participants with a QTcF increase from baseline of >30 msec and 
>60 msec will be summarized. 
9.4.4.2.4. 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. 
9.4.4.3. 
Laboratory Data 
The summary statistics (including number of participants, mean, median, SD, minimum and 
maximum) of all laboratory variables (laboratory values and changes from baseline), will be 
summarized at all baseline and postbaseline time points. 
Listings of participants with laboratory values that are outside of the reference range will be 
produced. 
9.4.4.3.1. Potential Drug-Induced Liver Injury 
The liver function tests, namely ALT, AST, ALP, and TBL, are used to assess possible 
drug-induced liver toxicity. 
 
 
 
 
 
9.4.4.4. 
Vital Signs Data 
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
vital sign variables (values and changes from baseline) will be summarized at all baseline and 
postbaseline time points. 
Listings of participants with vital sign values that are outside of the reference range will be 
produced. 
9.4.4.5. 
Other Safety Analyses 
Abnormal physical examination results will be listed. Concomitant medications will be 
summarized. 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Consideration 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
− Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• The study, inclusive of protocol amendments, will be conducted in accordance with 
local health authority requirements. Changes to the study conduct will not be 
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implemented without health authority notification or approval, as required, except as 
necessary to eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of US Title 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide MyoKardia or their designee with sufficient, 
accurate financial information as requested to allow MyoKardia or their designee to submit 
complete and accurate financial certification or disclosure statements to the appropriate 
regulatory authorities. Investigators are responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of US Title 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study center. 
• The study record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the 
ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 calendar days from the previous ICF signature date. 
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10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by MyoKardia or their designee. Any 
participant records or datasets that are transferred to MyoKardia or their designee will 
contain the identifier only; participant names or any information which would make 
the participant identifiable will not be transferred. 
• The participant must be informed that his/her personal study-related data will be used 
by MyoKardia or their designee in accordance with the local data protection law. The 
level of disclosure must also be explained to the participant who will be required to 
give consent for their data to be used as described in the informed consent 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
MyoKardia or their designee, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. 
10.1.5. 
Committees Structure 
10.1.5.1. Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) will meet at regular intervals to review 
ongoing study data. The role of the IDMC will be to act in an advisory capacity to MyoKardia or 
their designee with respect to safeguarding the interest of study participants, assessing interim 
safety data, and advising MyoKardia or their designee on important emerging study conduct 
issues. The IDMC may formulate recommendations in relation to the evaluation procedures and 
methodologies being employed to survey and detect potential safety signals. Meeting frequency, 
membership, and conduct will be described in the IDMC charter. 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic case 
report forms (CRFs) unless transmitted to MyoKardia or their designee or designee 
electronically (eg, laboratory data). The investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in CRF Completion Guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details, strategy, methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques will be delineated in the 
Monitoring Plan. 
• MyoKardia or designee is responsible for the data management of this study 
including quality checking of the data. 
• MyoKardia or their designee assumes accountability for actions delegated to other 
individuals (eg, contract research organizations). 
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• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 2 years following the date a marketing 
application is approved for the drug for the indication for which it is being 
investigated, or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and the FDA is 
notified (unless local regulations or institutional policies require a longer retention 
period). No records may be destroyed during the retention period without the written 
approval of MyoKardia or their designee. No records may be transferred to another 
location or party without written notification to MyoKardia or their designee. 
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
• Definition of what constitutes source data can be found in the Study Reference 
Manual. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
10.1.8. 
Study and Site Start and Closure 
Study Start Date and First Act of Recruitment 
The study start date is the date of informed consent for the first enrolled participant. 
The first act of recruitment is the screening of the first potential participant (after informed 
consent is obtained). 
Study/Site Termination 
MyoKardia or designee reserves the right to close the study site or terminate the study at any 
time for any reason at its sole discretion. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by MyoKardia or their designee or investigator may 
include but are not limited to: 
For study termination: 
• Discontinuation of further study drug development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, MyoKardia’s or their designee’s procedures, or 
GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants enrolled earlier than expected 
If the study is prematurely terminated or suspended, MyoKardia or their designee shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
10.1.9. 
Sponsor’s Responsibilities 
MyoKardia or their designee reserves the right to terminate the study at any time. MyoKardia or 
their designee and the investigators will assure that adequate consideration is given to the 
protection of the participants’ interests. MyoKardia or their designee 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 a regulatory agency or 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 
10.1.9.1. 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 or their designee ensures that the personal data are: 
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• 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 or their designee, 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 or their designee and will have the right to rectify erroneous or inaccurate data up 
until database lock. 
10.1.9.2. Study Supplies 
MyoKardia or their designee will supply or ensure the coordination of sufficient quantities of the 
following materials to each clinical site: 
• Mavacamten active capsules in 2 strengths (2.5 mg, 5 mg,) in 30-count bottles 
• Cardiac/activity monitoring devices, including accelerometers and ECG machines 
• Supplies for laboratory assessments 
• Study Reference Manual 
• Laboratory Manual 
• Pharmacy Manual 
• IXRS (Interactive Response System) Manual 
• IB 
10.1.9.3. Investigator Training 
All clinical sites will have a center-specific study initiation meeting to ensure the center staff 
understand 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 trained 
with information regarding GCP and regulations specific to the conduct of the clinical studies. 
Each clinical site will be responsible for ensuring that new study team members are adequately 
trained, and the training is documented. 
10.1.9.4. Ongoing Communication of Safety Information During the Study 
MyoKardia or their designee will provide investigators with documentation of SAEs from this 
study and other studies that are related to mavacamten and are unexpected, as appropriate. 
Investigators must forward this documentation to the IRB/IEC. 
MyoKardia or their designee will also notify investigators of any other significant safety findings 
that could alter the safety profile of the investigational medicinal product (IMP) from what is 
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described in the protocol and significantly affect the safety of participants, affect the conduct of 
the study, or alter the IRB/IEC opinion regarding continuation of the study. 
10.1.9.5. Study Monitoring 
MyoKardia, or their designee, and a contracted clinical research organization 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 investigators and clinical site staff are expected to provide adequate 
space for monitoring visits and allocate sufficient time to permit adequate review of the study’s 
progress. The investigators will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspections, providing direct access to source data/documents and study-related 
facilities (eg, pharmacy, diagnostic laboratories). 
10.1.9.6. Study Auditing and Inspecting 
MyoKardia or their designee may audit the study conduct, compliance with the protocol, and 
accuracy of the data at 1 or more study centers. 
The investigators/institutions will permit study-related monitoring, audits, and inspections by 
MyoKardia or their designee, IRBs/IECs, government regulatory authorities, and MyoKardia or 
their designee quality assurance personnel/designees by providing direct access to source 
data/documents after appropriate notification from MyoKardia or their designee. 
10.1.10. 
Publication Policy 
• The results of this multisite study may be published or presented at scientific 
meetings. Publication or presentation of the results of the study conducted at each 
individual site will not be made before the first multisite publication. 
• The investigator agrees to submit all manuscripts or abstracts to MyoKardia or their 
designee before submission. This allows MyoKardia or their designee to protect 
proprietary information and to provide comments. 
• MyoKardia or their designee will comply with the requirements for publication of 
study results. In accordance with standard editorial and ethical practice, MyoKardia 
or their designee will generally support publication of multicenter studies only in their 
entirety and not as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2. 
Appendix 2: Prohibited Medications 
The following medications are prohibited during the study. Generally, this directive should 
include the washout period (between Week 26 and Week 34). If a compelling clinical necessity 
to administer one of these medications arises, the investigator should contact the study medical 
monitor in advance to discuss a plan including whether/when to discontinue study drug. 
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Cardiotoxic Agents 
Prior or concomitant treatment with cardiotoxic agents, such as doxorubicin, or similar, is 
prohibited. 
Moderate and Potent CYP2C19 Inhibitors and Potent CYP3A4 Inhibitors 
Potent and moderate CYP2C19 inhibitors and potent CYP3A4 inhibitors are prohibited from 
14 days prior to Screening through the end of the study. Examples are listed below. 
• Efavirenz (antiviral) 
• Etravirine (antiviral) 
• Fluconazole (antifungal) 
• Fluvoxamine (selective serotonin reuptake inhibitor [SSRI]/antidepressant) 
• Fluoxetine (SSRI/antidepressant) 
• Moclobemide (monoamine oxidase inhibitor/antidepressant) 
• Omeprazole (proton pump inhibitor) 
• Esomeprazole (proton pump inhibitor) 
• Ticlopidine (platelet inhibitor) 
• Voriconazole (antifungal) 
St. John’s Wort 
Use of St. John’s Wort is prohibited from 14 days prior to Screening through the end of the 
study. 
Live COVID-19 Vaccines 
Live COVID-19 vaccines should not be administered to a participant during the study, including 
during the treatment period and within 3 months following the last dose of IMP. In addition, the 
administration of a live COVID-19 vaccine is prohibited up to 30 days prior to initiation of study 
treatment. 
10.3. 
Appendix 3: Safety Laboratory Tests 
• The tests detailed in Table 5 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study drug administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are 
used to make either a study drug decision or response evaluation, the results must be 
recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
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• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report. 
Table 5: 
Protocol-required Safety Laboratory Tests 
Laboratory 
Test 
Parameters 
Hematology 
WBC count with 
differential: 
• Neutrophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
Platelet count 
RBC count 
Hemoglobin 
Hematocrit 
RBC indices: 
• Mean corpuscular 
volume 
• Mean corpuscular 
hemoglobin 
• %Reticulocytes 
Coagulation 
International normalized 
ratio 
aPTT 
 
Clinical 
chemistrya 
Sodium 
Blood urea nitrogen 
Creatine phosphokinase 
 
Potassium 
Creatinine 
Glucose (fasting) 
 
Chloride 
ALPb 
Total protein 
 
Bicarbonate 
ALT/serum glutamic-
pyruvic transaminase 
Albumin 
 
Calcium 
AST/serum glutamic-
oxaloacetic transaminase 
 
 
Magnesium 
Total bilirubin 
 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, protein, glucose, leukocyte esterase, blood, nitrite by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
testing 
• 
Highly-sensitive serum or urine β-hCG pregnancy test (as needed for women of 
childbearing potential) 
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Table 5: 
Protocol-required Safety Laboratory Tests (Continued) 
Laboratory 
Test 
Parameters 
Other 
Screening 
Tests 
• 
Follicle-stimulating hormone (as needed in women of non-childbearing potential 
only to confirm postmenopausal status) 
• 
Thyroid-stimulating hormone 
• 
Estimated glomerular filtration rate 
• 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C 
virus antibody) 
• 
Serum free light chain ratio and SPEP w/immunofixation 
β-hCG = beta-human chorionic gonadotropin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
aPTT = activated partial prothrombin time; AST = aspartate aminotransferase; HIV = human immunodeficiency 
virus; IEC = independent ethics committee; INR = international normalized ratio; IRB = institutional review 
board; RBC = red blood cell; SPEP = serum protein electrophoresis; ULN = upper limit of normal; WBC = white 
blood cell. 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.1 and 
Section 10.5. All events of ALT or AST 3 × ULN and total bilirubin 2 × ULN (>35% direct bilirubin) or ALT 
or AST 3 × ULN and INR >1.5, (if INR measured) which may indicate severe liver injury (possible Hy’s Law), 
must be reported to MyoKardia or their designee in an expedited manner (excluding studies of hepatic impairment 
or cirrhosis). 
b If ALP is elevated, consider fractionating. 
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
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10.4. 
Appendix 4: 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 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. 
10.4.1. 
Definitions of Pretreatment Adverse Events, Adverse Events, Serious Adverse 
Events, and Adverse Events of Special Interest 
10.4.1.1. Pretreatment Adverse Events 
A 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. 
10.4.1.2. Adverse Events 
• According to the 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 is an AE. 
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• 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 is an AE. 
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, 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 
10.4.1.3. Serious Adverse Event 
An SAE is defined as any untoward medical occurrence at any dose that: 
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• Results in death 
• Is immediately life-threatening (places the participant at immediate risk of death from 
the event as it occurred) 
• 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 MyoKardia or their designee within 24 
hours after learning of the event. 
10.4.1.4. Adverse Events of Special Interest 
Symptomatic overdose, pregnancy, and LVEF ≤ 30% as determined by local site read 
echocardiogram are considered AESIs. 
AESIs are required to be reported by the investigator to MyoKardia or their designee within 
24 hours, irrespective of regulatory seriousness criteria. 
10.4.2. 
Collection and Reporting of Adverse Events 
10.4.2.1. 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. 
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Collection of TEAEs 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. 
10.4.2.2. 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 participant 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 is related 
to the study drug. The information to be documented for each event is described in the following 
sections. 
10.4.2.2.1. 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. 
10.4.2.2.2. 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. 
10.4.2.2.3. Relationship to Study Drug (Suspected Adverse Reactions) 
The investigator will assess causality by answering either “yes” or “no” to the question “Is there 
a reasonable possibility that the event may have been caused by the IMP/study medication?” 
10.4.2.2.4. 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) 
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10.4.2.2.5. Seriousness 
A PTAE or TEAE that meets any of the criteria for an SAE outlined in Section 10.4.1.3 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 10.4.1.3. 
10.4.2.2.6. Outcome 
The outcome of a PTAE or TEAE will be recorded according to the options provided on the eCRF. 
10.4.2.3. 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 or their 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 or their designee 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 MyoKardia or their designee. 
Prompt notification by the investigator to MyoKardia or their designee of SAEs is essential so 
that legal obligations and ethical responsibilities for the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
10.4.2.4. 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 resolution, 
stabilization, the event is otherwise explained, or the participant is considered lost to follow-up at 
the end of the study. 
10.4.3. 
Safety Reporting to Investigators, Institutional Review Boards, Independent 
Ethics Committees, and Regulatory Authorities 
MyoKardia or their designee has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention under clinical 
investigation. MyoKardia or their designee will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRBs/IECs, and 
investigators. 
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Investigational new drug (IND) safety reports/suspected unexpected serious adverse reactions 
(SUSARs) are SAEs that qualify for mandatory expedited reporting to regulatory authorities 
when the SAE is suspected to be caused by the study drug and is considered unexpected (ie, not 
defined as expected in the current IB, clinical study protocol, or approved labeling for marketed 
products). In this case, MyoKardia or their designee will report to the relevant regulatory 
authority(ies) and forward a formal notification describing the IND safety report/SUSAR to 
investigators, according to regulatory requirement. Each investigator must then notify his/her 
ethics committee IRB/IEC of the SUSAR as required by local regulatory authorities and in 
accordance with their IRB/IEC policy. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from MyoKardia or their designee will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
10.4.4. 
Pregnancy 
10.4.4.1. Avoidance of Pregnancy 
Female participants of childbearing potential must use appropriate methods of contraception as 
listed in the inclusion criteria (Section 5.1). Female participants of nonchildbearing potential are 
defined as those who are permanently (surgically) sterilized or are postmenopausal. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, and bilateral tubal occlusion or 
ligation. Female participants 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. 
10.4.4.2. Reporting and Follow-up of Pregnancies 
All pregnancies in female participants and female partners of male participants who received at 
least 1 dose of study drug must be reported if they occur anytime from the first dose of study 
drug 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. The 
participant will be asked to provide information on the outcome of the pregnancy through 
6 months after birth or details of premature termination of the pregnancy. Spontaneous 
miscarriage and congenital abnormalities will be reported as SAEs. 
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10.5. 
Appendix 5: Potential Drug-induced Liver Injury Reporting and 
Additional Assessments Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST/ALT and TBL 
elevation according to the criteria specified in Section 7.1.1.2 (3 × 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 or their designee as an SAE within 24 hours 
of discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• The appropriate eCRF (eg, Adverse Event CRF) that captures information necessary 
to facilitate the evaluation of treatment-emergent liver abnormalities is to be 
completed and sent to MyoKardia or their designee. 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Section 10.4.1.3. 
Additional Clinical Assessments and Observation 
All participants from whom study drug or protocol-required therapies 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 to be performed during this period include the 
following: 
• Repeat liver chemistries within 24 to 48 hours (ALT, AST, ALP, TBL); in cases of 
TBL > 2 × ULN or AST/ALT much greater than 3 × ULN, retesting is to be 
performed within 24 hours. 
For participants who are far from the study center, it may be difficult to return promptly to the 
study center. In this case, the participant should be retested locally, but normal laboratory ranges 
should be recorded, results should be made available to the study investigator immediately, and 
the data should be included in the eCRF. 
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 study drug or protocol-required 
therapies have been discontinued and the participant is asymptomatic. 
• Obtain prothrombin time/INR, 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 
 analysis if this has not already been 
collected. 
• Obtain a more detailed history of the following: 
− Prior and/or concurrent diseases or illness 
− Exposure to environmental and/or industrial chemical agents 
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− Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 
− Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
− Concomitant medications (including nonprescription medicines and herbal and 
dietary supplements). 
• Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A, B, 
C, D, E, Epstein-Barr virus, herpes simplex virus, etc.); evaluate for other potential 
causes of DILI, including but not limited to NASH, hypoxic/ischemic hepatopathy, 
and biliary tract disease. 
• Obtain gastroenterology or hepatology consult. 
• Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider 
these tests in cases of concurrent transaminase and TBL elevation. 
• Follow the participant until all laboratory abnormalities return to baseline or normal. 
The “close observation period” is to continue for a minimum of 4 weeks after 
investigational product(s) or protocol-required therapies discontinuation. 
The potential DILI event and additional information, such as medical history, concomitant 
medications, and laboratory results, must be captured in the appropriate eCRFs. 
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10.6. 
Appendix 6: Abbreviations and Definitions 
 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
 
 
BMI 
body mass index 
BNP 
brain natriuretic peptide 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
 
 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
cTnI 
cardiac troponin I 
cTnT 
cardiac troponin T 
CYP 
cytochrome P450 
DDI 
drug drug interaction 
DILI 
drug-induced liver injury 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLS 
global longitudinal strain 
HCM 
hypertrophic cardiomyopathy 
HFpEF 
heart failure with preserved ejection fraction 
HLGT 
high-level group term 
HLT 
high-level term 
HR 
heart rate 
 
 
hs-cTnT 
high-sensitivity cardiac troponin T 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)  
IDMC 
Independent Data Monitoring Committee 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IND 
investigational new drug 
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INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
 
 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
LVMI 
left ventricular mass index 
MedDRA 
Medical Dictionary for Regulatory Activities 
NASH 
nonalcoholic steatohepatitis 
nHCM 
nonobstructive hypertrophic cardiomyopathy 
NM 
Normal metabolizer 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
oHCM 
obstructive hypertrophic cardiomyopathy 
PASP 
pulmonary artery systolic pressure 
PK 
pharmacokinetic(s) 
PM 
poor metabolizer 
PR 
pulse rate 
PT 
preferred term 
PTAE 
pretreatment adverse event 
QD 
once daily 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
QT interval with Fridericia correction 
RR 
respiratory rate 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
 
 
SOC 
system organ class 
SPEP 
serum protein electrophoresis 
SSRI 
selective serotonin reuptake inhibitor 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
terminal half-life 
tmax 
Time to reach maximum concentration 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TTE 
transthoracic echocardiography, transthoracic echocardiogram 
ULN 
upper limit of normal 
US 
United States 
 
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11. 
REFERENCES 
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: 
executive summary: a report of the American College of Cardiology Foundation/American Heart 
Association Task Force on Practice Guidelines. Circulation. 2011 Nov 8;124(24):2761-96. 
Ho CY,Mealiffe ME, Bach RG, Bhattacharya M, Choudhury L, Edelberg JM, Hegde SM, Jacoby 
D, Lakdawala NK, Lester SJ, Ma Y, Marian AJ, Nagueh SF, Owens A, Rader F, Saberi S, 
Sehnert AJ, Sherrid MV, Solomon SD, Wang A, Wever-Pinzon O, Wong TC, Heitner SB. 
Evaluation of mavacamten in symptomatic patients with nonobstructive hypertrophic 
cardiomyopathy. J Am Coll Cardiol. 2020 Jun 2;75(21):2649-60. 
Pieske B, Tschöpe C, de Boer RA, Fraser AG, Anker SD, Donal E, Edelmann F, Fu M, Guazzi 
M, Lam CSP, Lancellotti P, Melenovsky V, Morris DA, Nagel E, Pieske-Kraigher E, 
Ponikowski P, Solomon SD, Vasan RS, Rutten FH, Voors AA, Ruschitzka F, Paulus WJ, 
Seferovic P, Filippatos. How to diagnose heart failure with preserved ejection fraction: the HFA–
PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association 
(HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019 Oct 21;40(40):3297-317. 
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-
Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, 
Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; ESC 
Scientific Document Group. 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 
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the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 14;37(27):2129-2200. 
Erratum in: Eur Heart J. 2016 Dec 30. 
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. 2013 ACCF/AHA guideline for the management of heart failure: executive 
summary: a report of the American College of Cardiology Foundation/American Heart 
Association Task Force on practice guidelines. Circulation. 2013 Oct 15;128(16):1810-52. 
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12. 
PROTOCOL ACCEPTANCE PAGE 
I have read and understood the contents of the clinical protocol, MYK-461-019 (An Exploratory, 
Open-label, Proof-of-concept, Phase 2a Study of Mavacamten [MYK-461] in Participants with 
Heart Failure with Preserved Ejection Fraction [HFpEF] and Chronic Elevation of Cardiac 
Biomarkers), 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 any other study conduct procedures provided by MyoKardia or 
their designee 
• That I am aware of, and will comply with, the internationally recognized code of 
Good Clinical Practice (GCP) and all other applicable regulatory requirements to 
obtain written and dated approval from the ethics committee (ie, central or 
institutional review board [IRB] or independent ethics committee [IEC]) for the study 
protocol, written informed consents, consent form updates, participant recruitment 
procedures, and any other written information to be provided to the participants 
before initiating this clinical study 
• Not to implement any changes to, or deviations from, the protocol without prior 
agreement from MyoKardia and documented approval from the IRB/IEC, except to 
eliminate an immediate hazard to the participants or when changes involve only 
logistical or administrative aspects of the clinical study 
• To permit direct monitoring and auditing by MyoKardia or their designee 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 their designee, 
including, but not limited to, the current Investigator’s Brochure 
• 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 the conduct of 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: ______________________________ 
 
Protocol Version: _____________________________ 
Protocol Date: 
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