A Phase 3, Open-label, Single Arm, Clinical Study to Evaluate Efficacy, Safety and Tolerability of Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
Phase: PHASE3
Conditions: Cardiomyopathy, Hypertrophic Obstructive
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 3, Open-label, Single Arm, Clinical Study to Evaluate Efficacy, Safety and Tolerability 
of Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy 
(HORIZON-HCM) 
 
NCT Number: NCT05414175 
Document Date (Date in which document was last revised): 18 October 2022 
 
 
 

Page:
1
Protocol Number:
CV027004
Date:
18-Jan-2022
Revised Date:
18-Oct-2022
CLINICAL PROTOCOL CV027004
A Phase 3, Open-label, Single Arm, Clinical Study to Evaluate Efficacy, Safety and Tolerability 
of Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy
(HORIZON-HCM)
Compound: BMS-986427
Brief Title: Mavacamten in Obstructive Hypertrophic Cardiomyopathy
Protocol Amendment 03
Incorporates Administrative Letter 01
Clinical Trial Physician - Medical Monitor
Bristol-Myers Squibb Company
1000 Sierra Point Pkwy
Brisbane, CA 94005
Phone:
email: 
Clinical Scientist
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Phone: 
email: 
24-hr Emergency Telephone Number
USA: 
International: 
Japan: 
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
1-2-1 Otemachi, Chiyoda-ku
Tokyo, 100-0004, Japan
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: NA
EudraCT/EU Trial Number: N/A
NCT: N/A
UTN: N/A
EUDAMED: N/A
Other: N/A
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Protocol Amendment No.: 03
Date: 18-Oct-2022
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This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. References to BMS in this protocol may apply to partners to which BMS 
has transferred obligations (eg, a Contract Research Organization [CRO]).
© 2022 Bristol-Myers Squibb Company
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CV027004
BMS-986427
Mavacamten
Protocol Amendment No.: 03
Date: 18-Oct-2022
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol Amendment 03
18-Oct-2022

Increase the screening period
 
 

Clarify pregnancy testing at screening, prior to dosing, 
and during the study

Clarify inclusion and exclusion criteria

Update safety laboratory test schedule 
 

Clarify management of overdose language

Update additional resesarch of residual samples to be 
optional

Clarify fasting requirements prior to exercise testing

Correct other typographical errors identified
Administrative Letter 01
22-Aug-2022

Updated contact information for the clinical trial 
physician and clinical scientist
Protocol Amendment 02
23-Mar-2022

Correction of typographical errors
Protocol Amendment 01
17-Mar-2022

Clarification of temporary/permanent discontinuation 
criteria
 
 
 

Updated language describing prohibited medications, 
dietary restrictions, and allowable concomitant 
medications 

Clarified required contraceptive methods that are 
approved in Japan.

Removed SARS-CoV-2 serology testing 

Corrected other typographical errors and removed 
redundancies
Original Protocol
18-Jan-2022
Not applicable
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BMS-986427
Mavacamten
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03:
The primary purpose of this amendment is to increase the Screening Period; 
 
 
 clarify pregnancy testing at Screening, prior to dosing, and 
during the study; clarify inclusion and exclusion criteria; update safety laboratory test schedule  
 clarify management of overdose 
language; update additional resesarch of residual samples to be optional; clarify fasting 
requirements prior to exercise testing; and correct other typographical errors identified. 
These revisions are specified below and have been incorporated into the Protocol Summary.
Administrative Letter 01, which updated contact information for the clinical trial physician and 
clinical scientist, has also been incorporated.
Revisions apply to future participants enrolled in the study and, where applicable, to all 
participants currently enrolled.
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-1: Screening 
Procedural Outline
Lengthened duration of 
Screening Period from 28 to 35 
days.
To allow more time for 
Screening assessments to 
be performed.
Table 2-1: Screening 
Procedural Outline
Table 2-2: On-Treatment -
Schedule of Activities for All 
Participants (Primary 
Analysis Treatment Period)
Table 2-3: On-Treatment -
Schedule of Activities for All 
Participants (Long-Term 
Treatment Period)
Reduced number of hours from 4 
to 3 for recommended fasting 
prior 
 and Post
exercise/Stress 
 
To align 
 
 
testing requirements.
Added to Notes that 
 can be 
completed on Day 1 prior to 
dosing, and hematology must be 
collected within 7 days of the 
 assessments (preferably on 
the day 
). In the event 
that a visit hematology sample is 
collected more than 7 days 
before or after 
 is 
performed, an unscheduled 
hematology sample must be 
collected on the same day as the 
 assessment.
To allow for more 
flexibility 
 
and clarify the 
need for hematology to be 
performed.
Protocol Amendment No.: 03
Date: 18-Oct-2022
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-1: Screening 
Procedural Outline
Table 2-2: On-Treatment -
Schedule of Activities for All 
Participants (Primary 
Analysis Treatment Period)
Table 2-3: On-Treatment -
Schedule of Activities for All 
Participants (Long-Term 
Treatment Period)
Table 2-4: Follow-Up 
Procedural Outline
Added to Notes that 
electrocardiogram (ECG) should 
be completed prior to blood 
draws.
To provide more 
flexibility and clarity.
Revised footnote regarding order 
of assessments.
Table 2-2: On-Treatment -
Schedule of Activities for All 
Participants (Primary 
Analysis Treatment Period)
Added to Notes and footnote that 
Kansas City Cardiomyopathy 
Questionnaire (KCCQ) should be 
completed prior to any other 
study procedure taking place, 
when possible.
To avoid bias in KCCQ.
Revised pregnancy test 
requirements in Notes.
To clarify requirement for 
serum pregnancy test 
during Screening and 
negative urine pregnancy 
test prior to dosing.
Table 2-3: On-Treatment -
Schedule of Activities for All 
Participants (Long-Term 
Treatment Period)
Added Week 90 and Week 114 
safety laboratory tests including 
hematology, chemistry, and 
coagulation assessments.
To add additional safety 
assessments.
Removed Week 102 safety 
laboratory tests to align with 
 
collection schedule.
To align laboratory test
collections 
 
.
Table 2-2: On-Treatment -
Schedule of Activities for All 
Participants (Primary 
Analysis Treatment Period)
Table 2-3: On-Treatment -
Schedule of Activities for All 
Participants (Long-Term 
Treatment Period)
Protocol Amendment No.: 03
Date: 18-Oct-2022
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Mavacamten
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: On-Treatment -
Schedule of Activities for All 
Participants (Primary 
Analysis Treatment Period)
Table 2-3: On-Treatment -
Schedule of Activities for All 
Participants (Long-Term 
Treatment Period)
Table 2-4: Follow-Up 
Procedural Outline
Added footnote for visit 
windows.
To clarify that the ± 7 day 
visit window does not 
apply to Day 1.
Section 3.2: Background
Updated cutoff date and the 
number of sites and participants 
in mavacamten clinical studies.
To align with current 
Investigator’s Brochure.
Table 4-1: Objectives and 
Endpoints
Section 5.1: Overall Design
Figure 5.1-1: Study Design 
Schema
Section 5.1.1: Screening 
Period
Section 6.5.1: Retesting 
During Screening
Section 7.7.1: Prior Therapy
Adjusted all timeframes to 
account for addition of 7 days to 
Screening and/or changed 28-day 
Screening window to 35-day 
Screening window.
To align with change in 
Screening duration.
Section 5.1.2.1: Treatment 
Period for Primary Analysis
Removed pregnancy status from 
Week 2 phone call to 
participants.
Pregnancy testing is 
required every 4 weeks 
and is already performed 
at Day 1 and Week 4.
Section 5.1.3: Post-Treatment 
Follow-up Period
Added clarification if participant 
is a cytochrome P450 (CYP)
2C19 poor metabolizer (PM) and 
requires additional follow-up.
To communicate when 
sites will be notified if 
participants are CYP 
2C19 PMs.
Protocol Amendment No.: 03
Date: 18-Oct-2022
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 5.1.4: Description of 
Other Procedures and 
Assessments
Corrected the second implantable 
cardioverter-defibrillator (ICD) 
data download to Week 12.
Fixed typographical error.
Added that participants who 
meet all inclusion/exclusion 
criteria 
 
requirements will undergo 
 
during Screening or Day 1 pre-
dose or up to 5 days before each 
visit after Day 1.
To allow for more 
flexibility 
 
and clarify 
 will only be 
performed at sites willing 
to participate in the 
assessments.
Section 5.3: End of Study 
Definition
Revised definition of end of 
Treatment Period for Primary 
Analysis and added definition of 
end of treatment (EOT).
To provide more clarity.
Section 6.1: Inclusion Criteria
4)a)iii): Clarified requirement for 
negative urine pregnancy test at 
Day 1 prior to start of study 
treatment.
To clarify a negative urine 
pregnancy test is required 
at Day 1 prior to dosing in 
addition to required 
negative serum pregnancy 
test during Screening.
Section 6.2: Exclusion 
Criteria
Section 7.7.2: Background 
HCM Therapy
Section 7.7.4: Prohibited 
and/or Restricted Treatments
Appendix 5: Prohibited 
Medications
Added “assessments” after 
“Screening” throughout the 
protocol.
To clarify that with 
regards to prior/
concomitant therapy 
affecting eligibility, the 
timing is in relation to 
when Screening 
assessments begin, not at 
the beginning of the 
Screening Period.
Protocol Amendment No.: 03
Date: 18-Oct-2022
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 7.7.1: Prior Therapy
Clarified that participants who 
have taken prohibited 
medications within 14 days prior 
to signing the informed consent 
form (ICF) must discontinue 
treatment for at least 14 days 
prior to Screening assessments.
Principal Investigator to 
determine if participant can 
discontinue prohibited 
treatments.
To clarify timing when 
Screening assessments 
begin in relation to prior/
concomitant therapy 
affecting eligibility.
Section 7.7.4: Prohibited 
and/or Restricted Treatments
Added that “if a compelling 
clinical necessity to administer 
one of these medications arises,” 
the investigator and medical 
monitor should discuss 
whether/when the participant 
would discontinue study drug.
To clarify that 
investigators should 
discuss how to safely 
administer prohibited 
concomitant medications 
with the medical monitor 
in cases where clinical 
necessity requires their 
use.
Section 8.1.3.1: Temporary 
Discontinuation in Treatment 
Period for Primary Analysis 
(Day 1 through Week 30)
Section 8.1.3.2: Temporary 
Discontinuation in Long-
Term Treatment Period 
(Week 30 to Week 138)
Removed the possibility of 
lengthening temporary 
discontinuation for CYP 2C19 
PMs.
To clarify that all 
participants will follow 
the same criteria with 
respect to temporary 
discontinuations and must 
meet the same 
requirements to restart 
treatment after a 
temporary 
discontinuation.
Section 9: Study Assessments 
and Procedures
Revised text regarding order of 
assessments.
To provide more 
flexibility and clarity.
Section 9.1.1: Efficacy 
Assessment for the Study
 
Added “and/or operational” to 
“technical capabilities” of 
conducting 
.
To allow flexibility where 
operational challenges 
may prevent 
 
 from being 
performed.
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Date: 18-Oct-2022
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Mavacamten
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 9.1.1: Efficacy 
Assessment for the Study
Reduced number of hours from 4 
to 3 for recommended fasting 
prior 
 and Post exercise/
Stress 
To align with 
 
echocardiography 
manuals.
Added participant requirements 
for withholding caffeine, 
nicotine, alcohol, food, and 
exercise prior to 
 
procedures.
To clarify participant 
requirements 
 
 
.
Section 9.1.2.1: 
Echocardiography
Reduced number of hours from 4 
to 3 for recommended fasting 
prior to Post exercise/Stress 
To align with 
echocardiography manual.
Added that the exercise test 
should be performed within the 
site’s standard protocol; if not 
available, the 
 exercise 
protocol must be utilized.
To clarify options for the 
exercise test protocol.
Section 9.2.5: Pregnancy
Increased time for follow-up of 
pregnancy outcome from 
6 months to 1 year after birth or 
premature termination.
To update follow-up time 
in line with Sponsor 
requirements. 
Removed requirement that the 
pregnancy of a male participant’s 
female partner be followed up.
Pregnant partner follow-
up is no longer required 
per asset-level guidance.
Section 9.3: Overdose
Added detail regarding 
management of overdoses and 
instructions for investigators.
To align overdose 
language with the 
Investigator’s Brochure.
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 9.4.3.2: Cardiac 
Monitoring Device
Corrected text regarding memory 
cards.
To correct cardiac 
monitoring device 
information.
Section 9.4.4: Clinical Safety 
Laboratory Assessments
Clarified that participants must 
have a negative urine pregnancy 
test at Day 1 prior to initiating 
study therapy.
To clarify a negative urine 
pregnancy test is required 
prior to dosing.
Added details to pregnancy test 
requirements during the Long-
Term Treatment Period.
To clarify requirement for 
serum pregnancy test 
during Screening and 
negative urine pregnancy 
test prior to dosing.
Section 9.7.2: 
Pharmacogenetic 
Assessments
Table 9.8-1: Biomarker 
Sampling Schedule for All 
Participants
Removed “panel” from text 
regarding gene testing.
Only CYP 2C19 
pharmacogenetic testing is 
being performed.
Section 9.9: Additional 
Research
Updated language to reflect that 
participation in additional 
research on residual samples is 
optional.
To provide more 
flexibility and clarity.
Section 10.1: Statistical 
Hypotheses
Revised text to clarify how 
results of safety and efficacy will 
be assessed to support 
registration in Japan.
To provide more clarity of 
the assessment approach.
Protocol Amendment No.: 03
Date: 18-Oct-2022
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 10.3: Analysis Sets
To align with statistical 
analysis plan.
Section 10.5: Interim 
Analyses
Added that an additional analysis 
will be conducted when all 
participants complete the Week 
54 visit or permanently 
discontinue treatment.
Appendix 2: Study 
Governance Considerations
Added 2 new sections.
To reflect BMS’ 
commitment to diversity 
and providing data 
protection, privacy, and 
security in clinical trials.
Appendix 5: Prohibited 
Medications
Removed grapefruit juice from 
prohibited medications because it 
is listed in Section 6.4.1, Meals 
and Dietary Restrictions.
To provide consistent 
guidance regarding 
grapefruit juice.
All
Minor formatting and 
typographical corrections.
Minor and therefore have 
not been summarized.
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03: ............................ 
 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 03 ......................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 PROTOCOL SUMMARY ......................................................................................... 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.2 Background ....................................................................................................... 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
3.3.1 Risk Assessment ....................................................................................... 
 
3.3.1.1 Important Known Risks for Mavacamten ....................................... 
 
3.3.1.2 Important Potential Risks for Mavacamten .................................... 
 
3.3.2 Benefit Assessment ................................................................................... 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Screening Period ...................................................................................... 
 
5.1.2 Treatment Period ..................................................................................... 
 
5.1.2.1 Treatment Period for Primary Analysis .......................................... 
 
5.1.2.2 Long-Term Treatment Period ......................................................... 
 
5.1.3 Post-treatment Follow-up Period ............................................................ 
 
5.1.4 Description of Other Procedures and Assessments ................................. 
 
5.1.5 Data Monitoring Committee and Other Committees ............................... 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 Participant Input Into Study Design ........................................................ 
 
5.5 Justification for Dose ........................................................................................ 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
 
 
 
 
 
 
6.4 Lifestyle Restrictions ........................................................................................ 
 
6.4.1 Meals and Dietary Restrictions ............................................................... 
 
6.4.2 Other Restrictions .................................................................................... 
 
6.5 Screen Failures .................................................................................................. 
 
6.5.1 Retesting During Screening ..................................................................... 
 
7 STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ....................... 
 
7.1 Study Interventions Administered .................................................................... 
 
7.2 Method of Study Intervention Assignment ....................................................... 
 
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7.3 Blinding ............................................................................................................ 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Dose Adjustments During Treatment Period ........................................... 
 
7.4.1.1 Dose Titration Period for Primary Analysis (Day 1 through Week 
30) ......................................................................................................... 
 
7.4.1.2 Dose for Long-Term Treatment Period (Week 30 to Week 138) .... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Formulation, Packaging, and Labeling of Study Drug ............................ 
 
7.5.2 Direct-to-Participant Study Drug Shipment (at Selected Sites) .............. 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prior Therapy........................................................................................... 
 
7.7.2 Background HCM Therapy ...................................................................... 
 
7.7.3 Concomitant Therapy............................................................................... 
 
7.7.4 Prohibited and/or Restricted Treatments................................................. 
 
 
 
7.8 Continued Access to Study Intervention After the End of the Study ............... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation From Study Intervention ........................................................ 
 
8.1.1 Temporary Treatment Discontinuation .................................................... 
 
8.1.2 Permanent Treatment Discontinuation .................................................... 
 
8.1.3 Criteria for Temporary Treatment Discontinuation ................................ 
 
8.1.3.1 Temporary Discontinuation in Treatment Period for Primary 
Analysis (Day 1 through Week 30) ....................................................... 
 
8.1.3.2 Temporary Discontinuation in Long-Term Treatment Period (Week 
30 to Week 138) .................................................................................... 
 
8.1.4 Criteria for Permanent Treatment Discontinuation ................................ 
 
8.1.5 Management of Participants After Permanent Treatment Discontinuation
..................................................................................................................... 
 
8.1.6 Rechallenge .............................................................................................. 
 
8.1.6.1 Hepatotoxicity Rechallenge ............................................................ 
 
8.1.6.2 Criteria for Rechallenge of Mavacamten After Potential 
Hepatotoxicity ....................................................................................... 
 
8.1.7 Post-study Intervention Study Follow-up................................................. 
 
8.2 Discontinuation From the Study ....................................................................... 
 
8.2.1 Withdrawal From the Study ..................................................................... 
 
8.2.1.1 Withdrawal of Consent for Ongoing Study Participation............... 
 
8.2.1.2 Replacement of Participants Who Withdraw from the Study .......... 
 
8.2.2 Individual Discontinuation Criteria ........................................................ 
 
8.3 Lost to Follow-up .............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Efficacy Assessment for the Study ............................................................ 
 
9.1.2 Imaging Assessment for the Study............................................................ 
 
9.1.2.1 Echocardiography........................................................................... 
 
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9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug-induced Liver Injury ....................................................... 
 
9.2.7.1 Criteria for Permanent Withholding of Mavacamten due to 
Potential Hepatotoxicity ....................................................................... 
 
9.2.7.2 Criteria for Conditional Withholding of Mavacamten Due to 
Potential Hepatotoxicity ....................................................................... 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital Signs ................................................................................................ 
 
9.4.3 Electrocardiograms and Cardiac Monitoring Device ............................. 
 
9.4.3.1 Electrocardiograms ........................................................................ 
 
9.4.3.2 Cardiac Monitoring Device ............................................................ 
 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
 
 
 
 
 
9.6 Immunogenicity Assessments ........................................................................... 
 
9.7 Genetics............................................................................................................. 
 
9.7.1 HCM Genotyping ..................................................................................... 
 
9.7.2 Pharmacogenetic Assessments ................................................................. 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Cardiac Biomarkers ................................................................................. 
 
 
 
9.9 Additional Research .......................................................................................... 
 
9.10 Other Assessments .......................................................................................... 
 
9.11 Health Economics OR Medical Resource Utilization and Health Economics
........................................................................................................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Statistical Hypotheses ..................................................................................... 
 
10.2 Sample Size Determination ............................................................................. 
 
10.3 Analysis Sets ................................................................................................... 
 
10.4 Statistical Analyses ......................................................................................... 
 
10.4.1 General Considerations ......................................................................... 
 
10.4.1.1 Participant Disposition ................................................................. 
 
10.4.1.2 Demographics and Baseline Characteristics ................................ 
 
10.4.1.3 Extent of Study Treatment Exposure and Compliance ................. 
 
10.4.2 Primary Endpoint................................................................................... 
 
10.4.3 Secondary Endpoints ............................................................................. 
 
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CV027004
Mavacamten
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10.4.5 Other Safety Analysis ............................................................................. 
 
10.4.5.1 Adverse Events .............................................................................. 
 
 
 
10.4.5.3 Overdose ....................................................................................... 
 
10.4.6 Other Analyses ....................................................................................... 
 
10.4.6.1 12-lead Electrocardiogram ........................................................... 
 
10.4.6.2 Laboratory Data ........................................................................... 
 
10.4.6.3 Vital Signs Data ............................................................................ 
 
 
 
10.5 Interim Analyses ............................................................................................. 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING ....................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 PROHIBITED MEDICATIONS .......................................................... 
 
APPENDIX 6 POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING AND 
ADDITIONAL ASSESSMENTS REPORTING ................................................... 
 
APPENDIX 7 MANAGEMENT OF PARTICIPANTS WHO ARE UNABLE TO 
ATTEND ONSITE STUDY VISITS (DUE TO COVID-19 OR OTHER 
PANDEMICS OR NATURAL DISASTERS) ....................................................... 
 
APPENDIX 8 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
 
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CV027004
Mavacamten
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CV027004
BMS-986427
Mavacamten
1
PROTOCOL SUMMARY
Protocol Title: A Phase 3, Open-label, Single-arm, Clinical Study to Evaluate Efficacy, Safety 
and Tolerability of Mavacamten in Adults with Symptomatic Obstructive Hypertrophic 
Cardiomyopathy
Brief Title: Mavacamten in Obstructive Hypertrophic Cardiomyopathy
Rationale:
Mavacamten (BMS-986427, also known as MYK-461) is a first-in-class, small-molecule, 
selective allosteric inhibitor of cardiac myosin ATPase specifically developed to target the 
underlying pathophysiology of hypertrophic cardiomyopathy by reducing actin–myosin 
cross-bridge formation, thereby reducing contractility and improving myocardial energetics.
In EXPLORER-HCM, a Phase 3, randomized, double-blind, placebo-controlled trial, treatment 
with mavacamten improved exercise capacity, left ventricular outflow tract (LVOT) obstruction, 
New York Heart Association (NYHA) functional class, and health status in patients with 
obstructive hypertrophic cardiomyopathy (HCM).
This Phase 3 open-label, single-arm, study is designed to evaluate the efficacy, safety, and 
tolerability of a 30‑week course of mavacamten and the long-term effects of mavacamten in 
Japanese participants with symptomatic obstructive HCM.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the effect of a 30-week 
course of mavacamten on post exercise 
peak LVOT gradient as determined by 
Doppler echocardiography.

Change from baseline to Week 30 in post exercise LVOT 
peak gradient.
Secondary

To assess the effect of a 30-week 
course of mavacamten on health status.

Change from baseline to Week 30 in KCCQ CSS.

To assess the effect of a 30-week 
course of mavacamten on symptoms.

Proportion of participants with at least 1 class improvement in 
NYHA functional class from baseline to Week 30.

To assess the effect of a 30-week 
course of mavacamten on cardiac 
biomarkers.

Change from baseline to Week 30 in NT-proBNP.

Change from baseline to Week 30 in cardiac troponins.
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CV027004
BMS-986427
Mavacamten
Objectives
Endpoints
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CV027004
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Mavacamten
Abbreviations: 
 
 CSS, Clinical Summary Score; 
 
 KCCQ, Kansas City 
Cardiomyopathy Questionnaire; 
 LVOT, left ventricular 
outflow tract; 
 NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, 
New York Heart Association; 
 
 
Overall Design:
Study Design Schema
Abbreviations: 
 CYP, 
cytochrome P450; ECG, electrocardiogram; EOS, end of study; FU, follow-up; 
 PM, poor 
metabolizer; QD, once daily; stress echo, post exercise stress echocardiography; TC, telephone call; Time 0, Day 1 
(start of Treatment Period for Primary Analysis); 
 wks, weeks.
a In addition to pre-dose ECG, post-dose ECG is to be performed around time of maximum observed concentration 
(Tmax) (0.5 to 3 hours post-dose) at Day 1 and Weeks 8, 14, and 20.
 
d Follow-up or EOS visit at Week 8 for all participants, and at Week 20 if cytochrome P450 (CYP) 2C19 PM.
Screening Period (Day -35 to Day -1):
Participants will undergo a variety of general and laboratory assessments to assess eligibility. Key 
screening tests include electrocardiogram (ECG); 
 conducted 
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CV027004
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Mavacamten
at rest, with Valsalva maneuver, and post exercise; 
 
 A goal of at least 25% of 
the participants will be NYHA functional Class III at Screening.
The following Screening assessments may be repeated, as long as they are within the 35-day 
screening window: blood tests, ECG, 
. Repeat assessments are allowed if central core 
laboratories require a repeat submission due to quality and in order to better assess 
inclusion/exclusion values. Participants who fail screening may be considered for rescreening 
based on the investigator’s discretion, taking into consideration the reason(s) for screening failure. 
One attempt at rescreening will be allowed, and all procedures must be repeated.
Participants who meet all eligibility criteria will be treated.
Treatment Period:
Treatment Period for Primary Analysis (Day 1 Through Week 30)
The initial treatment period (Day 1 through Week 30) for primary efficacy analysis will include 
dose titration designed to achieve safe and effective dosing for each participant based on their own 
response parameters. Participants will receive treatment with mavacamten at a 2.5-mg starting 
dose once daily (QD). The permissible doses during Day 1 through Week 30 are 1, 2.5, 5, 10, and 
15 mg mavacamten. Assessments including ECG, 
 
 will be performed at study visits and read by core laboratories. The dose will be 
adjusted or temporarily discontinued as described in the Study Treatment and Administration 
section. The dose may be reduced or discontinued at any time during the Treatment Period based 
on the clinical judgment of the investigator in discussion with the Medical Monitor.
At Week 30, participants will complete
at rest, with Valsalva maneuver, and post exercise; 
Long-Term Treatment Period (Week 30 to Week 138)
Participants will continue on the dose received at Week 30.
After the initial 30 weeks of the study, visits will occur every 12 weeks and will include but are 
not limited to clinical evaluation of symptoms, AE/serious adverse event assessments, ECGs, 
 
 and laboratory assessments including N-terminal pro b-type natriuretic 
peptide (NT-proBNP) and cardiac troponins.
The dose may be reduced or discontinued at any time during the Long-Term Treatment Period 
based on the clinical judgment of the investigator in discussion with the Medical Monitor.
The permissible doses during Week 30 to Week 138 are 1, 2.5, 5, 10, and 15 mg mavacamten.
Post-treatment Follow-up Period (End of Treatment to End of Study): 
Participants who prematurely discontinue the study will attend an early termination visit, be 
contacted by telephone 4 weeks later, and return to the study site 8 weeks later for an end of study 
(EOS) visit. CYP 2C19 poor metabolizers (PMs) will also return to the study site for an 8-week 
follow-up visit and a 20-week EOS visit. After the participant completes the EOT visit, the site 
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CV027004
BMS-986427
Mavacamten
will be contacted by the Sponsor to notify the investigator if the participant is a CYP 2C19 PM 
and requires an additional 20-week EOS visit.
Participants who complete 138 weeks of the study and do not roll over to commercially available 
mavacamten will attend an EOT visit, be contacted by telephone 4 weeks later, and return to the 
study site 8 weeks later for an EOS visit. CYP 2C19 PMs will also return to the study site for the 
8-week follow-up visit and a 20-week EOS visit. After the participant completes the EOT visit, 
the site will be contacted by the Sponsor to notify the investigator if the participant is a CYP 2C19 
PM and requires an additional 20-week EOS visit.
Participants who roll over to commercially available mavacamten at any time will be contacted by 
telephone 4 weeks and 8 weeks later for an EOS follow-up to assess AEs, concomitant 
medications, and pregnancy status. CYP 2C19 PMs will be contacted by telephone at Weeks 4, 8, 
and 20 post EOT.
Safety Monitoring:
Safety monitoring will be ongoing at scheduled study visits during the study through EOS. Clinic 
visits will include but are not limited to monitoring of AEs and concomitant medications, safety 
laboratory assessments, physical examinations, vital sign measurements, 
 and 
ECGs. 
 will be performed by study site sonographers at scheduled visits as per protocol following 
enrollment. If left ventricular ejection fraction (LVEF) of ≤ 30% is measured at the site, then 
mavacamten will be permanently discontinued as described within the protocol.
Assessments obtained during clinic visits will be used to guide dose reduction or temporary 
discontinuation, based on predefined criteria detailed within the protocol.
Number of Participants:
Approximately 30 participants will be treated.
It is estimated that approximately 50 screened participants will be required to achieve the 
30 treated participants.
Study Population:
Japanese participants with symptomatic obstructive HCM.
Intervention Groups and Duration:
Intervention groups: All participants will be treated with mavacamten.
Study duration: The study duration is a maximum of 151 weeks (163 weeks if CYP 2C19 PM): 
Screening Period (up to 5 weeks); Treatment Period for Primary Analysis (Day 1 through Week 
30), Long-Term Treatment Period (Week 30 to Week 138), and Post-treatment Follow-up Period 
(8 weeks [and 20 weeks if CYP 2C19 PM]) or until mavacamten becomes commercially available 
(at the discretion of the Sponsor).
The EOS is defined as the date of the last visit on the Schedule of Activities of the last participant.
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CV027004
BMS-986427
Mavacamten
Study Intervention:
Study Intervention for CV027004
Medication 
Potency 
IMP/Non-IMP/AxMP 
BMS-986427/MYK-461 immediate-
release capsules
1, 2.5, 5, 10, and 15 mg
IMP
Abbreviations: AxMP, auxiliary medicinal product IMP, investigational medicinal product.
Dosing: Treatment Period for Primary Analysis (Day 1 through Week 30)
Participants will begin treatment with mavacamten immediate-release capsules 2.5 mg QD for the 
first 6 weeks of the dosing period.
All dose adjustments will occur through the interactive response system, based on core laboratory 
read 
 data entered by the core laboratory. Participants will receive mavacamten in 30 count 
high-density polyethylene bottles that are appropriately labeled. Mavacamten is administered QD 
by mouth.
Scheduled dose adjustments will occur at Weeks 6, 8, 14, and 20 based on the core read 
echocardiography laboratory measurements of LVOT gradient with Valsalva maneuver 
 
 
If at Week 4 Valsalva LVOT gradient is < 30 mm Hg and LVEF is ≥ 50%, the dose will be 
decreased to 1 mg at Week 6. There are 3 opportunities for up-titration: at Week 8 based on Week 6 
assessments, at Week 14 based on Week 12 assessments, and at Week 20 based on Week 18 
assessments. Up-titration requires LVEF ≥ 55% and LVOT gradient with Valsalva maneuver 
≥30 mm Hg. Dose may be down-titrated by 1 dose level or discontinued for safety at any time 
during the study based on the clinical judgment of the investigator in consultation with the Medical 
Monitor.
Dose increases are designed to be stepwise and are not allowed to skip doses (eg, from 2.5 mg to 
10 mg). The permissible doses after dose adjustment at Week 8 will be 1, 2.5, or 5 mg. The 
permissible doses after dose adjustment at Week 14 will be 1, 2.5, 5, or 10 mg. The permissible 
doses after dose adjustment at Week 20 will be 1, 2.5, 5, 10, or 15 mg.
Dosing: Long-Term Treatment Period (Week 30 to Week 138)
Dose adjustments will occur on the day of the visit, based on site-read measurement of LVOT 
gradient with Valsalva maneuver 
. The permissible doses during Week 30 to 
Week 138 are 1, 2.5, 5, 10, and 15 mg mavacamten.
At any visit subsequent to Week 30, if the site-read LVOT gradient with Valsalva maneuver is 
≥30 mm Hg and resting LVEF is ≥ 55%, then a dose increase may be considered, up to a maximum 
of 15 mg QD, after discussion with the Medical Monitor.
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CV027004
BMS-986427
Mavacamten
If dose adjustment occurs, the participant should return to the clinic approximately 28 days later 
(± 7 days) for an unscheduled visit with resting 
 to confirm safety. Post exercise 
echocardiographic assessment of LVOT gradient during this period will be at the investigator’s 
discretion.
The dose may be reduced or discontinued at any time during the Long-Term Treatment Period 
based on the clinical judgment of the investigator in discussion with the Medical Monitor. 
Participants who have had a dose reduction should return to the clinic approximately 28 days later 
(± 7 days) for an unscheduled visit with AE and safety laboratory assessments, ECG, and resting 
 to confirm safety. Post exercise echocardiographic assessment of LVOT gradient will be at 
the investigator’s discretion. Based on results and clinical symptoms at follow-up visits, 
subsequent dose adjustments will be discussed with the Medical Monitor.
Temporary Discontinuation
Dosing will be temporarily discontinued if results as reported by the central laboratories from any 
visit during the first 30 weeks of study (or site-read 
 from Week 30 to Week 138) show resting 
LVEF < 50%, 
 or the QT interval with 
Fridericia correction (QTcF) stopping criterion is met (if baseline QRS is narrow [< 120 msec], 
the stopping criterion is the smaller of a 15% increase from baseline in QTcF or QTcF ≥520 msec; 
if baseline QRS is wide [≥120 msec], the stopping criterion is the smaller of a 15% increase from 
baseline in QTcF or QTcF ≥550 msec).
Upon receipt of this information, the study site/investigator will contact the participant and instruct 
the participant to discontinue mavacamten. If LVEF is ≥ 50%, 
 
and/or QTcF duration is below programmed discontinuation rules, then 
mavacamten will be restarted at a lower dose.
Statistical Methods:
Approximately 30 participants will be treated. Assuming the mean (SD) of the primary endpoint, 
the change from baseline to Week 30 in post exercise LVOT gradient is -40 (45) mm Hg, a sample 
size of 30 participants will have approximately 94% probability to observe a mean change of 
≤ -27 mm Hg, with an observed 95% CI of (-43, -11) mm Hg.
To determine the similarity of the results between this study and EXPLORER-HCM study, we 
consider the following 2 criteria:
1) The observed mean change in post exercise LVOT gradient in this study should be ≤-27 mm 
Hg, which is at least 57% of the change shown in the mavacamten arm of EXPLORER-HCM 
study.
2) The CI of the mean change in this study should exclude the mean change from baseline to 
Week 30 in placebo arm of EXPLORER-HCM study, ie, upper limit of the CI < -10.
When all participants complete the Week 30 visit or terminate the study treatment prior to week 
30, primary analysis will be performed to assess the efficacy and safety of mavacamten treatment 
for the 30-week period. When all participants complete the Week 54 visit or permanently 
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
discontinue treatment, an additional analysis will be conducted. Final analysis will be performed 
when all participants complete the EOS visit.
Efficacy Analyses
Descriptive statistics will be presented for all efficacy endpoints. Descriptive summary will be 
based on all data available. Missing data will not be imputed. In case the primary and secondary 
endpoints have missing data that are more than expected (eg, 10%), data imputation may be 
performed, and detailed methods will be discussed in the statistical analysis plan.
Primary Efficacy Endpoint Analysis
The primary efficacy endpoint of post exercise LVOT peak gradient change from baseline to 
Week 30 will be summarized along with 95% CIs. 
Secondary 
 Efficacy Endpoints Analyses
The general analytical rules for the secondary 
 efficacy endpoints are the following:

Change from baseline endpoints will be summarized with descriptive statistics, including 
mean, SD, minimum, median, maximum, and 95% CI. There is no formal testing for secondary 
 endpoints.

Response rate for the categorical endpoints will be summarized with number and percentage 
with 95% CI, and no formal testing will be performed.
Safety Analyses
Safety data will be analyzed using descriptive statistics without formal statistical testing. The 
safety analysis will focus on the Treatment-emergent Adverse Event Period. This period is defined 
as the time from the first administration of mavacamten to the last administration of mavacamten 
+ 56 days (or 140 days if CYP 2C19 PM).
Data Monitoring Committee: No
A Data Monitoring Committee will not be used in the study.
Other Committee: No
Other review committee will not be used in the study.
Brief Summary:
Condition/Disease: Patients with obstructive hypertrophic cardiomyopathy (HCM).
Study Hypothesis: This Phase 3 open-label, single-arm, study is designed to evaluate the efficacy, 
safety, and tolerability of a 30-week course of mavacamten and the long-term effects of 
mavacamten in Japanese participants with symptomatic obstructive HCM.
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CV027004
BMS-986427
Mavacamten
Study Duration: The study duration is a maximum of 151 weeks (163 weeks if CYP 2C19 PM).
Study Intervention Duration: Treatment Period for Primary Analysis (Day 1 through Week 30), 
Long-Term Treatment Period (Week 30 to Week 138).
Health Measurement/Observation: The primary efficacy endpoint will evaluate the effect of a 
30-week course of mavacamten on post exercise peak LVOT gradient as determined by 
echocardiography.
Study Visit Frequency: Visits will occur every 2 to 4 weeks during the Treatment Period for 
Primary Analysis. All visit dates will be scheduled based on Day 1. All visits after Day 1 should 
occur within the visit window (± 7 days) scheduled based on the projected study date. After the 
initial 30 weeks of the study, visits will occur every 12 weeks.
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
2
SCHEDULE OF ACTIVITIES
Study assessments and procedures for screening are presented in Table 2-1, and schedules of 
activities for on-treatment and follow-up are presented in Table 2-2, Table 2-3, and Table 2-4.
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BMS-986427
Mavacamten
Table 2-1:
Screening Procedural Outline (CV027004)
Procedurea
Screening Periodb
(Day -35 to Day -1)
Notes
Informed Consent
X
Informed consent must be signed prior to initiating any study procedures.
Inclusion/Exclusion Criteria
X
See Sections 6.1 and 6.2.
Medical History
X
All medical history relevant to disease under study.
ICD Download
X
For participants who have ICDs, information including rhythm strips and events will be 
downloaded from the ICDs.
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-1:
Screening Procedural Outline (CV027004)
Procedurea
Screening Periodb
(Day -35 to Day -1)
Notes
NYHA Functional Class
X
Physical Examination (PE)
X
A complete physical examination will be conducted, including a neurological 
examination.
Weight
X
Height
X
Vital Signs
X
Complete vital signs including temperature, HR, respiratory rate, and BP will be 
obtained. Vital signs should be taken with the study participant in the same position at all 
visits. BP should be taken via an automated recorder after resting for at least 5 minutes.
Concomitant Medication Use
X
ECG
X
12-lead ECGs will be performed after 10 minutes of rest. After the ECG is completed, a 
10-second paper ECG will be obtained and maintained in the study participant’s source 
documentation. ECG should be completed prior to blood draws.
Cardiac Monitoring Device
X
A cardiac monitoring device will be applied at Screening.
Laboratory Tests
See Table 9.4.4-1.
Hematology
X
Chemistry
X
Urinalysis
X
Follicle-stimulating Hormone (FSH)
X
FSH testing for postmenopausal women to confirm postmenopausal status.
Pregnancy Test (β-hCG)
X
Serum pregnancy testing for all females of childbearing potential.
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CV027004
BMS-986427
Mavacamten
Table 2-1:
Screening Procedural Outline (CV027004)
Procedurea
Screening Periodb
(Day -35 to Day -1)
Notes
Coagulation Panel
X
Serology
X
Includes hepatitis C antibody, hepatitis B surface antigen, and HIV-1 and -2 antibody.
Adverse Event Reporting
Monitor for Serious Adverse Events 
(SAEs)
X
All SAEs will be collected starting after the signed consent and at each visit through 
Follow-up Period. See Section 9.2.
Biomarker Assessments
Biomarkers
See Table 9.8-1 for biomarker sample collection.
Abbreviations: β-hCG, human chorionic gonadotropin; BP, blood pressure; 
 
ECG, electrocardiogram; FSH, follicle-stimulating hormone; HIV, human immunodeficiency virus; HR, heart rate; ICD, implantable cardioverter-defibrillator; 
 NYHA, New York Heart Association; PE, physical examination; SAE, serious 
adverse event; 
.
a All assessments should be performed prior to mavacamten dosing unless otherwise specified. ECG should be completed prior to blood draws. Blood draws (for 
biomarkers and laboratory tests) should be performed prior to exercise.
b Screening may require more than one visit to accommodate all study procedures.
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Mavacamten
Table 2-2:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Primary Analysis Treatment Period (Day 1 through Week 30)
Notes
D1
Wk 
2 
TC, 
D15
Wk 
4 
D29
Wk 
6 
D43
Wk 
8 
D57
Wk 
12 
D85
Wk 
14 
D99
Wk 
18 
D127
Wk 
20 
D141
Wk 
24 
D169
Wk 
26 
D183
Wk 
30c
D211
Physical 
Examination (PE)
X
X
X
X
X
X
X
X
X
X
X
At Week 30 and ET, a complete 
physical examination will be 
conducted, including a neurological 
examination. At all other visits, an 
abbreviated cardiopulmonary physical 
examination will be conducted, with 
other systems assessed as directed by 
interval history.
Weight
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
At Week 30 and ET, complete vital 
signs including temperature, HR, 
respiratory rate, and BP will be 
obtained. At all other visits, only HR 
and BP are required. If 
 is 
conducted at a visit, vital signs should 
be collected before 
. Vital 
signs should be taken with the study 
participant in the same position at all 
visits. BP should be taken via an 
automated recorder after resting for at 
least 5 minutes.
Concomitant 
Medication Use
X
X
X
X
X
X
X
X
X
X
X
X
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CV027004
BMS-986427
Mavacamten
Table 2-2:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Primary Analysis Treatment Period (Day 1 through Week 30)
Notes
D1
Wk 
2 
TC, 
D15
Wk 
4 
D29
Wk 
6 
D43
Wk 
8 
D57
Wk 
12 
D85
Wk 
14 
D99
Wk 
18 
D127
Wk 
20 
D141
Wk 
24 
D169
Wk 
26 
D183
Wk 
30c
D211
ECG
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGs will be performed after 
10 minutes of rest prior 
 
 at most on-site study visits. 
At Day 1, Weeks 8, 14, and 20, post-
dose ECG will also be performed 
around Tmax (0.5 – 3 hours after 
study drug dose) in addition to the 
pre-dose ECG. Each time an ECG is 
completed, a 10 second paper ECG 
will be obtained and maintained in the 
study participant’s source 
documentation. ECG should be 
completed prior to blood draws.
Cardiac 
Monitoring Device
X
X
A cardiac monitoring device will be 
applied at Weeks 12 and 26.
ICD Download
X
X
For participants who have ICDs, 
information including rhythm strips 
and events will be downloaded from 
the ICDs at Week 12, Week 30, and 
ET, or as clinically indicated after any 
ICD discharge interrogation occurring 
during the study.
KCCQ
X
X
X
X
X
The KCCQ should be completed by 
participants prior to any other study 
procedure taking place, when
possible.
Laboratory Tests
See Table 9.4.4-1.
Hematology
X
X
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CV027004
BMS-986427
Mavacamten
Table 2-2:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Primary Analysis Treatment Period (Day 1 through Week 30)
Notes
D1
Wk 
2 
TC, 
D15
Wk 
4 
D29
Wk 
6 
D43
Wk 
8 
D57
Wk 
12 
D85
Wk 
14 
D99
Wk 
18 
D127
Wk 
20 
D141
Wk 
24 
D169
Wk 
26 
D183
Wk 
30c
D211
Chemistry
X
X
X
X
X
Urinalysis
X
Pregnancy Test 
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy testing for all 
females of childbearing potential. 
Negative Day 1 urine pregnancy test is 
required prior to initiating study 
treatment. If a urine test is positive or 
cannot be confirmed as negative (eg, 
an ambiguous result), a serum 
pregnancy test is required. In such 
cases, the participant must be 
excluded from participation if the 
serum pregnancy result is positive.
Refer to Section 9.2.5.
Coagulation Panel
X
X
X
X
X
Adverse Event Reporting
Monitor for 
Adverse Events 
(AEs)
Continuously
Nonserious AEs will be collected 
starting with the first dose of study 
drug and at each visit through Follow-
up Period. See Section 9.2.
Monitor for 
Serious Adverse 
Events (SAEs)
Continuously
All SAEs will be collected starting 
after the signed consent and at each 
visit through Follow-up Period. See 
Section 9.2.
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-2:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Primary Analysis Treatment Period (Day 1 through Week 30)
Notes
D1
Wk 
2 
TC, 
D15
Wk 
4 
D29
Wk 
6 
D43
Wk 
8 
D57
Wk 
12 
D85
Wk 
14 
D99
Wk 
18 
D127
Wk 
20 
D141
Wk 
24 
D169
Wk 
26 
D183
Wk 
30c
D211
Biomarker Assessments
Biomarkers
See Table 9.8-1 for biomarker sampling schedule.
Efficacy Assessments
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CV027004
BMS-986427
Mavacamten
Table 2-2:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Primary Analysis Treatment Period (Day 1 through Week 30)
Notes
D1
Wk 
2 
TC, 
D15
Wk 
4 
D29
Wk 
6 
D43
Wk 
8 
D57
Wk 
12 
D85
Wk 
14 
D99
Wk 
18 
D127
Wk 
20 
D141
Wk 
24 
D169
Wk 
26 
D183
Wk 
30c
D211
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-2:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Primary Analysis Treatment Period (Day 1 through Week 30)
Notes
D1
Wk 
2 
TC, 
D15
Wk 
4 
D29
Wk 
6 
D43
Wk 
8 
D57
Wk 
12 
D85
Wk 
14 
D99
Wk 
18 
D127
Wk 
20 
D141
Wk 
24 
D169
Wk 
26 
D183
Wk 
30c
D211
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-2:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Primary Analysis Treatment Period (Day 1 through Week 30)
Notes
D1
Wk 
2 
TC, 
D15
Wk 
4 
D29
Wk 
6 
D43
Wk 
8 
D57
Wk 
12 
D85
Wk 
14 
D99
Wk 
18 
D127
Wk 
20 
D141
Wk 
24 
D169
Wk 
26 
D183
Wk 
30c
D211
NYHA Functional 
Class
X
X
X
X
X
X
X
X
X
X
X
Study Treatment 
QD
Continuously
Dose Adjustment 
Assessment 
X
X
X
X
Study Treatment 
Administered at 
Site
X
X
X
X
X
X
X
X
X
X
X
At all on-site visits, mavacamten will 
be administered at the investigational 
site to facilitate collection of 
 
sample ≤ 4 hours prior to dosing. 
Mavacamten will be administered at 
the end of the visit when all other 
assessments have completed, 
including any drawing of blood.
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-2:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Primary Analysis Treatment Period (Day 1 through Week 30)
Notes
D1
Wk 
2 
TC, 
D15
Wk 
4 
D29
Wk 
6 
D43
Wk 
8 
D57
Wk 
12 
D85
Wk 
14 
D99
Wk 
18 
D127
Wk 
20 
D141
Wk 
24 
D169
Wk 
26 
D183
Wk 
30c
D211
Study Treatment 
Compliance
X
X
X
X
X
X
X
X
X
X
All participants will return their 
mavacamten dosing containers to the 
site pharmacy for capsule counts. 
Refer to the Pharmacy Manual for 
details.
Abbreviations: AE, adverse event; BP, blood pressure; 
 d, day; ECG, 
electrocardiogram; ET, early termination; HCM, hypertrophic cardiomyopathy; HR, heart rate; ICD, implantable cardioverter-defibrillator; 
 
 KCCQ, Kansas City Cardiomyopathy Questionnaire; 
 NYHA, New 
York Heart Association; 
 QD, once daily; SAE, serious adverse event: TC, telephone call; Tmax, time of maximum observed concentration; 
 Wk, week; Wt, weight.
a All visit dates will be scheduled based on Day 1. All visits after Day 1 should occur within the visit window (± 7 days) scheduled based on the projected study 
date. 
b All assessments should be performed prior to mavacamten dosing unless otherwise specified. The KCCQ should be completed by participants prior to any other 
study procedure taking place, when possible. ECG should be completed prior to blood draws. Blood draws (for 
 biomarkers, and laboratory tests) should be 
performed prior to exercise.
c In case of unforeseen medical conditions preventing ability to perform procedures at Week 30, these procedures may be completed at the earliest possible time 
point based on investigator assessments of medical status (outside of the ± 7-day window).
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-3:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Long-Term Treatment Period (Week 30 to Week 138)
Notesd
Wk 
42 
D295
Wk 
54 
D379
Wk 
66 
D463
Wk 
78 
D547
Wk 
90 
D631
Wk 
102 
D715
Wk 
114 
D799
Wk 
126 
D883
Unscheduled 
Visitc
Wk 
138 
EOT
ET
Physical 
Examination 
(PE)
X
X
X
X
X
X
X
X
X
X
X
At ET and/or Week 138, a 
complete physical examination 
will be conducted, including a 
neurological examination. At all 
other visits, an abbreviated 
cardiopulmonary physical 
examination will be conducted, 
with other systems assessed as 
directed by interval history.
Weight
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
At ET and/or Week 138, 
complete vital signs including 
temperature, HR, respiratory rate, 
and BP will be obtained. At all 
other visits, only HR and BP are 
required. If 
 
conducted at a visit, vital signs 
should be collected before 
 
sampling. Vital signs should be 
taken with the study participant in 
the same position at all visits. BP 
should be taken via an automated 
recorder after resting for at least 5 
minutes.
Concomitant 
Medication Use
X
X
X
X
X
X
X
X
X
X
X
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-3:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Long-Term Treatment Period (Week 30 to Week 138)
Notesd
Wk 
42 
D295
Wk 
54 
D379
Wk 
66 
D463
Wk 
78 
D547
Wk 
90 
D631
Wk 
102 
D715
Wk 
114 
D799
Wk 
126 
D883
Unscheduled 
Visitc
Wk 
138 
EOT
ET
ECG
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGs will be performed 
after 10 minutes of rest prior  
 at most on-
site study visits. Each time an 
ECG is completed, a 10-second 
paper ECG will be obtained and 
maintained in the study 
participant’s source 
documentation. ECG should be 
completed prior to blood draws.
Cardiac 
Monitoring 
Device
X
X
X
A cardiac monitoring device will 
be applied at Weeks 66, 102, and 
126.
ICD Download
X
X
X
X
For participants who have ICDs, 
information including rhythm 
strips and events will be 
downloaded from the ICDs at 
Weeks 66, 102, ET, and/or Week 
138, or as clinically indicated 
after any ICD discharge 
interrogation occurring during the 
study.
KCCQ
X
X
X
X
X
X
Laboratory 
Tests
See Table 9.4.4-1.
Hematology
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
Urinalysis
X
X
X
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-3:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Long-Term Treatment Period (Week 30 to Week 138)
Notesd
Wk 
42 
D295
Wk 
54 
D379
Wk 
66 
D463
Wk 
78 
D547
Wk 
90 
D631
Wk 
102 
D715
Wk 
114 
D799
Wk 
126 
D883
Unscheduled 
Visitc
Wk 
138 
EOT
ET
Pregnancy test
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy testing for all 
females of childbearing potential. 
A pregnancy test will be taken 
every 4 weeks at home, at the site, 
or at a local laboratory when no 
clinic visit is scheduled until the 
end of the study. Refer to Section 
9.2.5. Conduct serum test if any 
urine test is positive.
Coagulation 
Panel
X
X
X
X
X
X
Monitor for 
Adverse Events 
(AEs)
See Notes.
Nonserious AEs will be collected 
starting with the first dose of 
study drug and at each visit 
through Follow-up Period. See 
Section 9.2.
Monitor for 
Serious 
Adverse Events 
(SAEs)
See Notes.
All SAEs will be collected 
starting after the signed consent 
and at each visit through Follow-
up Period. See Section 9.2.
Biomarker Assessments
Biomarker 
Assessments
See Table 9.8-1 for biomarker sampling schedule.
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-3:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Long-Term Treatment Period (Week 30 to Week 138)
Notesd
Wk 
42 
D295
Wk 
54 
D379
Wk 
66 
D463
Wk 
78 
D547
Wk 
90 
D631
Wk 
102 
D715
Wk 
114 
D799
Wk 
126 
D883
Unscheduled 
Visitc
Wk 
138 
EOT
ET
Efficacy Assessments
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-3:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Long-Term Treatment Period (Week 30 to Week 138)
Notesd
Wk 
42 
D295
Wk 
54 
D379
Wk 
66 
D463
Wk 
78 
D547
Wk 
90 
D631
Wk 
102 
D715
Wk 
114 
D799
Wk 
126 
D883
Unscheduled 
Visitc
Wk 
138 
EOT
ET
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-3:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Long-Term Treatment Period (Week 30 to Week 138)
Notesd
Wk 
42 
D295
Wk 
54 
D379
Wk 
66 
D463
Wk 
78 
D547
Wk 
90 
D631
Wk 
102 
D715
Wk 
114 
D799
Wk 
126 
D883
Unscheduled 
Visitc
Wk 
138 
EOT
ET
NYHA 
Functional 
Class
X
X
X
X
X
X
X
X
X
X
X
Study 
Treatment QD
Continuously
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-3:
On-Treatment - Schedule of Activities for All Participants (CV027004)
Week Visits
(± 7 d)a,b
Long-Term Treatment Period (Week 30 to Week 138)
Notesd
Wk 
42 
D295
Wk 
54 
D379
Wk 
66 
D463
Wk 
78 
D547
Wk 
90 
D631
Wk 
102 
D715
Wk 
114 
D799
Wk 
126 
D883
Unscheduled 
Visitc
Wk 
138 
EOT
ET
Study 
Treatment 
Administered at 
Site
X
X
X
X
X
X
X
X
X
X
At all on-site visits, mavacamten 
will be administered at the 
investigational site to facilitate 
collection of 
 sample 
≤4 hours prior to dosing. 
Mavacamten will be administered 
at the end of the visit when all 
other assessments have 
completed, including any drawing 
of blood.
Study 
Treatment 
Compliance
X
X
X
X
X
X
X
X
X
X
X
All participants will return their 
mavacamten dosing containers to 
the site pharmacy for capsule 
counts. Refer to the Pharmacy 
Manual for details.
Abbreviations: AE, adverse event; BP, blood pressure; 
 CYP, cytochrome 
P450; d, day; ECG, electrocardiogram; EOS, end of study; EOT, end of treatment; ET, early termination; HR, heart rate; Ht, height; ICD, implantable cardioverter-
defibrillator; KCCQ, Kansas City Cardiomyopathy Questionnaire; 
 NYHA, New York Heart Association; 
 
 PM, poor metabolizer; QD, once daily; SAE, serious adverse event; 
 Wk, week.
a All visits after Day 1 should occur within the visit window (± 7 days) scheduled based on the projected study date.
b All assessments should be performed prior to mavacamten dosing unless otherwise specified. The KCCQ should be completed by participants prior to any other 
study procedure taking place, when possible. ECG should be completed prior to blood draws. Blood draws (for 
 biomarkers, and laboratory tests) should be 
performed prior to exercise.
c Participants who have any dose adjustment should return to the clinic approximately 28 days later (± 7 days) for an unscheduled visit with AE and safety 
laboratory assessments, and ECG 
 to confirm safety (see Section 7.4.1.2).
d Participants who prematurely discontinue study treatment will attend an ET visit and be contacted by site 4 weeks later for a telephone call. They will return to 
the study site 8 weeks later for an EOS visit. CYP 2C19 PMs will return to the study site for the Week 8 follow-up visit and a Week 20 EOS visit.
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-4:
Follow-Up Procedural Outline (CV027004)
Week Visits
(± 7 d)a,b
Week 4 
Follow-up 
Telephone Call
Week 8 
Follow-up/EOSc
Week 20 
Follow-up/EOSc
Notes
Physical Examination (PE)
X
X
An abbreviated cardiopulmonary physical examination 
will be conducted, with other systems assessed as 
directed by interval history.
Vital Signs
X
X
Only HR and BP are required. If 
 sampling is 
conducted at a visit, vital signs should be collected before 
 sampling. Vital signs should be taken with the study 
participant in the same position at all visits. BP should be 
taken via an automated recorder after resting for at least 
5 minutes.
Concomitant Medication Use
X
X
X
ECG
X
X
12-lead ECGs will be performed after 10 minutes of rest 
prior 
. Each time an ECG is 
completed, a 10-second paper ECG will be obtained and 
maintained in the study participant’s source 
documentation. ECG should be completed prior to blood 
draws.
Laboratory Tests
See Table 9.4.4-1.
Hematology
X
X
Chemistry
X
X
Urinalysis
X
X
Pregnancy test
X
X
X
Urine pregnancy testing for all females of childbearing 
potential. A pregnancy test will be taken every 4 weeks at 
home, at the site, or at a local laboratory when no clinic 
visit is scheduled until the end of the study. Conduct 
serum test if any urine test is positive
Coagulation Panel
X
X
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
Table 2-4:
Follow-Up Procedural Outline (CV027004)
Week Visits
(± 7 d)a,b
Week 4 
Follow-up 
Telephone Call
Week 8 
Follow-up/EOSc
Week 20 
Follow-up/EOSc
Notes
Adverse Event Reporting
Monitor for Adverse Events 
(AEs)
Continuously
Nonserious AEs will be collected starting with the first 
dose of study drug and at each visit through Follow-up 
Period. See Section 9.2.
Monitor for Serious Adverse 
Events (SAEs)
Continuously
All SAEs will be collected starting after the signed 
consent and at each visit through Follow-up Period. See 
Section 9.2.
Biomarker Assessments
Biomarker Assessments
See Table 9.8-1 for biomarker sampling schedule.
Efficacy Assessments
NYHA Functional Class
X
X
Abbreviations: AE, adverse event; BP, blood pressure; CYP, cytochrome P450; d, day; ECG, electrocardiogram; EOS, end of study; EOT, end of treatment; FU, 
follow-up; HR, heart rate; 
 NYHA, New York Heart Association; PE, physical 
examination; 
 PM, poor metabolizer; SAE, serious adverse event; 
a All visits after Day 1 should occur within the visit window (± 7 days) scheduled based on the projected study date. 
b All assessments should be performed prior to mavacamten dosing unless otherwise specified. The KCCQ should be completed by participants prior to any other 
study procedure taking place, when possible. ECG should be completed prior to blood draws. Blood draws (for 
 biomarkers, and laboratory tests) should be 
performed prior to exercise.
c Follow-up visit/EOS will be completed at 8 weeks (and 20 weeks if CYP 2C19 PM).
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
3
INTRODUCTION
HORIZON-HCM (CV027004), a Phase 3 open-label, single-arm, study, is designed to evaluate 
the efficacy, safety, and tolerability of a 30-week course of mavacamten and the long-term effects 
of mavacamten in Japanese participants with symptomatic obstructive hypertrophic 
cardiomyopathy (HCM).
3.1
Study Rationale
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder defined by left ventricular 
(LV) hypertrophy that cannot be explained by another cardiac or systemic disease. HCM is a 
chronic, progressive disease of the cardiomyocyte, and largely of the cardiac sarcomere, with a 
diverse clinical presentation and course. Over time, HCM results in tissue remodeling 
characterized histologically by myocyte hypertrophy and disarray, microvascular remodeling, and 
fibrosis.1 Approximately 40% of affected individuals overall and 60% of those with a family 
history of clinical disease have a mutation in one or more sarcomeric structural genes.2,3,4,5
Mutations in cardiac myosin and other sarcomeric proteins appear to increase net power generation 
by the sarcomere,6,7,8 which is consistent with the generally hypercontractile state and impaired 
compliance of the myocardium observed clinically in HCM. Recent estimates of the prevalence of 
HCM using information from large administrative databases indicate that the prevalence of 
clinically diagnosed HCM ranges from 3 to 7 per 10,000.9,10,11,12
Two HCM phenotypes are recognized based on the presence or absence of obstruction of the LV 
outflow tract (LVOT), obstructive HCM (also known as HOCM) and non-obstructive HCM 
(nHCM), where obstruction is defined as a peak LV outflow gradient ≥ 30 mm Hg at rest or with 
provocation.3 Approximately 70% of individuals diagnosed with HCM have obstructive 
hypertrophic cardiomyopathy. 13 Therefore, the prevalence rate of obstructive hypertrophic 
cardiomyopathy is likely between 2 and 5 per 10,000, based on the recent estimates of HCM. The 
combination of the abnormal ventricular geometry caused by septal hypertrophy, reduced 
ventricular cavity size, and the pathologic elongation of the mitral valve are considered 
contributing factors,14 but the precise mechanism of LVOT obstruction is unknown. Ventricular 
obstruction produces increased LV systolic pressure and an array of subsequent abnormalities, 
including prolongation of ventricular relaxation, elevation of LV diastolic pressure, mitral 
regurgitation (MR), atrial fibrillation, myocardial ischemia, and decreased forward cardiac 
output.15 The presence of LVOT obstruction is an important prognostic factor in HCM and is 
associated with an increased risk of disease progression, congestive heart failure, stroke, and 
death.16,17 The risk of sudden cardiac death (SCD), which is one of the most common nontraumatic 
causes of death in young adults and sometimes the first manifestation of HCM, is also increased 
in the presence of LVOT obstruction.3,18,19
Current guidelines for the pharmacologic management of HCM rely on empirical use of 
established cardiovascular (CV) medications (including beta blockers, verapamil, diltiazem, and 
disopyramide)3,20 that may improve LV outflow, but offer limited and variable relief in symptoms 
and functional status. In obstructive hypertrophic cardiomyopathy, septal reduction therapy may 
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Clinical Protocol
CV027004
BMS-986427
Mavacamten
reduce obstruction and improve LV outflow, and an implantable cardioverter-defibrillator (ICD) 
may prevent SCD, but both involve invasive procedures, require specialized operators and clinic 
settings, and may not be available to all patients.21 Cardiac transplant is the only option when 
pharmacologic options fail to adequately manage nHCM. None of these treatment options address 
the underlying etiology of HCM.
Mavacamten is a small-molecule selective allosteric inhibitor of cardiac myosin that reversibly 
inhibits its binding to actin, thereby relieving systolic hypercontractility and improving ventricular 
compliance. BMS is developing mavacamten for the treatment of HCM and heart failure with 
preserved ejection fraction (HFpEF).
3.2
Background
Clinical Experience with Mavacamten
To date, 19 clinical studies have been initiated to investigate the safety and tolerability of 
mavacamten. As of 31-Aug-2021, a total of 599 participants with HCM, HFpEF, or healthy 
participants were exposed to at least 1 dose of mavacamten. Participants who received treatment 
in both parent and extension studies are only counted once. Please refer to the Investigator’s 
Brochure (IB) for more details.
In the EXPLORER-HCM (MYK-461-005) Phase 3, randomized, double-blind, placebo-controlled 
study, patients with obstructive hypertrophic cardiomyopathy were assigned (1:1) to receive 
mavacamten (starting at 5 mg) or placebo for 30 weeks.22 Treatment with mavacamten was 
superior to placebo across the primary endpoint and all secondary endpoints in a study population 
with 92% of participants on either beta blocker or non-dihydropyridine calcium channel blocker 
therapy. Participants treated with mavacamten demonstrated twice the response rate of those in the 
placebo group on the composite functional primary endpoint (36.6% vs 17.2%), with a highly 
statistically significant between-group difference (19.4% [95% CI: 8.67, 30.13], P = 0.0005). 
Additionally, 20.3% of participants treated with mavacamten met the criteria of ≥ 3.0 mL/kg/min 
increase in peak oxygen consumption (peak VO2) and ≥ 1 New York Heart Association (NYHA) 
class improvement compared with 7.8% of participants on placebo. Mavacamten treatment was 
also effective in reducing LVOT gradients and improving symptoms, exercise performance, and
health status, as shown by significant improvement in all secondary endpoints.23
The safety of mavacamten has been evaluated for single and multiple doses in healthy participants 
and participants with HCM.
Treatment with mavacamten was well tolerated in the EXPLORER-HCM (MYK-461-005) study 
through 30 weeks of treatment. Overall, treatment-emergent adverse events (TEAEs) were higher 
in the mavacamten group compared with the placebo group during the on-treatment (Day 1 
through Week 30) period (87.8% vs 78.9%) and treatment-emergent (Day 1 through Week 38) 
period (87.8% and 81.3%). It is notable that the TEAE rate did not increase in the mavacamten 
group with 8 weeks of additional observation during study drug washout. The proportion of 
participants in the mavacamten group with treatment discontinuations due to TEAEs was 1.6% 
(2 of 123 participants). No participants in the placebo group discontinued treatment due to TEAEs, 
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although one participant experienced sudden death. Serious adverse events (SAEs) were balanced 
between treatment groups: on-treatment rates of SAEs were 8.1% in the mavacamten group versus 
8.6% in the placebo group, and rates of treatment-emergent SAEs through washout were 11.4% 
and 9.4%, respectively.23
The pharmacokinetic (PK) profile of mavacamten is characterized by a biphasic profile with a 
rapid absorption (time of maximum observed concentration [Tmax] generally between 1 and 2 h) 
and a long terminal half-life (t1/2) with a mean of 6 to 9 days in cytochrome P450 (CYP) 2C19 
normal metabolizers (NMs). In cytochrome P450 (CYP) 2C19 poor metabolizers (PMs), t1/2 is 
approximately 23 days and the area under the concentration-time curve (AUC) is increased up to 
approximately 3-fold and maximum observed concentration (Cmax) by 50% compared to NMs 
(ie, *1/*1 genotype). Based on population PK studies, the exposure is largely dose proportional 
between 2.5 and 15 mg. At steady state, the peak-to-trough plasma concentration ratio with once
daily (QD) dosing is very low (1.5 to 1). Clearance and volume of distribution have not been 
determined in humans, as they require intravenous (IV) administration; however, data are 
consistent with a low clearance and high volume of distribution, as shown in nonclinical studies. 
Only minor metabolites have been detected in human plasma from the multiple ascending dose 
clinical trial (MYK-461-003). The systemic exposure of the most abundant metabolite in human 
plasma was less than 2% of the exposure of mavacamten. This was confirmed in a human 14C 
absorption, metabolism, and excretion (AME) study where all plasma metabolites were < 4% of 
the mavacamten exposure. The available data indicate that approximately 74% of the metabolism 
occurs through CYP 2C19, 18% through CYP 3A4/5, and the rest through CYP 2C9 liver 
enzymes. Less than 3% of the administered drug is found unchanged in the urine. A dedicated food 
effect study (MYK-461-014) showed that while absorption is delayed, the overall bioavailability 
is not affected to a clinically significant degree. An ethno-bridging study (MYK-461-011) 
indicated no important PK differences between Japanese and Caucasian CYP 2C19 NMs. In most 
cases, the between-participant variability (coefficient of variation) for exposure is moderate (in the 
30% to 50% range).
Because proton pump inhibitors such as omeprazole may be used by many HCM patients, and 
several of them are CYP 2C19 inhibitors, the effect of over-the-counter-strength omeprazole 
(20 mg) on mavacamten exposure was determined in a dedicated drug-drug interaction (DDI) 
study (MYK-461-018). The coadministration of a weak CYP 2C19 inhibitor like omeprazole 
20 mg increased the mavacamten AUC by 50% with no change in Cmax after a single dose of 
mavacamten. The data from the omeprazole DDI study and from the PM versus NM study 
(MYK-461-012) indicate that CYP 2C19 inhibitors may increase mavacamten exposure from 
approximately 1.5-fold for a weak inhibitor to at most 3.4-fold for a strong inhibitor. In this study, 
omeprazole and esomeprazole are prohibited.
A drug-interaction study with the moderate CYP 3A4 inhibitor verapamil, which is frequently used 
in obstructive hypertrophic cardiomyopathy patients, revealed no changes in AUC and a 50% 
increase in Cmax after a single dose of mavacamten. These changes are not considered clinically 
significant, especially when using a dosing strategy of starting every participant on a low dose of 
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mavacamten and increasing the dose as needed. Physiologically based PK modeling indicates that 
a strong CYP 3A4 inhibitor may be expected to increase mavacamten exposure up to 1.6-fold.
Because of the potential for mavacamten to cause induction of CYP 3A4, a drug-interaction study 
was conducted with a typical oral contraceptive consisting of ethinyl estradiol and norethindrone 
(Ortho-Novum®), which was administered before and after a 17-day course of mavacamten (25 mg 
on Days 1 and 2, followed by 15 mg daily for 15 days). Mavacamten did not decrease the exposure 
to either ethinyl estradiol or norethindrone, thus ruling out a drug interaction with oral 
contraceptives. Another dedicated CYP 3A4 induction study with the more sensitive probe 
midazolam confirmed overall no clinically meaningful induction by mavacamten. These data 
indicate that therapeutic levels of mavacamten do not result in clinically significant CYP 3A4 
induction. The individualized, clinically guided dosing approach addresses sources of 
inter-individual variability.
3.3
Benefit/Risk Assessment
The potential clinical benefit of mavacamten in this study is to provide therapeutic effect in patients 
with symptomatic obstructive hypertrophic cardiomyopathy.
3.3.1
Risk Assessment
Based on nonclinical data and the available clinical data, cardiac failure due to systolic dysfunction 
(symptomatic left ventricular ejection fraction; LVEF <50%), has been identified as an important 
known risk. Heart failure (HF) due to drug-drug interactions with CYP 2C19 and potent 3A4 
inhibitors, embryofetal toxicity, and arrhythmia due to QT prolongation have been identified as 
important potential risks.
3.3.1.1
Important Known Risks for Mavacamten
Cardiac Failure due to Systolic Dysfunction
In the mavacamten program, systolic dysfunction associated with mavacamten was observed as 
episodes of reversible LVEF reduction below the normal range. This systolic dysfunction ranged 
from drops in LVEF (either symptomatic or asymptomatic), and contrasted with LVEF reductions 
in the setting of clinical events of cardiac failure observed in complex clinical scenarios with other 
acute conditions such as stress cardiomyopathy, atrial fibrillation, anaphylactic shock, or other 
intercurrent acute conditions that confounded the causality assessment for mavacamten. Systolic 
dysfunction with mavacamten has been reversible and has not resulted in a picture of progressive 
cardiac failure (recurrent hospitalizations and progressive LVEF reduction) as described in the 
literature associated with progression of underlying HCM. However, the serious risk of cardiac 
failure due to systolic dysfunction (defined as symptomatic LVEF < 50%) is an important 
identified risk, and cardiac failure and systolic dysfunction are considered adverse drug reactions 
for mavacamten.
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3.3.1.2
Important Potential Risks for Mavacamten
Heart Failure due to Interaction with CYP 2C19 and Potent 3A4 Inhibitors
Mavacamten is metabolized primarily by CYP 2C19 (74%) and CYP 3A4 (18%). CYP 2C19 
inhibitors and potent CYP 3A4 inhibitors have the potential to increase mavacamten 
concentrations. Mavacamten exposures (AUC) increase by about 2-fold when it is taken with 
moderate CYP 2C19 inhibitors. Higher mavacamten concentrations may contribute to new events 
of systolic dysfunction, which may lead to heart failure.
Embryofetal Toxicity
There are no clinical data available on the safety of mavacamten during human pregnancy. 
However, in nonclinical reproductive toxicology studies, mavacamten was found to cause external, 
visceral, and skeletal fetal abnormalities, and developmental abnormalities occurred at exposure 
levels that were less than the maximum recommended human exposures. The risk of embryofetal 
toxicity due to paternal exposure in semen was assessed based on preclinical data, actual semen 
concentrations in healthy male volunteers, and the potential for these concentration levels to cause 
maternal systemic exposures that could be teratogenic. Based upon measurements of mavacamten 
in semen of 4 male participants who received 18.5 mg and 6 male participants who received 25 mg 
of mavacamten for 28 days, it was concluded that the risk of teratogenic effects caused by 
mavacamten transferred by semen or other body fluids is negligible. Highly effective contraception 
is required for females of childbearing potential in the ongoing clinical studies.
Arrhythmia due to QT Prolongation
In healthy hearts, modest dose-dependent and concentration-dependent corrected QT interval 
(QTc) prolongation has been observed. However, nonclinical data demonstrated that QTc 
prolongation in healthy hearts is not torsadogenic and did not result from an off-target direct effect 
of mavacamten; instead, the findings are attributed to an adaptive response to myosin inhibition in 
hearts with normal LV contractility. No torsadogenic clinical events (eg, malignant ventricular 
arrhythmias, seizures, or sudden death) have been observed to date in the mavacamten clinical 
program other than 1 event of sudden death (study MYK-005) observed on placebo treatment. In 
patients with obstructive hypertrophic cardiomyopathy, centrally read ECG results were consistent 
with a regression analysis demonstrating a negative correlation between mavacamten plasma 
concentrations and changes in QT interval with Fridericia correction (QTcF).
Based on the findings in healthy hearts, and due to abnormalities of QTcF in HCM patients in 
clinical practice (eg, interventricular conduction delay, bundle branch block, or repolarization 
changes due to underlying disease; use of implantable cardioverter-defibrillators/pacemakers; or 
concomitant use of proarrhythmic drugs), as well as the limited experience of concomitant use of 
mavacamten with known QT prolonging drugs commonly used in the HCM population, QTc 
interval change remains an important potential risk for mavacamten.
More detailed information about benefits and risks is provided in the Investigator’s Brochure.
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3.3.2
Benefit Assessment
The potential clinical benefit of mavacamten in this study is to provide therapeutic effect in patients 
with symptomatic obstructive hypertrophic cardiomyopathy.
4
OBJECTIVES AND ENDPOINTS
Table 4-1 summarizes the primary, secondary, 
 objectives and 
endpoints of the study.
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the effect of a 30-week course of 
mavacamten on post-exercise peak LVOT 
gradient, as determined by Doppler 
echocardiography.

Change from baseline to Week 30 in post exercise 
LVOT peak gradient.
Secondary

To assess the effect of a 30-week course of 
mavacamten on health status.

Change from baseline to Week 30 in KCCQ CSS.

To assess the effect of a 30-week course of 
mavacamten on symptoms.

Proportion of participants with at least 1 class 
improvement in NYHA functional class from baseline 
to Week 30.

To assess the effect of a 30-week course of 
mavacamten on cardiac biomarkers.

Change from baseline to Week 30 in NT-proBNP.

Change from baseline to Week 30 in cardiac 
troponins.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations: 
 
 CSS, Clinical Summary Score; 
 
 KCCQ, Kansas 
City Cardiomyopathy Questionnaire; 
 LVOT, left 
ventricular outflow tract; 
 NT-proBNP, N-terminal pro b-type natriuretic 
peptide; NYHA, New York Heart Association; 
 
 
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5
STUDY DESIGN
5.1
Overall Design
This is a Phase 3, open-label, single-arm, study to evaluate the safety, tolerability, and efficacy of 
mavacamten in Japanese patients with symptomatic obstructive hypertrophic cardiomyopathy. 
Approximately 30 participants will be treated.
The study duration is a maximum of 151 weeks (163 weeks if CYP 2C19 PM).
The study will comprise 3 periods:

Screening Period (up to 5 weeks)

Treatment Period

Treatment Period for Primary Analysis (Day 1 through Week 30)

Long-Term Treatment Period (Week 30 to Week 138)

Post-treatment Follow-up Period (8 weeks [and 20 weeks if CYP 2C19 poor metabolizer 
{PM}]), or until mavacamten becomes commercially available (at the discretion of the 
Sponsor).
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schema
Abbreviations: 
 
CYP, cytochrome P450; ECG, electrocardiogram; EOS, end of study; FU, follow-up; 
 
PM, poor metabolizer; QD, once daily; stress echo, post exercise stress echocardiography; TC, telephone call; Time 0, 
Day 1 (start of Treatment Period for Primary Analysis); 
 wks, weeks.
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a In addition to pre-dose ECG, post-dose ECG is to be performed around Tmax (0.5 to 3 hours post-dose) at Day 1, 
and Weeks 8, 14, and 20.
 
d Follow-up or EOS visit at Week 8 for all participants, and at Week 20 if CYP 2C19 PM.
5.1.1
Screening Period
Participants will undergo a variety of general and laboratory assessments to assess eligibility (see 
Figure 5.1-1 and Table 2-1). Key screening tests include ECG; 
 
 
 A goal of at least 25% of the 
participants will be NYHA functional Class III at Screening.
The following Screening assessments may be repeated, as long as they are within the 35-day 
screening window: blood tests, ECG, 
. Repeat assessments are allowed if central core 
laboratories require a repeat submission due to quality and in order to better assess 
inclusion/exclusion values. Participants who fail screening may be considered for rescreening 
based on the investigator’s discretion, taking into consideration the reason(s) for screening failure. 
One attempt at rescreening will be allowed, and all procedures must be repeated.
Screening test results as reported by core laboratories (ECG core laboratory and echocardiography 
core laboratory) will be used to confirm eligibility.
Participants who meet all eligibility criteria may be treated.
5.1.2
Treatment Period
In the context of coronavirus disease 2019 (COVID-19) or other pandemics, natural disasters, or 
major disruptions, provisions may be made to accommodate participants who are unable to attend 
on-site study visits for scheduled assessments and dispensation of mavacamten. Guidance on 
participant management in these situations is outlined in Appendix 7.
5.1.2.1
Treatment Period for Primary Analysis
The initial treatment period (Day 1 through Week 30) for primary efficacy analysis will include 
dose titration designed to achieve safe and effective dosing for each participant based on their own 
response parameters. Participants who meet all eligibility criteria at Screening will be entered into 
the study via an interactive response system (IXRS), and will receive treatment with mavacamten 
2.5 mg starting dose once daily (QD). The permissible doses during Day 1 through Week 30 are 
1, 2.5, 5, 10, and 15 mg mavacamten. Assessments including ECG, 
 
 will be performed at study visits and read by core laboratories (Table 2-2
and Table 2-3). The dose will be adjusted or temporarily discontinued as described in Section 
7.4.1. The dose may be reduced or discontinued at any time during the Treatment Period based on 
the clinical judgment of the investigator in discussion with the Medical Monitor.
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After the Day 1 visit, participants will be contacted by telephone at Week 2 to check on AEs and
concomitant medications. Participant will first be seen at Week 4 for an initial evaluation of clinical 
tolerability and safety. 
Participants will subsequently be seen at Weeks 6, 8, 12, 14, 18, 20, 24, 26, and 30 for repeat 
evaluation. Core read assessments 
 of LVEF and LVOT gradient with Valsalva 
will be performed to guide dose adjustment via the IXRS. At Week 6, dose may be decreased or 
remain unchanged based upon results of Week 4 assessments. At Weeks 8, 14, and 20, the dose 
will be adjusted (dose increase, dose decrease, dose unchanged) based upon results of Week 6, 12, 
and 18 assessments, respectively, as specified in Section 7.4.1.
After Week 20, there are no additional scheduled dose titrations. Assessments at any visit can 
inform dose reduction or temporary discontinuation of mavacamten based on predefined criteria 
detailed in Section 8.1.3.1.
All clinic visits will include but are not limited to clinical evaluation (symptoms, 
 
AE/SAE assessments, concomitant medications). Assessments including ECG, 
 
 will be performed at study visits and read by core laboratories 
(see Section 2). If LVEF ≤ 30% is measured at the site, then the investigator will be notified and 
mavacamten will be permanently discontinued (Section 8.1.4).
At Week 30, participants will complete 
 at rest, with Valsalva maneuver, and post exercise; 
For any participant permanently discontinuing treatment prior to Week 30, an early termination 
(ET) visit should be conducted as soon as possible after stopping study drug. Participants who 
prematurely discontinue the study will attend an ET visit and should return to the study site 
8 weeks later for an end of study (EOS) visit as outlined in Section 5.1.3. CYP 2C19 PMs will also 
return to the study site for an 8-week follow-up (FU) visit and a 20-week EOS visit.
5.1.2.2
Long-Term Treatment Period
Participants will continue on the dose received at Week 30.
After the initial 30 weeks of the study, visits will occur every 12 weeks and will include but are 
not limited to clinical evaluation of symptoms, AE/SAE assessments, ECGs, 
 
 laboratory assessments including N-terminal pro b-type natriuretic peptide 
(NT-proBNP) and cardiac troponins.
At any visit subsequent to Week 30, a dose increase may be considered, up to a maximum of 
15 mg QD. Site-read assessments 
 of LVEF and LVOT gradient with Valsalva 
will be performed to guide dose adjustment via the IXRS. The dose may be reduced or 
discontinued at any time during the Long-Term Treatment Period based on the clinical judgment 
of the Investigator in discussion with the Medical Monitor (Section 7.4.1.2). The permissible doses 
during Week 30 to Week 138 are 1, 2.5, 5, 10, and 15 mg mavacamten.
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All participants will receive mavacamten QD for a duration of 108 weeks during the Long-Term 
Treatment Period, or until mavacamten becomes commercially available, whichever comes first.
Data from central laboratories and electrocardiography core laboratories will be used for safety 
(eg, monitor criteria for temporary discontinuation, down-titration, and/or permanent 
discontinuation); see Section 8.1.3.2.
For any participant permanently discontinuing treatment prior to Week 138, an early termination 
(ET) visit should be conducted as soon as possible after stopping study drug. Participants who 
prematurely discontinue the study will attend an ET visit and should return to the study site 
8 weeks later for an EOS visit as outlined in Section 5.1.3. CYP 2C19 PMs will also return to the 
study site for an 8-week follow-up visit and a 20-week EOS visit.
5.1.3
Post-treatment Follow-up Period
Participants who prematurely discontinue the study will attend an early termination visit, be 
contacted by telephone 4 weeks later, and return to the study site 8 weeks later for an EOS visit. 
CYP 2C19 PMs will also return to the study site for an 8-week follow-up visit and a 20-week EOS 
visit. After the participant completes the EOT visit, the site will be contacted by the Sponsor to 
notify the investigator if the participant is a CYP 2C19 PM and requires an additional 20-week 
EOS visit.
Participants who complete 138 weeks of the study and do not roll over to commercially available 
mavacamten will attend an EOT visit, be contacted by telephone 4 weeks later, and return to the 
study site 8 weeks later for an EOS visit. CYP 2C19 PMs will also return to the study site for the 
8-week follow-up visit and a 20-week EOS visit. After the participant completes the EOT visit, 
the site will be contacted by the Sponsor to notify the investigator if the participant is a CYP 2C19 
PM and requires an additional 20-week EOS visit. 
Participants who roll over to commercially available mavacamten at any time will be contacted by 
telephone 4 weeks and 8 weeks later for an EOS follow-up to assess AEs, concomitant 
medications, and pregnancy status. CYP 2C19 PMs will be contacted by telephone at Weeks 4, 8, 
and 20 post EOT.
Telephone Assessments
Telephone assessments will be conducted at the 4-week follow-up (FU)/telephone call (TC) to 
assess AEs, concomitant medications, and results of pregnancy test.
5.1.4
Description of Other Procedures and Assessments
Participants with ICDs will have their data downloaded at Screening, Week 12, Week 30, 
Week 66, Week 102, ET and/or Week 138 (EOT), or as clinically indicated whenever device 
discharge is interrogated and/or prior to any device reset.
Participants who meet all inclusion and exclusion criteria 
 requirements will 
undergo 
 during Screening or Day 1 prior to dosing, Week 30, Week 90, ET and/or Week 138 
(EOT) (or up to 5 days before each visit after Day 1) 
 
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The KCCQ assessment will be completed at Baseline/Day 1, Week 6, 12, 18, 30, 54, 66, 78, 114, 
and ET (and/or Week 138/EOT) (Section 9.1.1).
Participants may consent separately to have blood drawn for assessment of HCM genotype (Table 
9.8-1), preferably on Day 1 or any visit thereafter. This assessment is optional.
In addition, blood samples will be collected for analysis of biomarkers of efficacy, safety, 
 parameters. 
 
 
 
5.1.5
Data Monitoring Committee and Other Committees
Not applicable.
5.2
Number of Participants
Assuming a 40% screen failure rate, it is estimated that approximately 50 screened participants 
will be required to achieve approximately 30 treated participants.
Approximately 30 participants will be treated with mavacamten.
5.3
End of Study Definition
The start of the study is defined as the first participant first screening visit.
End of Treatment Period for Primary Analysis is defined as last participant has completed Week 
30 visit or terminated the initial 30-week treatment period prematurely.
End of treatment (EOT) is defined as last participant has completed Week 138 visit or has 
terminated early.
End of study (EOS) is defined as the last participant last visit on the Schedule of Activities.
A participant is considered to have completed the study if he/she has completed the last visit shown
in the Schedule of Activities.
5.4
Scientific Rationale for Study Design
Sponsor is developing mavacamten, a novel, small-molecule, allosteric inhibitor of cardiac-
specific myosin, for the treatment of patients with symptomatic obstructive hypertrophic 
cardiomyopathy, a condition with significant unmet medical need, with the goals of improving 
exercise capacity, functional capacity, and symptoms including fatigue and dyspnea. This Phase 3 
open-label study is designed to evaluate the efficacy, safety, and tolerability of a 30-week course 
of mavacamten and the long-term effects of mavacamten in Japanese patients with symptomatic 
obstructive hypertrophic cardiomyopathy. The study is designed 
 
. The results of efficacy and safety in this study will 
be assessed comprehensively and are intended to be used in combination with the 
EXPLORER-HCM study to support its registration in Japan.
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In preclinical and early clinical studies, treatment with mavacamten successfully relieved LVOT 
gradients and improved parameters of left ventricular filling. In the Phase 2, open-label 
PIONEER-HCM study, mavacamten was well tolerated and significantly reduced post exercise 
LVOT gradients in obstructive hypertrophic cardiomyopathy.24 The EXPLORER-HCM study 
demonstrated a mean change in post exercise LVOT gradient of -47 (40.3) mm Hg at Week 30 in 
the mavacamten group vs -10 (29.6) mm Hg in the placebo group (between-group difference based 
on analysis of covariance model is -35 mm Hg [-43.2, -28.1], P < 0.0001).23
The primary endpoint in HORIZON-HCM is the change from baseline to Week 30 in post exercise 
LVOT peak gradient. Assuming the mean (SD) of the primary endpoint, the change from baseline 
to Week 30 in post exercise LVOT gradient, is -40 (45) mm Hg, a sample size of 30 participants 
will have approximately 94% probability to observe a mean change of ≤-27 mm Hg, with an 
observed 95% CI of (-43, -11) mm Hg. (Section 10.2).
Since patients to be enrolled in HORIZON-HCM remain symptomatic despite optimal medical 
therapy, an important additional measure of the benefit of mavacamten will be to assess its effect 
on improvement of their symptoms, a benefit that is related but different from improvement in 
functional capacity. 25 NYHA classification is the functional status classification used most 
commonly in patients with CV disease, especially HF and HCM, in both clinical practice and 
research studies. For an individual patient, a change in NYHA Class of 1 or more represents a 
clinically meaningful improvement.
In PIONEER Cohort A, 70% of patients achieved an improvement of at least 1 in NYHA class. In 
the EXPLORER-HCM study, more than twice the proportion of patients in the mavacamten group 
compared with the placebo group showed an improvement from baseline of ≥ 1 NYHA class at 
Week 30 (80 [65.0%] in the mavacamten group vs 40 [31.3%] in the placebo group; P < 0.0001 
for stratified and unstratified analyses).23 In a cohort of 44 HCM patients followed for 2 to 4 years, 
a symptomatic improvement was observed with a mean decrease in NYHA Class of 0.9 and 0.6, 
observed in surgical myectomy and alcohol septal ablation (ASA), respectively.26 In another larger 
cohort of 223 HCM patients followed for up to 20 years, treatment with invasive septal reduction 
therapy was associated with long-term patient symptom relief, with an observed mean decrease in 
NYHA class ranging from 1.2 to 1.49, with myectomy and ASA, respectively.27
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Participants will begin treatment with mavacamten 2.5 mg, with scheduled dose increases at 3 time 
points in the first 30 weeks. After 30 weeks of treatment, participants will continue on the dose 
received at Week 30, into the Long-Term Treatment Period. During this Long-Term Treatment 
Period, NYHA functional class, 
 
 Kansas City Cardiomyopathy Questionnaire (KCCQ), and safety of 
mavacamten will be assessed to determine long-term outcomes of participants receiving 
mavacamten.
5.4.1
Participant Input Into Study Design
Participants did not provide input into study design.
5.5
Justification for Dose
The starting dose of 2.5 mg/day was selected using integrated clinical data within a population 
pharmacokinetic (PPK) and exposure-response (E-R) modeling and simulation framework 
(PPK/ER M&S).
An ethno-bridging study (MYK-461-011) compared exposure in Japanese versus Caucasian 
healthy participants with normal CYP 2C19 metabolizer status after single-dose administration of 
mavacamten and demonstrated that no significant differences in PK, safety, and tolerability were 
observed. The PPK analysis and covariate effects modeling showed that mavacamten PK was most 
influenced by dose level, CYP 2C19 genotype, and body weight. Japanese patients generally 
exhibit a lower body weight and higher CYP 2C19 prevalence compared to the EXPLORER-HCM 
study population. Adjustment of these participant characteristics in the simulated population was 
expected to better reflect the Japanese obstructive hypertrophic cardiomyopathy population.
Based on PPK/ER M&S, a 2.5 mg starting dose with a 3-step up-titration scheme to 15 mg in the 
Treatment Period for Primary Analysis suggested acceptable safety and efficacy profiles based on 
LVOT and LVEF outcomes compared to the 5 mg starting dose in the EXPLORER-HCM study. 
Therefore, a 2.5 mg starting dose has been selected to assure safety among Japanese patients who 
generally exhibit a lower body weight and higher CYP 2C19 prevalence compared to the 
EXPLORER-HCM study population. The recommended 2.5 mg starting dose is appropriate for all 
Japanese patients, regardless of covariates identified as affecting mavacamten exposure (eg, body 
weight, CYP 2C19 genotype).
Furthermore, the individualized, clinically guided dosing approach addresses sources of 
inter-individual variability. The fact that individual patients may require higher or lower 
mavacamten exposure to achieve a clinically relevant improvement in LVOT obstruction supports 
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an individualized dose-titration strategy that is guided by clinical response. The permissible doses 
are 1, 2.5, 5, 10, and 15 mg mavacamten.
Based on the results from the PPK/ER M&S, it was determined 
 
 
 
6
STUDY POPULATION
Participants eligible for the study include both male and females, at least 18 years old, with 
obstructive HCM diagnosis.
A total of approximately 30 participants are expected to be treated with mavacamten in the study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply.
1) Signed Written Informed Consent
Participants, or their legally acceptable representative (refer to Appendix 2), must have signed 
and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved 
written informed consent form (ICF) in accordance with regulatory, local, and institutional 
guidelines. This must be obtained before the performance of any protocol-related procedures 
that are not part of normal patient care.
2) Type of Participant and Target Disease Characteristics
a) Body weight is greater than 35 kg at Screening.
b) Has adequate acoustic windows to enable accurate TTEs (refer to Echocardiography Site 
Instruction Manual).
c) Diagnosed with obstructive hypertrophic cardiomyopathy consistent with current 
American College of Cardiology Foundation/American Heart Association, European 
Society of Cardiology, and Japanese Circulation Society guidelines, ie, satisfy all criteria 
below (criteria to be documented by the echocardiography core laboratory):
i)
Has unexplained LV hypertrophy with nondilated ventricular chambers in the absence 
of other cardiac (eg, hypertension, aortic stenosis) or systemic disease and with 
maximal LV wall thickness ≥ 15 mm (or ≥ 13 mm with positive family history of 
hypertrophic cardiomyopathy).
ii) Has LVOT peak gradient ≥ 50 mm Hg during Screening as assessed 
 at rest, 
after Valsalva maneuver, or post exercise.
iii) Has LVOT gradient with Valsalva at Screening 
 of ≥ 30 mm Hg.
d) Has a valid measurement of LVOT post exercise peak gradient at Screening as determined 
by echocardiography core laboratory.
e) Has documented LVEF ≥ 60% by echocardiography core laboratory read of Screening 
 
at rest.
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f)
Has NYHA Class II or III symptoms at Screening.
g) Not applicable per Protocol Amendment 01, 
.
3) Age of Participant
Participant must be at least 18 years of age inclusive at the time of signing the informed 
consent.
4) Reproductive Status

Investigators shall counsel women of childbearing potential (WOCBP) participants, and male 
participants who are sexually active with WOCBP, on the importance of pregnancy prevention 
and the implications of an unexpected pregnancy.

The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention.

Local laws and regulations may require the use of alternative and/or additional contraception 
methods.

Note: Intravaginal and transdermal combined hormonal contraception are not approved by 
Japan Health Authority. Also, progestogen-only hormonal contraception is not approved 
by Japan Health Authority.
a) Female Participants:
i)
Female participants must have documented proof that they are not of childbearing 
potential.
ii) Women who are not of childbearing potential are exempt from contraceptive 
requirements.
iii) WOCBP must have a negative highly sensitive serum pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]). A 
negative urine pregnancy test result is required at Day 1 prior to the start of study 
treatment. 

Additional requirements for pregnancy testing during and after study intervention 
are located in Section 2, Schedule of Activities.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
iv) WOCBP must agree to follow instructions for method(s) of contraception defined in 
Appendix 4 and as described below and included in the ICF.

WOCBP are permitted to use hormonal contraception methods (as described in Appendix 4).
i)
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies:
1) Is not a WOCBP 
OR
2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), with low user dependency, as described in Appendix 
4, during the intervention period (starting from Screening) and for at least 4 months 
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after the last dose of mavacamten and agrees not to donate eggs (ova, oocytes) for 
the purpose of reproduction for the same time period
b) Male Participants:
i)
No additional contraceptive measures are required to be used.
6.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply.
1) Medical Conditions
a) Known infiltrative or storage disorder causing cardiac hypertrophy that mimics obstructive 
hypertrophic cardiomyopathy, such as Fabry disease, amyloidosis, or Noonan syndrome 
with LV hypertrophy.
b) Has any condition that precludes upright exercise stress testing.
c) Has a history of syncope or sustained ventricular tachyarrhythmia with exercise within 
6 months prior to Screening.
d) Has a history of resuscitated sudden cardiac arrest (at any time) or known history of 
appropriate implantable cardioverter-defibrillator (ICD) discharge for life-threatening 
ventricular arrhythmia within 6 months prior to Screening.
e) Has paroxysmal atrial fibrillation with atrial fibrillation present per the investigator’s 
evaluation of the participant’s ECG at the time of Screening.
f)
Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks 
prior to Screening and/or not adequately rate controlled within 6 months prior to Screening 
(Note: Participants with persistent or permanent atrial fibrillation who are anticoagulated 
and adequately rate-controlled are allowed).
g) Has been successfully treated with invasive septal reduction (surgical myectomy or 
percutaneous alcohol septal ablation [ASA]) within 6 months prior to Screening or plans 
to have either of these treatments during the study (note: individuals with an unsuccessful 
myectomy or percutaneous ASA procedure performed > 6 months prior to Screening may 
be enrolled if study eligibility criteria for LVOT gradient criteria are met).
h) ICD placement within 2 months prior to Screening or planned ICD placement during the 
study.
i)
Has QT interval with Fridericia correction (QTcF) > 500 msec when QRS interval is 
< 120 msec or QTcF is > 520 msec when QRS is ≥ 120 msec if participant has left bundle 
branch block or any other ECG abnormality considered by the investigator to pose a risk 
to participant safety (eg, second-degree atrioventricular block type II).
j)
Has documented obstructive coronary artery disease (> 70% stenosis in one or more 
epicardial coronary arteries) or history of myocardial infarction.
k) Has known moderate or severe (as per investigator’s judgment) aortic valve stenosis at 
Screening.
l)
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.
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m) Has pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation.
n) History of malignant disease within 10 years of Screening:
i)
Participants who have been successfully treated for nonmetastatic cutaneous squamous 
cell or basal cell carcinoma, or have been adequately treated for cervical carcinoma in 
situ or breast ductal carcinoma in situ may be included in the study.
ii) Participants with other malignancies who are cancer free for more than 10 years before 
Screening can be included in the study.
o) Has a history or evidence of any other clinically significant disorder, condition, or disease 
that, in the opinion of the investigator, would pose a risk to participant safety or interfere 
with the study evaluation, procedures, or completion.
2) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7.4
(refer to Appendix 5).
b) Current treatment (within 14 days prior to Screening assessments) or planned treatment 
during the study with cibenzoline, disopyramide, or ranolazine.
c) Current treatment (within 14 days prior to Screening assessments) or planned treatment 
during the study with a combination of beta blockers and verapamil or a combination of 
beta blockers and diltiazem.
Combination treatment with beta blockers and 
dihydropyridine calcium channel blockers is allowed.
d) For individuals on any beta blockers or any calcium channel blockers, any dose adjustment 
of these medications < 14 days prior to Screening assessments or any anticipated change 
in treatment regimen during the first 30 weeks of the study.
e) Is currently taking, or has taken within 14 days prior to Screening assessments, a prohibited 
medication, such as a cytochrome P450 (CYP) 2C19 inhibitor (eg, omeprazole or 
esomeprazole), a strong CYP 3A4 inhibitor, or St. John’s Wort (see Section 7.7.4 and refer 
to Appendix 5). Alternatives such as pantoprazole are allowed and may be discussed with 
the Medical Monitor.
f)
Prior treatment with cardiotoxic agents such as doxorubicin or similar agents.
g) Is currently taking, or has taken within 14 days prior to Screening assessments, biotin 
supplements (multivitamins that contain < 1000 mg QD of biotin are allowed during the 
study but must be stopped 24 hours prior to each study visit).
3) Physical and Laboratory Test Findings
a) Has safety laboratory parameters (chemistry, hematology, coagulation, and urinalysis) 
outside normal limits (according to the central laboratory reference range) at Screening as 
assessed by the central laboratory; however, a participant with safety laboratory parameters 
outside normal limits may be included if he or she meets all of the following criteria:
i)
The safety laboratory parameter outside normal limits is considered by the investigator 
to be clinically not significant.
ii) 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.
iii) The body size-adjusted estimated glomerular filtration rate is ≥ 30 mL/min/1.73 m2.
b) Has a positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or human 
immunodeficiency virus 1 (HIV-1) and HIV-2 antibody at Screening. Note: participants 
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with a treated and completely resolved hepatitis C infection without any sequelae are 
permitted.
c) Known active infection with severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) (coronavirus disease of 2019) polymerase chain reaction positive (PCR+) 
within 30 days of Screening.
4) Allergies and Adverse Drug Reaction
a) Hypersensitivity to any of the components of the mavacamten formulation.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated.
b) Previously participated in a clinical study with mavacamten.
c) Participated in a clinical trial in which the participant received any investigational drug (or 
is currently using an investigational device) within 30 days prior to Screening, or at least 
5 times the respective elimination half-life of the investigational drug (whichever is 
longer).
d) Is unable to comply with the study requirements, including the number of required visits 
to the clinical site.
e) Is a first degree relative of personnel directly affiliated with the study at the clinical study 
site, any study vendor, or the study sponsor.
f)
Inability to comply with restrictions as listed in Section 6.4 (Lifestyle Restrictions).
g) Not Applicable per Protocol Amendment 01, 
.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
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6.4
Lifestyle Restrictions
6.4.1
Meals and Dietary Restrictions

Refrain from consumption of Seville oranges, grapefruit or grapefruit juice and quinine (eg, 
tonic water) from Day 1 before the start of study intervention until after the final follow-up 
visit. 

Biotin supplements are prohibited from 14 days prior to screening through the EOS visit. 
Multivitamins that contain < 1000 mg QD of biotin are allowed during the study but must be 
stopped 24 hours prior to each study visit.
6.4.2
Other Restrictions

Starting 72 hours prior to the first dose until the final follow-up visit, participants should not 
engage in unaccustomed intensive exercise except during protocol-specified exercise tests.

Starting at Screening, participants will be required to abstain from blood or plasma donation 
until 3 months after the final study visit.
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6.5
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently entered in the study/included in the analysis population.
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, as applicable, and to respond to queries from regulatory authorities. 
Minimal information includes date of consent, demography, screen failure details, eligibility 
criteria, and any serious AEs.
6.5.1
Retesting During Screening
Assessments that are out of range at Screening may be repeated once. Participants who screen fail 
may be considered for rescreening based on the investigator’s discretion, taking into consideration 
the reason(s) for screen fail. One attempt at rescreening will be allowed, and all procedures must 
be repeated. Further repeat assessments after rescreening may be conducted only after discussion 
with the Medical Monitor.
The following Screening assessments may be repeated, as long as they are within the 35-day 
screening window: blood tests, ECG, 
. Repeat assessments are allowed if central core 
laboratories require a repeat submission due to quality and in order to better assess 
inclusion/exclusion values. 
7
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
procedure(s) or medical device intended to be administered to a study participant according to the 
study protocol.
Study intervention includes both Investigational [Medicinal] Product (IP/IMP) and 
Non-investigational/Auxiliary [Medicinal] Product (Non-IP/Non-IMP/AxMP) as indicated in 
Table 7.1-1.
An IP, also known as IMP in some regions, is defined a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a clinical study, including products already with 
a marketing authorization but used or assembled (formulated or packaged) differently from the 
authorized form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form.
In this study, investigational product is mavacamten, which is supplied as 1, 2.5, 5, 10, and 15 mg 
capsules.
Participants will receive mavacamten (1, 2.5, 5, 10, or 15 mg capsule) QD during the Treatment 
Period for Primary Analysis, and the Long-Term Treatment Period, for up to a total of 138 weeks 
of treatment. During the study, there is an opportunity for mavacamten dose titration as described 
in Section 7.4.
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Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
Non-IPs/AxMPs.
7.1
Study Interventions Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Study Intervention
ARM Name
Mavacamten
Intervention Name
Mavacamten (BMS-986427/MYK-461)
Type
Study drug
Dose Formulation
Immediate-release capsule
Unit Dose Strength(s)
1, 2.5, 5, 10, and 15 mg
Dosage Level(s)
1, 2.5, 5, 10, or 15 mg once daily
Route of Administration
Oral
Use
Experimental
IMP and Non-IMP/AxMP
IMP
Sourcing
Sponsor
Packaging and Labeling
Study intervention will be provided in high-density polyethylene 
bottles. Each bottle will be labeled as required per country 
requirement.
Current/Former Name(s) or Alias(es)
Mavacamten (BMS-986427/MYK-461)
Abbreviations: AxMP, auxiliary medicinal product IMP, Investigational Medicinal Product.
Mavacamten will be supplied to participants via the IXRS in 30 count high-density polyethylene 
bottles that are appropriately labeled. See Table 7.1-1 for the complete schedule of mavacamten 
administration. The participants will be instructed to store the mavacamten capsules and bottles in 
a cool, dry place.
Participants will take mavacamten as directed by the study investigator.
Each participant will receive a single oral dose of mavacamten at approximately the same time 
every day (± 8 hours).
At the time of dosing, 240 mL of water will be administered to the participant along with his/her 
dose of study intervention. If the dosing window is missed, the participant should not take 
mavacamten that day. In the event of vomiting, dose should not be repeated, but taken again the 
next day. Restrictions related to food and fluid intake are described in Section 6.4.
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7.2
Method of Study Intervention Assignment
Study using IXRS: All participants will be centrally assigned to treatment using IXRS. Before the 
study is initiated, each user will receive log-in information and directions on how to access the 
IXRS.
Study intervention will be dispensed at the study visits as listed in Schedule of Activities 
(Section 2).
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 
 (eg, 
). Those enrolled participants meeting 
inclusion and exclusion criteria will be eligible to be dosed. Sequential numbering may restart at 
 for each participating site as the distinct patient identification number (PID) will ultimately 
be comprised of the site number and participant number (eg, 
).
Participants who withdraw from the study after receiving an initial dose of treatment will not be 
replaced. If a participant withdraws after enrollment and before dosing, that participant may be 
replaced. The replacement participant will undergo the same enrollment procedures as a new 
participant.
7.3
Blinding
This is a nonrandomized, open-label, single-arm study. It has been determined that blinding is not 
required to meet study objectives. Blinding procedures are not applicable and access to treatment 
assignment information is unrestricted. The specific treatment to be taken by a participant will be 
assigned using IXRS. The site will contact the IXRS prior to the start of study intervention 
administration for each participant. The site will record the treatment assignment on the applicable 
Case Report Form (CRF), if required.
7.4
Dosage Modification
All dose adjustments will occur using the IXRS. During the first 30 weeks of the study, dose 
adjustments will occur via IXRS based on the echocardiogram core read data. After 30 weeks, all 
dose adjustments will occur via IXRS on the day of the visit based on site-read echocardiogram 
data entered by the site. The tables in this section outline how the dose may be adjusted and the 
IXRS will be programmed.
7.4.1
Dose Adjustments During Treatment Period
7.4.1.1
Dose Titration Period for Primary Analysis (Day 1 through Week 30)
The initial treatment period (Day 1 through Week 30) for primary efficacy analysis will include 
dose titration designed to achieve safe and effective dosing for each participant based on their own 
response parameters. Participants who meet all eligibility criteria at Screening will be entered into 
the study via an interactive response system (IXRS) and will receive treatment with mavacamten 
2.5 mg starting dose once daily (QD). This Treatment Period will include a 3-step dose up-titration 
scheme at Weeks 8, 14, and 20 (see Figure 5.1-1).
In this study, the starting dose of study drug is mavacamten 2.5 mg QD.
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If at Week 4, core read 
 Valsalva LVOT gradient < 30 mm Hg and LVEF ≥ 50%, the dose 
will be decreased to 1 mg at Week 6 via IXRS.
At Weeks 8, 14, and 20, participants will undergo dose adjustment (dose increase, dose decrease, 
or dose unchanged) based on their results from core read 
 Valsalva LVOT gradient 
assessments at Weeks 6, 12, and 18, respectively. Up-titration requires LVEF ≥ 55% and LVOT 
gradient with Valsalva maneuver ≥ 30 mm Hg (Table 7.4.1.1-1). Sites and investigators will not 
be actively adjusting doses. All dose adjustments will occur via IXRS.
Mavacamten dose may be down-titrated by 1 dose level or discontinued for safety at any time 
during the study based on the clinical judgment of the Investigator in consultation with the Medical 
Monitor.
Table 7.4.1.1-1:
Dose Titration (Day 1 through Week 30)
Time of 
Assessmenta
Valsalva 
LVOT 
Gradient
LVEF
Dose 
Titration
Time and Dose
Week 4
≥30 mm Hg
≥ 50%
No change
Week 6
Dose remains at 2.5 mg
< 30 mm Hg
≥ 50%
Decrease
Week 6
Dose decrease from:
•
2.5 mg to 1 mg
Week 6
≥30 mm Hg
≥ 55%
Increase
Week 8 
Dose increase from:
•
1 mg to 2.5 mg
•
2.5 mg to 5 mg
< 30 mm Hg
≥ 50%
No change
Week 8
Dose remains at 1 mg or 2.5 mg
≥30 mm Hg
50% < LVEF < 55%
No change
Week 8
Dose remains at 1 mg or 2.5 mg
Week 12
≥30 mm Hg
≥ 55%
Increase
Week 14
Dose increase from:
•
1 mg to 2.5 mg
•
2.5 mg to 5 mg
•
5 mg to 10 mg
< 30 mm Hg
≥ 50%
No change
Week 14
Dose remains at 1, 2.5, or 5 mg
≥30 mm Hg
50% < LVEF < 55%
No change
Week 14
Dose remains at 1, 2.5, or 5 mg
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Table 7.4.1.1-1:
Dose Titration (Day 1 through Week 30)
Time of 
Assessmenta
Valsalva 
LVOT 
Gradient
LVEF
Dose 
Titration
Time and Dose
Week 18
≥30 mm Hg
≥ 55%
Increase
Week 20
Dose increase from:
•
1 mg to 2.5 mg
•
2.5 mg to 5 mg
•
5 mg to 10 mg
•
10 mg to 15 mgb
< 30 mm Hg
≥ 50%
No change
Week 20
Dose remains at 1, 2.5, 5, or 10 mg
≥30 mm Hg
50% < LVEF < 55%
No change
Week 20
Dose remains at 1, 2.5, 5, or 10 mg
Abbreviations: IXRS, interactive response system; LVEF, left ventricular ejection fraction; LVOT, left ventricular 
outflow tract; 
.
a Dose adjustments will also be communicated directly to the IXRS based on Week 4, 6, 12, and 18 assessments 
including measures of 
 peak Valsalva LVOT gradient reported by the core laboratory.
b 15 mg once daily is the maximum allowable dose of mavacamten.
Note: Table is provided for IXRS programming.
7.4.1.2
Dose for Long-Term Treatment Period (Week 30 to Week 138)
After Week 30, participants will return to the clinical site for monitoring at every 12 weeks until 
Week 138. At each visit, AEs, concomitant medications, and symptoms will be assessed, and ECG, 
 will be performed for ongoing safety monitoring. Compliance with 
mavacamten will also be monitored by capsule count at each visit. 
At any visit subsequent to Week 30, if the site-read LVOT gradient with Valsalva maneuver is 
≥30 mm Hg and resting LVEF is ≥ 55%, then a dose increase may be considered, up to a maximum 
of 15 mg QD, after discussion with the Medical Monitor (Table 7.4.1.2-1). Any dose adjustments 
will occur on the day of the visit, based on site-read measurement of LVOT gradient with Valsalva 
maneuver and LVEF 
. Mavacamten dose may be reduced or discontinued at any time 
during the Long-Term Treatment Period based on the clinical judgment of the investigator in 
discussion with the Medical Monitor.
Participants who have any dose adjustment should return to the clinic approximately 28 days later 
(± 7 days) for an unscheduled visit with AE and safety laboratory assessments, ECG, 
 
 to confirm safety. Post exercise echocardiographic assessment of LVOT gradient will be at 
the investigator’s discretion. Based on results and clinical symptoms at follow-up visits, 
subsequent dose adjustments will be discussed with the Medical Monitor.
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Table 7.4.1.2-1:
Optional Dose Titration Guidelines for Week 42 to Week 126a
Time of 
Assessment
Valsalva 
LVOT 
gradient 
LVEF
Dose Titration
Dose
Week 42 –
Week 126
≥30 mm Hg
50% < LVEF < 55%
Dose remains unchanged
Dose remains at:
1, 2.5, 5, 10, or 15 mg
≥30 mm Hg
LVEF ≥ 55%
Dose increase
•
1 mg to 2.5 mg
•
2.5 mg to 5 mg
•
5 mg to 10 mg
•
10 mg to 15 mga
< 30 mm Hg
LVEF ≥ 50%
Dose remains unchanged
Dose remains at:
1, 2.5, 5, 10, or 15 mg
Abbreviations: IXRS, interactive response system; LVEF, left ventricular ejection fraction; LVOT, left ventricular 
outflow tract; 
.
a 15 mg once daily is the maximum allowable dose of mavacamten.
Note: Table is provided for IXRS programming.
7.5
Preparation/Handling/Storage/Accountability
The IP/AxMP must be stored in a secure area according to local regulations. It is the responsibility 
of the investigator, or designee where permitted, to ensure that IP/AxMP is only dispensed to study 
participants. The IP/AxMP must be dispensed only from official study sites by authorized 
personnel according to local regulations.
The product storage manager should ensure that the study intervention is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study intervention arise, the study intervention 
should not be dispensed, and BMS should be contacted immediately.
Study intervention not supplied by BMS will be stored in accordance with the package insert.
IP/AxMP documentation (whether supplied by BMS or not) must be maintained that includes all 
processes required to ensure the drug is accurately administered. This includes documentation of 
drug storage, administration and, as applicable, storage temperatures, reconstitution, and use of 
required processes (eg, required diluents, administration sets).

The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention.

Only participants enrolled into the study may receive study drug, and only authorized study 
staff may supply or administer study drug. All study drug must be stored in a secure and 
monitored area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
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
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
7.5.1
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 1, 2.5, 5, 10, and 15 mg strengths. Mavacamten capsules of 
all strengths are identical in appearance.
Mavacamten capsules are manufactured according to current Good Manufacturing Practice 
regulations. They are supplied in high-density polyethylene bottles with induction seals and 
child-resistant caps with 30 capsules in each bottle. All bottles are labeled according to applicable 
local regulatory guidelines.
Mavacamten capsules must be stored in the packaging supplied by the Sponsor (refer to the label 
for storage condition details).
7.5.2
Direct-to-Participant Study Drug Shipment (at Selected Sites)
In certain circumstances, it may be necessary to ship study drug directly to a participant (refer to 
Appendix 7). When study drug is shipped directly to the participant, a qualified individual who is 
contracted by the Sponsor/contract research organization (CRO) or study site will open the 
package of study drug, review temperature monitoring data, and confirm receipt. Study sites 
should contact participants by telephone to confirm study drug delivery. The study drug bottle(s) 
from the previous study visit will be returned to the site. Refer to the Pharmacy Manual for details.
7.6
Treatment Compliance
Compliance with study drug will be monitored by capsule count at all study visits. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit. Refer to the Pharmacy Manual for details.
On study visit days, participants should wait to take study drug until after they reach the clinic 
 
 as indicated in the schedule of study procedures 
 
Any concomitant medication may be administered prior to all exercise testing.
7.7
Concomitant Therapy
7.7.1
Prior Therapy
At the time of signing the ICF, participants will be asked about their medication history over the 
previous 28 days, including prescription and nonprescription medications, herbal medications, 
vitamins, and minerals. Prior medications are those with a stop date within the Screening Period 
(35 days prior to the first dose of study drug).
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If the participants have taken prohibited medications within 14 days prior to signing the ICF, they 
may sign the ICF and then must discontinue treatment for at least 14 days before proceeding to the 
Screening assessments. If participants have not taken any prohibited medications in the past 14 
days prior to signing the ICF, they may proceed to Screening assessments. The Principal 
Investigator will determine if the participant can discontinue prohibited treatments.
7.7.2
Background HCM Therapy
Background cardiomyopathy therapy (eg, beta blocker, verapamil, or diltiazem) is allowed,
(although not a combination of beta blockers and verapamil or a combination of beta blockers and 
diltiazem, per exclusion criteria). Participants should be on optimal medical therapy as determined 
by the investigator and informed by HCM treatment guidelines.32 The treatment should be well 
tolerated for at least 2 weeks prior to Screening assessments, and the investigators are encouraged 
to maintain this treatment unchanged (ie, at a stable dose) during the first 30 weeks of the study. 
After Week 30, investigators should manage background HCM medications (eg, beta blocker, 
verapamil, or diltiazem) as clinically appropriate in conjunction with the Medical Monitor. Any 
change in HCM medications must be entered into the electronic Case Report Form (eCRF) with 
the rationale for the change.
COVID-19 vaccination status will be collected from all study participants.
7.7.3
Concomitant Therapy
Concomitant medications are those with a stop date on or after the first dose of study drug of 
analysis interest or that were ongoing at the end of the analysis period.
Concomitant therapy will be collected at all clinic visits from the first dose until the end of the 
study. Document all concomitant therapies on the appropriate eCRF, whether prescription or over 
the counter, vitamin and/or mineral supplements, herbs, and medications taken for an event or 
procedure (eg, biopsy). Include start/stop dates, dose, route, and indication.
7.7.4
Prohibited and/or Restricted Treatments
Prior or concomitant treatment with cardiotoxic agents such as doxorubicin or similar agents is 
prohibited.
Use of disopyramide, cibenzoline, or ranolazine is prohibited from 14 days before Screening
assessments to the EOS.
Potent and moderate CYP 2C19 inhibitors and potent CYP 3A4 inhibitors are prohibited from 
14 days before Screening assessments through the EOS.
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.
Additional prohibited medications are listed in Appendix 5.
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7.8
Continued Access to Study Intervention After the End of the Study
At the end of the study, BMS will not continue to provide BMS-supplied study intervention to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS-supplied study intervention if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of 
mavacamten is terminated for other reasons, including, but not limited to, lack of efficacy and/or 
not meeting
the study objectives; c) the participant can obtain medication from a 
government-sponsored or other health program. In all cases, BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation From Study Intervention

In general, every effort should be made to keep a participant on treatment for as long as possible 
during the study unless a safety concern arises. Treatment discontinuation may either be 
temporary or permanent and if permanent, the degree to which a study participant withdraws 
can vary. Each of these circumstances is described below.
Participants MUST discontinue IP (and Non-IP/AxMP at the discretion of the investigator) for any 
of the following reasons:

Participant’s request to stop study intervention. Participants who request to discontinue study 
intervention prior to Week 30 or Week 138, an early termination visit should be conducted as 
soon as possible after stopping study drug. Participants who prematurely discontinue the study 
will attend an ET visit and should return to the study site 8 weeks later for an EOS visit as 
outlined in Section 5.1.3. CYP 2C19 PMs will return to the study site for an 8-week follow-up 
visit and a 20-week EOS visit. The only exception to this is when a participant specifically 
withdraws consent for any further contact with him/her or persons previously authorized by 
the participant to provide this information.
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Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant.

Termination of the study by BMS.

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
All participants who discontinue study intervention should comply with protocol-specified early 
termination (ET) procedures as outlined in Section 2. The only exception to this requirement is 
when a participant withdraws consent for all study procedures, including post-treatment study 
follow-up, or loses the ability to consent freely (eg, is imprisoned or involuntarily incarcerated for 
the treatment of either a psychiatric or physical illness).
If study intervention is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records per local 
regulatory requirements in each region/country and entered on the appropriate CRF page.
8.1.1
Temporary Treatment Discontinuation
Temporary treatment discontinuation

Will be implemented when a predefined safety threshold has been met (Section 8.1.3)

May be considered by the investigator in the case of an AE/SAE or for another reason
As a general rule, any discontinuation of study drug should be initially considered temporary 
unless permanent treatment discontinuation is mandated by the protocol (Section 8.1.4).
If a temporary treatment discontinuation was caused by a safety threshold being met, treatment 
will be resumed approximately 4 to 6 weeks later at a lower dose, transmitted via IXRS 
(Section 8.1.3).
In the case of discontinuation for an AE/SAE, the investigator should make a best effort to resume 
study drug as soon as practically possible, assuming there are no safety concerns (ie, the 
investigator is satisfied that in his or her medical judgment, the study drug is unlikely to be 
responsible for the event concerned).
All temporary treatment interruptions should be recorded in the eCRF.
8.1.2
Permanent Treatment Discontinuation
After a temporary treatment discontinuation, if a safety concern has not resolved or stabilized or 
the investigator suspects that study drug is responsible, the investigator may consider a treatment 
discontinuation as permanent. The investigator should make a best effort to contact the monitoring 
team before considering any treatment discontinuation as permanent. Permanent treatment 
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discontinuation should be considered a last resort. Every effort should be made to collect important 
safety data if feasible and the study participant agrees.
In all cases, participants should be encouraged to discuss stopping study drug with the investigator 
or the investigator’s designee so that questions can be addressed, concomitant therapy can be 
adjusted if needed, and a follow-up assessment can be arranged.
All permanent treatment discontinuation should be recorded in the eCRF.
8.1.3
Criteria for Temporary Treatment Discontinuation 
In addition to the dose adjustments described in Section 7.4.1, at any time (T) during the Treatment 
Period, dosing will be temporarily discontinued in the case of systolic dysfunction (LVEF < 50%), 
, or excessive QTcF prolongation as described below.
If participant has a resting LVEF < 50%, 
, or QTcF stopping 
criteria described below, as determined by the echocardiography central laboratory in the 
Treatment Period for Primary Analysis and the site-read echocardiography in the Long-Term 
Treatment Period, or ECG core laboratory, respectively, it will be communicated to the 
investigator and Medical Monitor that a criterion for temporary discontinuation has been met. 
Criteria for temporary discontinuation due to QTcF prolongation are as follows and depend on 
QRS width as determined by the ECG core laboratory:

If QRS is narrow (< 120 msec), then temporary discontinuation criteria are the smaller of: a 
15% increase from baseline QTcF OR QTcF ≥ 520 msec

If QRS is wide (≥ 120 msec), then temporary discontinuation criteria are the smaller of: a 15% 
increase from baseline QTcF OR QTcF ≥ 550 msec
8.1.3.1
Temporary Discontinuation in Treatment Period for Primary Analysis 
(Day 1 through Week 30)
Upon receipt of information that participant has a resting LVEF < 50%
 
 or QTcF stopping criteria, as determined by the core-read echocardiography results 
and ECG core laboratory, respectively, the study site/investigator will contact the participant and 
instruct the participant to discontinue mavacamten and to return for an on-site visit within 2 to 
4 weeks (T + 2 to 4 weeks). This could correspond to a scheduled or unscheduled visit.
At the follow-up visit (T + 2 to 4 weeks), ECG, 
 will be repeated and another 
scheduled/unscheduled visit will be planned for 2 weeks later (T + 4 to 6 weeks). If LVEF ≥ 50% 
AND 
 AND QTcF duration is below 
programmed discontinuation rules, then mavacamten will be restarted at a lower dose 
(at T + 6 weeks) as follows (previous dose → restart dose):
Mavacamten Dose Reduction Guide:

15 mg → 10 mg

10 mg → 5 mg

5 mg → 2.5 mg
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2.5 mg → 1 mg

1 mg → none (permanent treatment discontinuation)
If LVEF, 
 and/or QTcF persist out of range at the follow-up 
visit, then mavacamten will be discontinued.
8.1.3.2
Temporary Discontinuation in Long-Term Treatment Period (Week 30 to 
Week 138)
Temporary Discontinuations Due to LVEF < 50% Only
If the reason for temporary discontinuation is LVEF < 50% only, as determined by site-read 
echocardiography results, sites will be notified.
In this case, at the first follow-up visit (T + 2 to 4 weeks), 
 will be repeated to confirm if the 
LVEF is ≥ 50%. The QTcF 
 do not need to be repeated. If the LVEF is ≥ 50% at this visit, 
then mavacamten may be restarted at a lower dose as described below (see Dose Reduction Guide 
below).
If at the first follow-up visit (T + 2 to 4 weeks), the LVEF is < 50%, then the second follow-up 
visit will be planned for 2 weeks later (T + 4 to 6 weeks). Mavacamten will be restarted at a lower 
dose if the LVEF is ≥ 50% at this visit.
If LVEF performed at the follow-up visit persists out of range, mavacamten will be discontinued 
permanently.
Temporary Discontinuations Due to QTcF Alone 
 or 
 in Combination with LVEF < 50%:
If the reason for temporary discontinuation is QTcF as determined by ECG core laboratory and/or 
 in combination with LVEF < 50%, as determined 
by site-read echocardiography results, sites will be notified. At the first follow-up visit (T + 2 to 
4 weeks), ECG, 
 will be repeated and another unscheduled visit will be planned 
for 2 weeks later (T + 4 to 6 weeks).
If LVEF ≥ 50% AND 
 QTcF duration are 
below programmed discontinuation rules, then mavacamten will be restarted at a lower dose as 
follows (previous dose → restart dose):
Mavacamten Dose Reduction Guide:

15 mg → 10 mg

10 mg → 5 mg

5 mg → 2.5 mg

2.5 mg → 1 mg

1 mg → none (permanent discontinuation)
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If LVEF, 
 and/or QTcF persist out of range at the follow-up 
visit, then mavacamten will be discontinued. 
If participants are on 1 mg mavacamten and meet permanent discontinuation criteria, it will be 
communicated to the investigator and Medical Monitor.
8.1.4
Criteria for Permanent Treatment Discontinuation
The following reasons will lead to permanent treatment discontinuation:

Pregnancy

LVEF ≤ 30% as determined by local site
Note: If LVEF ≤ 30% is measured at the site for any participant, the sonographer should review 
and re-measure the findings with at least one other professional qualified in echocardiography 
assessment (eg, the investigator, echocardiogram laboratory director, another experienced 
sonographer, or cardiologist). If the result is confirmed (LVEF ≤ 30%), the investigator will 
be notified immediately, and mavacamten will be discontinued. The site must report 
 
 within 24 hours.

Continued administration of study drug is considered by the investigator to be detrimental to 
the participant’s safety or well-being

If all the criteria are met for possible drug-induced liver injury (DILI) (Section 9.2.7.1)

The participant requests to discontinue study drug

The Sponsor requests that the participant permanently discontinue study drug
8.1.5
Management of Participants After Permanent Treatment 
Discontinuation
There may be situations in which it is necessary for a participant to permanently discontinue study 
drug. In all cases, participants should be encouraged to discuss stopping study drug with the 
investigator/designee so that questions can be addressed, and concomitant therapy can be adjusted 
if needed. Investigators should contact the Medical Monitor prior to permanent study drug 
discontinuation to discuss the situation.
If a participant permanently discontinues treatment prior to Week 138, the participant will be asked 
to undergo an ET visit as soon as possible after stopping study drug, using the procedure normally 
planned for the EOT and EOS assessments as outlined in Section 2.
For participants who do not withdraw consent for ongoing study participation but fail to return to 
the site, the investigator should make every effort to contact the participant (eg, contacting 
participant’s family or private physician, reviewing available registries or health care databases), 
and to determine his/her health status, particularly vital status. Attempts to contact such 
participants must be documented in the participant’s records (eg, number of attempts and dates of 
attempted telephone contact and receipt for sending a registered letter).
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8.1.6
Rechallenge
8.1.6.1
Hepatotoxicity Rechallenge
Participants with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL], or international 
normalized ratio [INR]) or signs/symptoms of hepatitis may meet the criteria for withholding of 
mavacamten or other protocol-required therapies.
If mavacamten is withheld, the participant should be followed according to recommendations in 
Section 9.2.7 for possible DILI. Rechallenge may be considered if an alternative cause such as 
acute hepatitis B infection is discovered and the laboratory abnormalities resolve to normal or 
baseline.
8.1.6.2
Criteria for Rechallenge of Mavacamten After Potential Hepatotoxicity
The decision to rechallenge the participant should be discussed and unanimously agreed by the 
investigator and Sponsor.
If signs or symptoms recur with rechallenge, then mavacamten will be permanently discontinued. 
Participants who clearly meet the criteria for permanent discontinuation (Section 9.2.7.1) should 
never be rechallenged.
8.1.7
Post-study Intervention Study Follow-up
Participants who discontinue study intervention may continue to be followed.
Participants who prematurely discontinue the study will attend an early termination visit, be 
contacted by telephone 4 weeks later, and return to the study site 8 weeks later for an EOS visit. 
CYP 2C19 PMs will also return to the study site for an 8-week follow-up visit and a 20-week EOS 
visit.
8.2
Discontinuation From the Study
Participants who request to discontinue study intervention will remain in the study and must 
continue to be followed for protocol-specified follow-up procedures. The only exception to this is 
when a participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study intervention 
only or also from study procedures and/or post-treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
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8.2.1
Withdrawal From the Study
8.2.1.1
Withdrawal of Consent for Ongoing Study Participation
Participants may withdraw from the study before study completion if they decide to do so, at any 
time and for any reason. Withdrawal of consent for treatment (permanent treatment 
discontinuation) described above should be distinguished from withdrawal of consent for ongoing 
study participation with scheduled visits and from withdrawal of consent for non-participant 
contact follow-up (eg, medical records check).
Participants who withdraw from the study should be explicitly asked about the reason and the 
contribution of any AE(s) that led to their decision, and any AE information elicited should be 
documented. The participant may withdraw consent verbally or in writing. If the consent is 
withdrawn verbally, the site should document it appropriately. 
All study withdrawals should be recorded by the investigator in the appropriate eCRF and in the 
participant’s medical records when considered as confirmed. The date of the withdrawal and the 
reason should be documented.
The statistical analysis plan (SAP) will specify how these participants lost to follow-up will be 
considered for their primary endpoints.
Participants who have withdrawn from the study cannot be retreated in the study. Their inclusion 
and treatment numbers must not be reused.
8.2.1.2
Replacement of Participants Who Withdraw from the Study
Participants who withdraw from the study after receiving an initial dose of treatment will not be 
replaced. If a participant withdraws after enrollment and before dosing, that participant may be 
replaced. The replacement participant will undergo the same enrollment procedures as a new 
participant.
8.2.2
Individual Discontinuation Criteria

A participant may withdraw completely from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. Stopping study 
intervention is not considered withdrawal from the study.

At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted, as shown in the Schedule of Activities. See the Schedule of Activities for data to 
be collected at the time of study discontinuation and follow-up and for any further evaluations 
that need to be completed.

The participant will be permanently discontinued both from the study intervention and from 
the study at that time.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
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8.3
Lost to Follow-up
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of 
three (3) documented phone calls, faxes, or emails, as well as lack of response by participant 
to one (1) registered mail letter. All attempts should be documented in the participant’s medical 
records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If the investigator’s use of third-party representative to assist in the follow-up portion of the 
study has been included in the participant’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining the participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, to obtain updated contact information.

If, after all attempts, the participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s 
medical records.
9
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities (see Section 2).
The investigator is responsible for ensuring that all staff involved in the study are familiar and 
comply with the content of this section.
The following describes the study procedures to be performed during the study. Additional details 
are provided in Table 2-2 and Table 2-3 of this document. All assessments should be performed 
prior to mavacamten dosing unless otherwise specified. The KCCQ should be completed by 
participants prior to any other study procedure taking place, when possible. ECG should be 
completed prior to blood draws. Blood draws (for 
 biomarkers, and laboratory tests) should be 
performed prior to exercise. The order of assessments may vary slightly at specific time points to 
facilitate the most contemporaneous performance of the required assessments. Unscheduled or 
additional safety assessments may be performed if necessary, in the opinion of the investigator. 
Whenever possible, discussion with the Medical Monitor is encouraged.
For assessments that require the participants to be in a semi-recumbent or supine position, 
assessments should be conducted with participants in the same position at all time points.
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Visit Scheduling
All visits after Day 1 should occur within the visit window (± 7 days) scheduled based on the 
projected study date. If an evaluation is missed, reschedule and perform it as close as possible to 
the original date.
In case of unforeseen medical conditions preventing ability to perform procedures at Week 30, 
these procedures may be completed at the earliest possible time point based on investigator 
assessments of medical status (outside of the ± 7-day window).
9.1
Efficacy Assessments
9.1.1
Efficacy Assessment for the Study
New York Heart Association Functional Class
The NYHA Functional Classification of HF assigns participants to 1 of 4 categories based on the 
participant’s symptoms (Table 9.1.1-1). Heart failure classification will be assessed by the 
investigator at every study visit (preferably before echocardiography assessment), and recorded as 
indicated in the clinical database. A goal of at least 25% of the participants will be NYHA 
functional Class III at Screening.
Table 9.1.1-1:
New York Heart Association Functional Classification of Heart 
Failure
Class
Patient Symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea (shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less-than ordinary-activity 
causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases.
Source: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp#.VrtuzPkrKUl.
Kansas City Cardiomyopathy Questionnaire (23-item Version)
The Kansas City Cardiomyopathy Questionnaire (23-item version) (KCCQ) is a patient-reported 
questionnaire that measures the impact of patients’ CV disease or its treatment on 6 distinct 
domains using a 2-week recall: symptoms/signs, physical limitations, quality of life, social 
limitations, self-efficacy, and symptom stability. 33
 
 
 
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 The KCCQ will be administered to 
participants as indicated. The KCCQ should be completed by participants at study visits as outlined 
in Section 2, prior to any other study procedure taking place, when possible.
9.1.2
Imaging Assessment for the Study
9.1.2.1
Echocardiography
Details are provided in the Echocardiogram Instruction Manual. Echocardiography assessments 
will take place as described in Section 2.
During Screening echocardiography results will be sent to a central imaging laboratory and 
transmitted to the IXRS to confirm eligibility.
In the Treatment Period for Primary Analysis, all echocardiography data will be sent to a central 
imaging laboratory.
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In the Long-Term Treatment Period, echocardiograms will be site-read. All echocardiography data 
will be sent to the IXRS for LVEF stopping criteria (LVEF < 50% by local site read). 
Echocardiograms will also be sent to a core laboratory for future assessment during data analysis.
If necessary, contrast may be administered to ensure that good quality echocardiogram images are 
obtained.
Resting 
Resting 
 will be assessed prior to dosing during on-site visits as described in Section 2. 
Instantaneous peak LVOT gradient at rest and provoked peak LVOT gradient (Valsalva maneuver) 
will be assessed. The investigator should confirm during Screening that participant can adequately 
perform the Valsalva maneuver. Care should be taken to select the best window and angle when 
obtaining Doppler signal to assess the LVOT gradient and to avoid contamination by mitral 
regurgitation (MR) jet if present. Left ventricular ejection fraction (2 dimensional LVEF) and left 
ventricular fractional shortening will also be analyzed along with a variety of other 
echocardiographic measures (see Echo Instruction Manual).
At Screening and Week 30, resting 
 should be performed prior to post exercise 
echocardiography 
.
Post exercise/Stress Echocardiography
Participants will undergo a standard symptom-limited exercise test (after a recommended 3-hour 
fast) at Screening and Week 30 (see Section 2) prior to study drug dosing. The exercise test should 
be performed per the institution’s standard exercise protocol. If the site does not have a standard 
protocol, the study
 exercise protocol must be utilized. This test may be performed on a 
different day 
; however, if both procedures are performed on the same day, participants 
must exercise only once for both tests, with the participant undergoing first 
 and then 
post exercise stress echocardiography. Post exercise echocardiography needs to be acquired within 
72 hours of resting 
 
 post exercise gradient can be done on 2 different days, but the
same sequence of visits must be used for both screening and EOT. Instantaneous peak LVOT 
gradient will be assessed immediately post exercise by 
 Care should be taken to select the 
best window and angle when obtaining Doppler signal to assess the LVOT gradient, obtain valid 
LVOT gradient value, and avoid contamination by MR jet if present. Participants on standard 
cardiomyopathy therapy (eg, beta blockers or calcium channel blocker) should be on the same 
dose at Screening and Week 30 stress echocardiogram whenever possible, and this medication 
should be administered prior to exercise testing. Biomarker sampling should be performed prior 
to exercise.
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9.2
Adverse Events
The definitions of an AE, SAE, or 
 can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, or a surrogate), or 
the participant’s legally acceptable representative.
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following up 
on AEs that are serious, considered related to the study intervention or the study, or that caused 
the participant to discontinue before completing the study.
Refer to Appendix 3 for SAE reporting.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures, and within 56 days (to 140 days for CYP 2C19 PM) 
following discontinuation of dosing.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study intervention or protocol-specified procedure.

Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the appropriate section of the CRF module.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3.

The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants.
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 reasonably related to the study 
intervention or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs, SAEs, and AESIs, and the procedures 
for completing and reporting/transmitting SAE reports are provided in Appendix 3.
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9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AEs and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context of known 
AEs, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study intervention and for those present at the EOS intervention as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and nonserious AEs of special interest (as defined in 
Section 9.2 and Appendix 3) will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the participant is lost to follow-up (as defined in Section
8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
The Sponsor or designee must report AEs to regulatory authorities and ethics committees 
according to local applicable laws and regulations. A SUSAR (suspected, unexpected serious 
adverse reaction) is a subset of SAEs and must be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study intervention, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
4 months after the last dose of study product administration, the investigator must immediately 
notify the BMS Medical Monitor/designee of this event and complete and forward a Pregnancy 
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Surveillance Form to the BMS designee within 24 hours of awareness of the event and in 
accordance with SAE reporting procedures described in Appendix 3.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, must be reported on the Pregnancy 
Surveillance Form. The participant will be asked to provide information on the outcome of the 
pregnancy through 1 year after birth or details of premature termination.
Pregnancy in a female participant will lead to permanent treatment discontinuation.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE eCRF, as appropriate. Paper forms are only intended as a back-up option when the 
electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the participant to have study intervention 
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that, wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value).
9.2.7
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs meeting 
the defined criteria must be reported as SAEs (see Section 9.2 and refer to Appendix 3 for reporting 
details).
Potential DILI is defined as:

Aminotransaminase (AT:ALT or AST) elevation > 3× upper limit of normal (ULN)
AND

Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
AND

No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
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9.2.7.1
Criteria for Permanent Withholding of Mavacamten due to Potential 
Hepatotoxicity
Mavacamten should be discontinued permanently, and the participant should be followed 
according to the recommendations in Appendix 6 for possible drug-induced liver injury (DILI), if 
all of the criteria below are met:

TBL > 2× upper limit of normal (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 gallbladder or bile duct disease

Viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E), Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, or varicella

Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with significant 
right-sided HF

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 mavacamten 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.
9.2.7.2
Criteria for Conditional Withholding of Mavacamten Due to Potential 
Hepatotoxicity
For participants who do not meet the criteria for permanent withholding of study medication 
outlined above, mavacamten should be withheld if ANY of the following criteria are met, and the 
participant should be evaluated for DILI:

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
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
OR: 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%).

OR: TBL > 3× ULN at any time

OR: ALP > 8× ULN at any time
Mavacamten should be withheld pending an investigation into alternative causes of DILI. If 
mavacamten is withheld, the participant should be followed according to recommendations in 
Appendix 6 for possible DILI. Rechallenge may be considered if an alternative cause, such as 
acute hepatitis B infection, is discovered and the laboratory abnormalities resolve to normal or
baseline.
9.2.8
Other Safety Considerations
Any significant worsening of conditions noted during interim or final physical examinations, ECG, 
x-ray filming, or any other potential safety assessment required or not required by the protocol 
should also be recorded as a nonserious AE or SAE, as appropriate, and reported accordingly.
9.3
Overdose

For this study, any dose of mavacamten greater than once daily (QD) within a 24-hour time 
period (8 hours) will be considered an overdose. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Section 9.2 and refer to Appendix 3).
An overdose is defined as taking more capsules of study intervention 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. 
In the event of symptomatic overdose or in the presence of significant symptoms and/or clinical 
compromise, including depressed cardiac contractility or asystole, the investigator should contact 
the BMS Medical Monitor, and no further study intervention should be administered until further 
notice. 
The participant should be closely monitored clinically for AEs/SAEs, with supportive measures 
undertaken as clinically indicated. There is no specific antidote for mavacamten. In acute overdose 
or toxic ingestion, gastrointestinal decontamination should be considered. If necessary, corrective 
measures, as described in the 2013 American College of Cardiology Foundation/American Heart 
Association (ACCF/AHA) Guideline for the Management of Heart Failure and in the 2016 
European Society of Cardiology (ESC) Guidelines for the Diagnosis and Treatment of Acute and 
Chronic Heart Failure should be implemented. Based on its almost exclusive hepatic metabolism 
through the CYP2C19 and CYP3A4 enzymes, administration of inducers of CYP2C19 and 
CYP3A4 may be helpful. 
Nonclinical experiments have established that beta adrenergic agonists and dobutamine can 
counteract mavacamten’s modulation of myosin activity, providing the rationale for the use of 
these widely used clinical agents to support individuals who may be inadvertently overexposed. 
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The efficacy of other measures of elimination has not been established. Reintroduction of study 
intervention must be approved by the BMS Medical Monitor.
In the event of an overdose, the investigator should:

Closely monitor the participant for AEs/SAEs and laboratory test result abnormalities.

Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Please refer to the Investigator’s Brochure (IB) for more details.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
Safety will be assessed throughout the study. Safety assessments include medical history, physical 
examinations, ECGs, vital signs, observed and participant-reported AEs, pregnancy testing, and 
safety laboratory results. Any abnormal findings judged by the investigator to be clinically 
important will be recorded as an AE.
Safety data will be monitored on an ongoing basis by the study Sponsor.
9.4.1
Physical Examinations
See Schedule of Activities (Section 2).
At Screening, Week 30, ET, and/or Week 138 (EOT), a complete physical examination will be 
conducted including a neurological examination (gross motor and deep tendon reflexes), height 
(Screening only) and weight, and assessment of the following: general appearance; skin; head and 
neck; mouth; lymph nodes; thyroid; abdomen; musculoskeletal, CV, and respiratory systems. At 
all other visits, an abbreviated cardiopulmonary physical examination will be conducted, with 
other systems assessed as directed by interval history.
Height (cm) and body weight (kg) will be measured at Screening, and body mass index (kg/m2) 
will be calculated. Participants will be required to remove their shoes and wear clothing as 
specified by the clinical site.
Body weight will be captured in clinic at Screening, Weeks 30, 66, 102, ET, and/or Week 
138/EOT.
9.4.2
Vital Signs
See Schedule of Activities (Section 2).
Vital signs are to be assessed at each on-site study visit. At Screening, Week 30, ET, and/or Week 
138/EOT, complete vital signs including temperature, HR, respiratory rate, and blood pressure 
(BP) will be obtained. At all other visits, only HR and BP are required.
Vital signs will be obtained with the participant in the same position; BP will be taken after resting 
for at least 5 minutes via an automated recorder.
At all visits, vital signs will be taken prior to dosing. Alert values will be flagged. Refer to the 
Study Laboratory Manual for additional details.
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9.4.3
Electrocardiograms and Cardiac Monitoring Device
See Schedule of Activities (Section 2).
9.4.3.1
Electrocardiograms
12-lead ECG evaluations will be performed after 10 minutes of rest at Screening and at the on-site 
study visits every 2 to 4 weeks through Week 30, then every 12 weeks until the EOT, Week 8 
EOS, and Week 20 EOS (if CYP 2C19 PM). At Day 1, Weeks 8, 14, and 20, post-dose ECG will 
also be performed around Tmax (0.5 to 3 hours after study drug dose) in addition to the pre-dose 
ECG. On visits during the Treatment Period, ECGs will be taken prior to dosing. All ECG data 
will be sent to a central cardiac laboratory and transmitted to IXRS.
The investigator may perform 12-lead ECG safety assessments if he/she considers it is required 
for any other safety reason. These assessments should be recorded as an unscheduled assessment.
9.4.3.2
Cardiac Monitoring Device
At 6 time points during the study, participants will wear a small device to collect continuous HR 
and rhythm data for approximately 48 hours. The monitoring device uses surface electrodes, 
internal electronics to capture a continuous ECG waveform, a removable memory card to store 
data over 48 hours, and a battery to power the device. Following a period of data collection, the 
memory card will be uploaded to a core laboratory where the continuous ECG waveforms will be 
analyzed. The analysis will provide full disclosure capabilities for HR and heart rhythm over the 
period during which the device was properly applied and functioning. The device will be used to 
explore the pattern of HR and heart rhythm before and during treatment with study drug.
9.4.4
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Serum pregnancy testing will be performed at Screening for all females of childbearing potential. 
Participants must have a negative urine pregnancy test result at Day 1 prior to initiating study 
treatment.
In addition, urine pregnancy testing will be conducted in the clinic at every on-site visit throughout 
the study. During the Long-Term Treatment Period, pregnancy testing will be performed every 4 
weeks at the clinic, or at home when no on-site visit is scheduled, until the end of the study. During 
the Long-Term Treatment Period, the site will contact the participant every 4 weeks in between 
clinic visits to confirm at-home pregnancy test results. If a participant has a positive urine 
pregnancy test at home, they will be instructed to notify the site immediately. If a urine test cannot 
be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. 
Confirmatory serum testing will be performed if any urine test is positive.
Safety laboratory results will be assessed in an ongoing manner. A central safety laboratory will 
perform the analyses and will provide reference ranges for these tests. The following safety 
laboratory parameters will be measured by the central laboratory.
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Table 9.4.4-1:
Clinical Safety Laboratory Assessments
Hematology/Coagulation
Serum Chemistry
Urinalysisa
CBC, including differential count
Sodium
Specific gravity
Potassium
pH
Platelet count
Chloride
Protein
INR
Bicarbonate
Glucose
aPTT
Calcium
Leukocyte esterase
Magnesium
Blood
BUN
Creatinine
ALP
ALT
AST
TBL
CPK
Glucose
Protein
Albumin
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin 
time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; CPK, creatine 
phosphokinase; INR, international normalized ratio; TBL, total bilirubin.
a Urine microscopy will be performed if there is a significant abnormality in the dipstick.
At the investigator’s discretion, safety laboratory assessments may be repeated on Day -1 to 
confirm study eligibility before dosing of study medication.
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9.6
Immunogenicity Assessments
Not applicable.
9.7
Genetics
9.7.1
HCM Genotyping
For participants who provide consent for HCM genotyping, blood will be drawn preferably on Day 
1 or any visit thereafter for assessment of HCM genotype. See Table 9.8-1 for sample collection 
schedule.
9.7.2
Pharmacogenetic Assessments
Blood will be drawn preferably on Day 1 for commercially available testing of gene(s) encoding 
for drug metabolism enzymes and drug transporters (DMET). Genetic variations in DMET have 
the potential to significantly impact an individual’s metabolic capacity. For mavacamten, genetic 
variations for CYP 2C19 are known to have particular significance and will be assessed in this 
study. See Table 9.8-1 for sample collection schedule.
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9.8
Biomarkers
Table 9.8-1:
Biomarker Sampling Schedule for All Participants
Study Day of Sample 
Collection
(1 week = ± 7 days)a
Blood Sample for 
HCM 
Genotypingb
Pharmacogenetic 
Assessmentsc
Cardiac 
Biomarkers
Screening
X
Day 1
X
X
X
Week 6 Day 43
X
Week 12 Day 85
X
Week 18 Day 127
X
Week 30 Day 211
X
Week 42 Day 295
X
Week 54 Day 379
X
Week 66 Day 463
X
Week 78 Day 547
X
Week 90 Day 631
X
Week 102 Day 715
X
Week 114 Day 799
X
Week 126 Day 883
X
Unscheduled Visit
Week 138/EOT
X
ET
X
Follow-up Period
Week 8 Follow-up EOS
X
Week 20 Follow-up EOS
X
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Abbreviations: EOS, end of study; EOT, end of treatment; ET, early termination; HCM, hypertrophic cardiomyopathy.
a All blood draws must be drawn at rest and prior to any exercising.
b Blood for assessment of HCM genotype will be drawn preferably on Day 1 or any visit thereafter.
c The pharmacogenetic testing will include CYP 2C19 genotyping and will be obtained preferably on Day 1.
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9.8.1
Cardiac Biomarkers
Blood samples will be collected for cardiac biomarkers NT-proBNP and cardiac troponins 
(troponin I and troponin T) concentrations. All blood draws for these cardiac biomarkers must be 
drawn at rest and prior to any exercising. Concentrations of NT-proBNP and cardiac troponins will 
be analyzed for efficacy. Unscheduled or additional blood samples may be collected if appropriate 
in the opinion of the investigator (eg, for medical management of HF) and/or Sponsor. Whenever 
possible, discussion with the Medical Monitor is encouraged.
9.9
Additional Research
This protocol will include residual sample storage for additional research (AR).
For All sites:
Additional research is optional for all study participants, except where retention is prohibited by 
IRBs/ethics committees, prohibited by local laws or regulations, or academic/institutional 
requirements.
Additional research is intended to expand the R&D capability at Bristol-Myers Squibb, and will 
support as yet undefined research aims that will advance our understanding of disease and options 
for treatment. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc.
Sample Collection and Storage

Residual blood samples from 
 pharmacogenetic, or HCM genotyping, cardiac 
biomarker, 
 collections (see Table 9.9-1) will also be retained for 
additional research purposes
Samples kept for future research will be stored at the BMS Biorepository in 
 or 
an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
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Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 9.9-1:
Residual Sample Retention for Additional Research
Sample Type
Time points for which residual samples will be retained
Pharmacogenetic
All
HCM Genotyping
All
Cardiac Biomarkers
All
Abbreviations: HCM, hypertrophic cardiomyopathy; 
.
9.10
Other Assessments
The following non-safety laboratory parameters will be measured at Screening:

Hepatitis panel (HBV and HCV)

HIV test

FSH
9.11
Health Economics OR Medical Resource Utilization and Health 
Economics
Health economics/medical resource utilization and health economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Statistical Hypotheses
To support registration in Japan, the results of efficacy and safety in this study will be assessed 
comprehensively, and to further aid in the interpretation of these findings, the results from the 
EXPLORER-HCM study will be used.
10.2
Sample Size Determination 
Approximately 30 participants will be treated with mavacamten. Assuming the mean (SD) of the 
primary endpoint, the change from baseline to Week 30 in post exercise LVOT gradient is -40 (45) 
mm Hg, a sample size of 30 participants will have approximately 94% probability to observe a 
mean change of ≤ -27 mm Hg, with an observed 95% CI of (-43, -11) mm Hg.
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To determine the similarity of the results between this study and EXPLORER-HCM study, we 
consider the following 2 criteria:
1) The observed mean change in post exercise LVOT gradient in this study should be 
≤-27 mm Hg, which is at least 57% of the change shown in the mavacamten arm of 
EXPLORER-HCM study.
2) The CI of the mean change in this study should exclude the mean change from baseline to 
Week 30 in placebo arm of EXPLORER-HCM study, ie, upper limit of the CI < -10.
10.3
Analysis Sets
For the purposes of analysis, the following populations are defined:
Population
Description
ITT Population
All participants past screening or assigned study drug.
Safety Analysis Population
All participants who receive at least one dose of study drug.
Abbreviations: 
 ITT, intent-to-
treat; 
.
10.4
Statistical Analyses
The statistical analysis plan (SAP) will describe the selection of participants to be included in the 
analyses and procedures for accounting for missing, unused, and spurious data. Below is an outline 
of the intended methodology for key endpoints.
10.4.1
General Considerations
Descriptive summary statistics for continuous variables will include the number of participants, 
mean, SD or standard error, median, first quartile, third quartile, minimum, and maximum. 
Categorical variables will be summarized using counts and percentages.
Baseline is defined as the last non-missing assessment before the first dose of study drug.
All efficacy analyses will be performed on the ITT Population. Descriptive statistics will be 
presented for all efficacy endpoints.
Missing AE start date will be imputed for the purpose of determining whether the AE is treatment 
emergent. Missing concomitant medication start date will be imputed when determining whether 
the medication is prior or concomitant. Imputation rule will be specified in the SAP.
All other analyses will be based on observed data with no imputations. In case the primary and 
secondary endpoints have missing data which are more than expected (eg, 10%), data imputation 
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may be performed, and detailed methods will be discussed in the SAP. Otherwise, missing data 
will generally not be imputed unless specified in SAP.
10.4.1.1
Participant Disposition
The number and percentage of participants who complete and discontinue as well as reasons for 
early discontinuation will be presented.
10.4.1.2
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized descriptively.
10.4.1.3
Extent of Study Treatment Exposure and Compliance
The extent of study treatment exposure and compliance will be assessed and summarized by actual 
treatment received within the Safety Population.
The duration of study drug exposure is defined as last dose date – first dose date + 1 day, regardless 
of intermittent discontinuations. Adjusted duration will also be derived by taking protocol-defined 
interruptions into account.
Compliance will be calculated based on the total cumulative dose received divided by the total 
expected cumulative dose. Compliance of taking pills will be calculated based on the total number 
of pills taken divided by the adjusted duration. Treatment exposure and compliance will be 
summarized descriptively (number [n], mean, SD, median, minimum, and maximum). The 
compliance of participants with compliance < 80% and those with compliance > 100% will be 
summarized.
10.4.2
Primary Endpoint
The primary efficacy endpoint is change from baseline to Week 30 in post exercise LVOT peak 
gradient. The change from baseline to Week 30 in post exercise LVOT peak gradient will be 
summarized with descriptive statistics, including mean, SD, minimum, maximum, and 95% CIs.
To determine the similarity of the results between this study and EXPLOER-HCM study, we 
consider the following two criteria:
1) the observed mean change in post exercise LVOT gradient in this study should be 
≤-27 mm Hg, which is at least 57% of the change shown in the mavacamten arm of 
EXPLORER-HCM study
2) the CI of the mean change in this study should exclude the mean change from baseline to 
Week 30 in placebo arm of EXPLORER-HCM study, ie, upper limit of the CI < -10.
10.4.3
Secondary Endpoints
The secondary endpoints are:

Change from baseline to Week 30 in Kansas City Cardiomyopathy Questionnaire (KCCQ) 
Clinical Summary Score (CSS)

Proportion of participants with at least 1 class improvement in NYHA functional class from 
baseline to Week 30
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
Change from baseline to Week 30 in N-terminal pro b-type natriuretic peptide (NT-proBNP)

Change from baseline to Week 30 in cardiac troponins
The general analytical rules for the secondary efficacy endpoints are the following:

Change from baseline endpoints will be summarized in a similar way as primary endpoint, 
where descriptive statistics, including mean, SD, minimum, median, maximum, and 95% CI 
will be presented. There is no formal testing for secondary endpoints. 

Response rate for the categorical endpoints will be summarized with number and percentage 
with 95% CI, and no formal testing will be performed.
10.4.5
Other Safety Analysis
10.4.5.1
Adverse Events
All safety analyses will be performed on the Safety Analysis Population using descriptive statistics 
without formal statistical testing. The safety analysis will focus on the Treatment-emergent 
Adverse Event Period. This period is defined as the time from the first administration of 
mavacamten to the last administration of mavacamten + 56 days (140 days for CYP 2C19 PM).
AEs will be mapped to system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). AEs will be monitored during the study and the 
data analyzed with respect to overall incidence as well as severity and potential relationship of 
AEs to study medication. AEs with onset during the treatment-emergent period, or with an onset 
before the first dose of study medication that increases in severity or becomes serious during the 
treatment-emergent period, will be considered treatment emergent.
Adverse event incidence tables will present the number and percentage of participants 
experiencing at least one TEAE by SOC and PT in alphabetical order. Multiple occurrences of the 
same event in the same participant will be counted only once in the tables within a treatment phase. 
The denominator for computation of percentages is the Safety Population.
Adverse event incidence tables will be provided for all types of TEAEs: all TEAEs, all 
treatment-emergent SAEs, and all TEAEs leading to permanent treatment discontinuation.
All deaths will be listed for the event time relative to the first study dose and the relevant AE 
descriptions, if applicable.
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10.4.5.3
Overdose
The following summaries for reports of overdose will be generated:

Number of participants who experienced overdose

Analysis of the cause and occurrence of the overdose

TEAE experienced during the overdose by primary SOC and PT showing the number and 
percent of participants sorted by SOC and PT
10.4.6
Other Analyses
10.4.6.1
12-lead Electrocardiogram
The RR, PR, QRS, and QT intervals will be measured and read by a central laboratory. HR will 
be calculated as 60/ (RR × 1000) (with RR expressed in msec) and rounded to the nearest integer.
Correction for Heart Rate
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. Each 
individual ECG QT value will be corrected for HR. The measured QT data will be corrected for 
HR using QTcF as per the following formulae/method (with QT, RR, and QTc expressed in msec):
Fridericia’s Correction:
ECG Numeric Variables
HR, PR, QRS, and QTcF will be summarized using descriptive statistics. QRS duration, manually 
over-read, will be used to determine which threshold criterion rules to apply for temporary 
discontinuation based on QTcF (eg, QRS duration < 120 msec or QRS duration ≥120 msec) (see 
Section 8.1.3). The change from baseline of these ECG parameters at each time point will be listed 
for each participant. For each time point of measurement, the changes from baseline will be 
summarized using descriptive statistics.
Categorical Analysis
The incidence count and percentage of participants with any QTcF values of > 450 msec, > 480 
msec, > 500 msec, > 520 msec, and > 550 msec will be tabulated for all participants. Participants 
with QTcF values > 500 msec will be listed with corresponding baseline values, ∆QTcF, and 
baseline and treatment HR. The incidence count and percentage of participants with QTcF increase 
from baseline of > 30 msec and > 60 msec will be tabulated.
Morphology Findings
ECG morphologies for each participant will be listed.
Concentration-QTc Analyses
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A concentration-QTc regression analysis, based on data collected from the ECG recordings after 
drug administration and concentration values for each participant at each matching time point, will 
be performed. Linear or nonlinear models will be implemented to estimate the slope and 95% CI 
of the relationship. Predictions at selected concentration values will be computed within the model.
10.4.6.2
Laboratory Data
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
laboratory variables (laboratory values and changes from baseline) will be calculated for each visit 
(baseline and post-baseline time points).
Listings of participants with laboratory values that are out of the reference range will be produced.
Potential Drug-induced Liver Injury
The liver function tests, namely ALT, AST, ALP, and TBL, are used to assess possible 
drug-induced liver toxicity.
A graph of distribution of peak values of ALT versus peak values of TBL will be presented. Note 
that the ALT and TBL values are presented on a logarithmic scale. The graph will be divided into 
4 quadrants with a vertical line corresponding to 3× ULN for ALT and a horizontal line 
corresponding to 2× ULN for TBL.
The number and percentage of participants with elevated liver function tests (based on safety 
laboratory data) during the TEAE period will be summarized by categories of elevation 
(> 3× ULN, > 5× ULN, > 10× ULN, and > 20× ULN for ALT and AST; > 1.5× ULN for ALP; 
and > 1.5× ULN and > 2× ULN for TBL). Potential Hy’s law cases will be investigated by 
summarizing the number of participants with elevated ALT or AST (> 3× ULN) and with elevated 
TBL (> 2× ULN) where transaminase elevation coincides with or precedes bilirubin elevation.
10.4.6.3
Vital Signs Data
The summary statistics (including number, mean, median, SD, minimum, and maximum) of all 
vital sign variables (values and changes from baseline) will be calculated for each visit (baseline 
and post-baseline time points).
10.5
Interim Analyses
No formal interim analysis will be performed. When all participants complete the Week 30 visit 
or terminate the treatment prematurely, the primary analysis will be performed to assess the 
efficacy and safety of mavacamten treatment for the 30-week period.
When all participants complete the Week 54 visit or permanently discontinue treatment, an 
additional analysis will be conducted.
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Final analysis will be performed when all participants complete the EOS visit.
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11
REFERENCES
1
Frey N, Luedde M, Katus HA. Mechanisms of disease: hypertrophic cardiomyopathy. Nat Rev
Cardiol 2011;9:91-100.
2
Hershberger RE, Cowan J, Morales A, et al. Progress with genetic cardiomyopathies:
screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right
ventricular dysplasia/cardiomyopathy. Circ Heart Fail 2009;2:253-61.
3
Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and
treatment of hypertrophic cardiomyopathy: a report of the American college of cardiology
foundation/American heart association task force on practice guidelines. Developed in
collaboration with the American association for thoracic surgery, American society of
echocardiography, American society of nuclear cardiology, Heart failure society of America, 
Heart rhythm society, society for cardiovascular angiography and interventions, and Society 
of Thoracic Surgeons. J Am Coll Cardiol 2011;58:212-60.
4
Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: 
clinical perspectives. J Am Coll Cardiol 2012b;60:705-15.
5
Alfares AA, Kelly MA, McDermott G, et al. Results of clinical genetic testing of 2,912 
probands with hypertrophic cardiomyopathy: expanded panels offer limited additional 
sensitivity. Genet Med 2015;17:880-8.
6
Chuan P, Sivaramakrishnan S, Ashely EA, et al. Cell-intrinsic functional effects of the α-
cardiac myosin Arg-403-Gln mutation in familial hypertrophic cardiomyopathy. Biophys J
2012;102:2782-90.
7
Sommese RF, Sung J, Nag S, et al. Molecular consequences of the R453C hypertrophic
cardiomyopathy mutation on human beta-cardiac myosin motor function. Proc Natl Acad Sci
USA 2013;110:12607-12.
8
Sung J, Choe E, Elting M, et al. Single molecule studies of recombinant human α- and β-
cardiac myosin to elucidate molecular mechanism of familial hypertrophic and dilated
cardiomyopathies. 
Biophysical 
J 
2012;102(3 
suppl 
1):613a-614a. 
Available 
at: 
http://www.cell.com/biophysj/fulltext/S0006-3495(11)04693-5.
9
Maron MS, Rowin EJ, Olivotto I, et al. Contemporary natural history and management of
nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2016;67:1399-409.
10 Husser DL, Ueberham J, Jacob D, et al. Prevalence of clinically apparent hypertrophic 
cardiomyopathy in Germany-an analysis of over 5 million patients. PLoS One 2018;13: 
e0196612.
11 Pujades-Rodriguez M, Guttmann OP, Gonzalez-Izquierdo A, et al. Identifying unmet clinical 
need in hypertrophic cardiomyopathy using national electronic health records. PLoS One 
2018;13:e0191214.
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12 Moon I, Lee SY, Kim HK, et al. Trends of the prevalence and incidence of hypertrophic
cardiomyopathy in Korea: a nationwide population-based cohort study. PLoS One 
2020;15:e0227012.
13 Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a
disease of left ventricular outflow tract obstruction. Circulation 2006;114:2232-9.
14 Sherrid MV, Gunsburg DZ, Moldenhauer S, et al. Systolic anterior motion begins at low left
ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy. J Am Coll
Cardiol 2000;36:1344-54.
15 Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on
clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295-303.
16 Elliott PM, Gimeno JR, Thaman R, et al. Historical trends in reported survival rates in patients
with hypertrophic cardiomyopathy. Heart 2006;92:785-91.
17 Autore CP, Bernabo P, Barilla CS, et al. The prognostic importance of left ventricular outflow
obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J
Am Coll Cardiol 2005;45:1076-80.
18 Ho CY, Sweitzer NK, McDonough B, et al. Assessment of diastolic function with Doppler
tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation
2002;105:2992-7.
19 Ho CY, Day SM, Ashley EA, et al. Genotype and lifetime burden of disease in hypertrophic
cardiomyopathy: insights from the sarcomeric human cardiomyopathy registry (SHaRe).
Circulation 2018;138:1387-98.
20 Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and
management of hypertrophic cardiomyopathy: the task force for the diagnosis and management 
of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 
2014;35:2733-79.
21 Kim LK, Swaminathan RV, Looser P, et al. Hospital volume outcomes after septal myectomy 
and alcohol septal ablation for treatment of obstructive hypertrophic cardiomyopathy: US 
nationwide inpatient database, 2003-2011. JAMA Cardiol 2016;1:324-32.
22 Ho CY, Olivotto I, Jacoby D, et al. Study design and rationale of Explorer-HCM; evaluation 
of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. 
Circulation 2020;13:e006853. doi.org/10.1161/CIRCHEARTFAILURE.120.00685.
23 Olivotto O, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic 
obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, 
placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759-69.
24 Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten treatment for obstructive hypertrophic 
cardiomyopathy: a clinical trial. Ann Intern Med 2019;170:741-8.
25 Bennett JA, Riegel B, Bittner V, et al. Validity and reliability of the NYHA classes for
measuring research outcomes in patients with cardiac disease. Heart Lung 2002;31:262-70.
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26 Firoozi S, Elliott PM, Sharma S, et al. Septal myotomy-myectomy and transcoronary septal 
alcohol ablation in hypertrophic obstructive cardiomyopathy: a comparison of clinical, 
haemodynamic and exercise outcomes. Eur Heart J 2002;23:1617-24.
27 Sedehi D, Finocchiaro G, Tibayan Y, et al. Long-term outcomes of septal reduction for 
obstructive hypertrophic cardiomyopathy. J Cardiol 2015;66:57-62.
32 Kitaoka H, Tsutsui H, Kubo T, et al. JCS/JHFS 2018 guideline on the diagnosis and treatment 
of cardiomyopathies. Circ J 2021;85:1590-1689.
33 Green CP, Porter CB, Bresnahan DR, et al. Development and evaluation of the Kansas City
Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll
Cardiol 2000;35:1245-55.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AME
absorption, metabolism, and excretion
aPTT
activated partial thromboplastin time
ASA
alcohol septal ablation
AST
aspartate aminotransferase
AT
aminotransaminase
AUC
area under the concentration-time curve
AxMP
auxiliary medicinal product
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CLT
total body clearance
cm
centimeter
Cmax
maximum observed concentration
COVID-19
coronavirus disease 2019
CRF
Case Report Form, paper or electronic
CRO
contract research organization
CSR
Clinical Study Report
CSS
Clinical Summary Score
CTAg
Clinical Trial Agreement
CV
cardiovascular
CYP
cytochrome P450
DDI
drug-drug interaction
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Term
Definition
DILI
drug-induced liver injury
dL
deciliter
DMET
drug metabolism enzymes and drug transporters
DSM 5
Diagnostic and Statistical Manual of Mental Disorders (5th Edition)
EA
extent of absorption
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EHR
electronic health record
EMR
electronic medical record
EOS
end of study
EOT
end of treatment
E-R
exposure-response
ET
early termination
FSH
follicle-stimulating hormone
FU
follow-up
g
gram
GCP
Good Clinical Practice
h
hour
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCM
hypertrophic cardiomyopathy
HCV
hepatitis C virus
HF
heart failure
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HFpEF
heart failure with preserved ejection fraction
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
implantable cardioverter-defibrillator
ICF
informed consent form
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Term
Definition
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
INR
international normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
IU
international unit
IUS
intrauterine hormone-releasing system
IV
intravenous
IXRS
interactive response system
KCCQ
Kansas City Cardiomyopathy Questionnaire
kg
kilogram
L
liter
LAM
lactation amenorrhea method
LV
left ventricular
LVEF
left ventricular ejection fraction
LVOT
left ventricular outflow tract
M&S
modeling and simulation
MAO
monoamine oxidase
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
mitral regurgitation
g
microgram
N/A
not applicable
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Term
Definition
NASH
nonalcoholic steatohepatitis
nHCM
non-obstructive hypertrophic cardiomyopathy
NM
normal metabolizer
Non-IMP
Non-investigational Medicinal Product
NP
nurse practitioner
NT-proBNP
N-terminal pro b-type natriuretic peptide
NYHA
New York Heart Association
PA
physician assistant
PK
pharmacokinetic(s)
PM
poor metabolizer
PPK
population pharmacokinetic
PT
preferred term
pVO2
peak oxygen consumption
QD
once daily
QTc
corrected QT interval
QTcF
QT interval with Fridericia correction
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCD
sudden cardiac death
SD
standard deviation
SOC
system organ class
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected, unexpected serious adverse reaction
T
time
TBL
total bilirubin
TC
telephone call
TEAE
treatment-emergent adverse event
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Term
Definition
T1/2
half-life
Tmax
time of maximum observed concentration
TR_Cmax
Cmax treatment ratio
TTE
transthoracic echocardiography, transthoracic echocardiogram, 
transthoracic echocardiography
ULN
upper limit of normal
VO2
oxygen consumption
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The terms “participant” and “subject” refer to a person who has consented to participate in the 
clinical research study. Typically, the term “participant” is used in the protocol and the term
“subject” is used in the Case Report Form (CRF).
REGULATORY AND ETHICAL CONSIDERATIONS
This study will be conducted in accordance with:

Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP)
Guidelines

Applicable laws, regulations, and requirements
The study will be conducted in compliance with the protocol. The protocol,
any 
revisions/amendments,
and the participant informed consent form (ICF) will receive 
approval/favorable 
opinion 
by 
Institutional 
Review 
Board/Independent 
Ethics 
Committee (IRB/IEC), and regulatory authorities according to applicable regulations prior to 
initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation) that is likely to affect, 
to a significant degree, one or more of the following: (1) the rights, physical safety or mental 
integrity of one or more participants; (2) the scientific value of the clinical trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP regulation(s) or 
trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, Investigator’s Brochure, product labeling information, ICF, 
participant recruitment materials (eg, advertisements), and any other written information to be 
provided to participants.
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, administrative letters) annually, or more 
frequently, in accordance with regulatory requirements or institution procedures.
The investigator is responsible for providing oversight of the conduct of the study at the site and 
adherence to requirements of the following where applicable:
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
ICH guidelines, 

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)

European Union Directive 2001/20/EC; or

European Regulation 536/2014 for clinical studies (if applicable), 

European Medical Device Regulation 2017/745 for clinical device research (if applicable),

the IRB/IEC

and all other applicable local regulations.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and, if 
applicable, also by the local Health Authority), except where necessary to eliminate an immediate 
hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s), the deviation or change will be submitted as soon 
as possible to:

IRB/IEC

Regulatory authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and, if applicable, also by the local Health Authority, must be sent to Bristol-Myers 
Squibb (BMS).
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the ICF must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from participants 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new participants prior to enrollment.
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information, in accordance with regulations, to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health 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.
INFORMED CONSENT PROCESS
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
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The Sponsor or designee will provide the investigator with an appropriate sample ICF, which will 
include all elements required by the ICH GCP, and applicable regulatory requirements. The sample 
ICF will adhere to the ethical principles that have their origin in the Declaration of Helsinki.
The investigator or his/her representative must:

Obtain IRB/IEC written approval/favorable opinion of the written ICF and any other 
information to be provided to the participant prior to the beginning of the study and after any 
revisions are completed for new information.

Provide a copy of the ICF and written information about the study in the language in which 
the participant is proficient prior to clinical study participation. The language must be 
nontechnical and easily understood. 

Explain the nature of the study to the participant or his/her legally acceptable representative
and answer all questions regarding the study.

Inform participant that his/her participation is voluntary. Participant or his/her legally 
acceptable representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.

Allow time necessary for participant or his/her legally acceptable representative to inquire 
about the details of the study.
Obtain an ICF signed and personally dated by participant or his/her legally acceptable 
representative and by the person who conducted the informed consent discussion. 

Include a statement in participant’s medical record that written informed consent was obtained 
before 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.

Re-consent participant to the most current version of the ICF(s) during his/her participation in 
the study, as applicable.
Revise the ICF whenever important new information becomes available that is relevant to the 
participant’s consent. The investigator, or a person designated by the investigator, should fully 
inform the participant or his/her legally acceptable representative of all pertinent aspects of the 
study and of any new information relevant to the participant’s willingness to continue participation 
in the study. This communication should be documented. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participant’s signed 
ICF, and, in the US, the participant’s signed HIPAA Authorization.
The ICF must also include a statement that BMS and local and foreign regulatory authorities have 
direct access to participant records. 
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In situations where consent cannot be given by participants, their legally acceptable representatives 
(as per country regulation) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Participant unable to give their written informed consent (eg, stroke or participants with severe 
dementia) may only be enrolled in the study with the consent of a legally acceptable representative. 
The participant must also be informed about the nature of the study to the extent compatible with 
his or her understanding, and should this participant become capable, he or she should personally 
sign and date the ICF as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time, should be 
considered by the investigator.
The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
BMS COMMITMENT TO DIVERSITY IN CLINICAL TRIALS
The mission of BMS is to transform patients’ lives through science by discovering, developing, 
and delivering innovative medicines that help them prevail over serious diseases.
BMS is committed to doing its part to ensure that patients have a fair and just opportunity to 
achieve optimal health outcomes.
BMS is working to improve the recruitment of a diverse participant population with the goal that 
the clinical trial becomes more reflective of the real-world population and the people impacted by 
the diseases studied.
DATA PROTECTION, DATA PRIVACY, AND DATA SECURITY
BMS collects and processes personal data of study participants, patients, health care providers, 
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. BMS ensures the privacy, protection, 
and confidentiality of such personal data to comply with applicable laws. To achieve these goals, 
BMS has internal policies that indicate measures and controls for processing personal data. BMS 
adheres to these standards to ensure that collection and processing of personal data are limited and 
proportionate to the purpose for which BMS collects such personal data. This purpose is clearly 
and unambiguously notified to the individual at the time of collection of personal data. In the true 
spirit of science, BMS is dedicated to sharing clinical trial information and data with participants, 
medical/research communities, the media, policy makers, and the general public. This is done in a 
manner that safeguards participant privacy and informed consent while respecting the integrity of 
national regulatory systems. Clinical trial data, health-related research, and pharmacovigilance 
activities on key-coded health data transferred by BMS across national borders is done in 
compliance with the relevant data protection laws in the country and GCP requirements.
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BMS protects Personal Information with adequate and appropriate security controls as indicated 
under the data protection laws. To align with the recommended security standards, BMS has 
adopted internal security standards and policies to protect personal data at every stage of 
its processing.
To supplement these standards, BMS enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
BMS takes unauthorized access and disclosure of Personal Information very seriously. BMS has 
adopted the security standards that include National Institute of Standards and Technology 
Cybersecurity Framework for studies in the US. BMS aligns with these standards to continuously 
assess and improve its ability to protect, detect, and respond to cyber attacks and other 
unauthorized attempts to access personal data. These standards also aid in mitigating possible 
adverse effects. Furthermore, BMS Information Technology has defined 6 principles to protect our 
digital resources and information: 
1)
Responsibilities of IT Personnel
2) Securing the BMS Digital Infrastructure
3) Identity and Access Management
4) External Partner Connections
5) Cyber Threat Detection and Response
6) Internal Cyber Incident Investigation
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 electronic CRF (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.

Definitions of what constitutes source data can be found in systems may include, but are not 
limited to, electronic medical/health records (EMRs/EHRs), adverse event tracking/reporting, 
protocol-required assessments, and/or drug accountability records. Also, see “Guidelines for 
good clinical practices, ICH-GCP, 2015”.
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are handwritten on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
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Such systems may include, but are not limited to, electronic medical records/electronic health 
records, adverse event (AE) tracking/reporting, protocol-required assessments, and/or drug 
accountability records.
When paper records from such systems are used in place of an electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
STUDY INTERVENTION RECORDS
Records for study intervention (whether supplied by BMS, its vendors, or the site) must 
substantiate study intervention integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/designee or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each 
participant, including unique participant 
identifiers

amount transferred to another area/site for 
dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for 
bioavailability/bioequivalence/biocomparability, 
if applicable 

dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form
Sourced by site and not supplied by BMS 
or its vendors (examples include IP 
sourced 
from 
the 
sites 
stock or 
commercial supply or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study treatment 
integrity in accordance with requirements applicable 
under 
law 
and 
the 
standard 
operating 
procedures/standards of the sourcing pharmacy
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BMS or its designee will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents, or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture (EDC) tool, eCRFs will be prepared 
for all data collection fields except for fields specific to SAEs and pregnancy, which will be 
reported on the electronic SAE form and Pregnancy Surveillance Form, respectively. If the 
electronic SAE form is not available, a paper SAE form can be used.
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF and SAE/pregnancy CRFs must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. The investigator must retain a copy of the CRFs, including records of the changes 
and corrections.
Each individual electronically signing eCRFs must meet Sponsor or designee training 
requirements and must only access the BMS EDC tool using the unique user account provided by 
the Sponsor or designee. User accounts are not to be shared or reassigned to other individuals.
MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site, they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
Certain CRF pages and/or electronic files may serve as the source documents.
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In addition, the study may be evaluated by the Sponsor or designee internal auditors and 
government inspectors who must be allowed access to CRFs, source documents, other study files, 
and study facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities 
and promptly forward copies of inspection reports to the Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or its designee, whichever is longer. 
The investigator (or head of the study site in Japan) must contact BMS prior to destroying any 
records associated with the study.
BMS or its designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed-upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or its designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS or a vendor or sourced by the 
investigator), such as partially used study treatment containers, vials, and syringes, may be 
destroyed on site. 
If
Then
Study treatments supplied by BMS (including 
its vendors)
Any unused study interventions supplied by 
BMS can only be destroyed after being 
inspected and reconciled by the responsible 
Study Monitor,
unless study treatments 
containers must be immediately destroyed as 
required for safety, or to meet local regulations 
(eg, cytotoxics or biologics).
Partially used study interventions and/or 
empty containers may be destroyed after 
proper reconciliation and documentation. But 
unused IMP must be reconciled by site 
monitor/Clinical Research Associate prior to 
destruction.
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
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If
Then
Study treatments sourced by site, not supplied 
by BMS (or its vendors; eg, study treatments 
sourced from the site’s stock or commercial 
supply or a specialty pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal of study interventions, 
provided that procedures for proper disposal have been established according to applicable federal, 
state, local, and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s standard operating procedures and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal (eg, incinerator, licensed sanitary landfill, or licensed waste-disposal 
vendor) must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Study 
Monitor to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met, the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non-study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
STUDY AND SITE START AND CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
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Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor 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.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, health care providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR).
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the Sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the Clinical Trial Agreement (CTAg) governing [study site or investigator] 
participation in the study. These requirements include, but are not limited to, submitting proposed 
publications to the Sponsor or designee at the earliest practicable time prior to submission or 
presentation and otherwise within the time period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
Principal Investigator, sub-investigator, or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
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4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a clinical investigation participant administered study 
treatment that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, electrocardiograms, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.

Exacerbation of a chronic or intermittent pre-existing condition, including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration, even though 
it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/serious adverse event (SAE) unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae and should specify “intentional overdose” as the verbatim 
term.
Events NOT Meeting the AE Definition

Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE, even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death.
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe).
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below).
NOTE: 
The following hospitalizations are not considered SAEs in Bristol-Myers Squibb (BMS) clinical 
studies: 

A visit to the emergency room or other hospital department < 24 hours that does not result 
in admission (unless considered an important medical or life-threatening event).

Elective surgery, planned prior to signing consent.

Admissions as per protocol for a planned medical/surgical procedure.

Routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy).

Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases.

Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).

Admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols).
Results in persistent or significant disability/incapacity.
Is a congenital anomaly/birth defect.
Is an important medical event (defined as a medical event[s] that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm and blood dyscrasias or convulsions that do not result in 
hospitalization. Potential drug-induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
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Pregnancy and DILI must follow the same transmission timing and processes to BMS as used for 
SAEs. (See Section 9.2.5 for reporting pregnancies.)
Adverse Events of Special Interest
AESIs are required to be reported by the investigator to the Sponsor within 24 hours, irrespective 
of regulatory seriousness criteria, and recorded as AEs. The required information in the electronic 
data capture (EDC) system will be completed 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.
EVALUATING AES AND SAES
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration,
will be considered and investigated.

The investigator will also consult the Investigator’s Brochure and/or product information for 
marketed products in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.

Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
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
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity of 
an event, and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Follow-up of AEs, SAEs, and AESIs
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports must include the same investigator term[s] initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form.

The required method for SAE data reporting is through the electronic case report 
form (eCRF).

The paper SAE Report Form is intended only as a back-up option when the electronic 
data capture system is unavailable/not functioning for transmission of the eCRF to BMS 
(or designee).
In this case, the paper form is transmitted via email or confirmed facsimile 
transmission.
When paper forms are used, the original paper forms are to remain on site.

Pregnancies must be recorded on paper Pregnancy Surveillance Forms and transmitted via 
email or confirmed facsimile transmission.
SAE Email Address: 
SAE Facsimile Number: Will be provided by local site monitor.
SAE Telephone Contact (required for SAE and pregnancy reporting): Will be provided by local 
site monitor.
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to Woman of Childbearing 
Potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle-stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. Suggested 
guidelines for the duration of the washout periods for HRT types are presented below. Investigators 
should use their judgement in checking serum FSH levels. 

1-week minimum for vaginal hormonal products (rings, creams, gels)

4-week minimum for transdermal products

8-week minimum for oral products
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have decreased to a concentration that is no longer 
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
context of safety margins from the no-observed-adverse-effect level or the time required for 5 half-
lives of the IMP to pass.
METHODS OF CONTRACEPTION
Note: Intravaginal and transdermal combined hormonal contraception are not approved by Japan 
Health Authority. Also, progestogen-only hormonal contraception is not approved by Japan Health 
Authority.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation. (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol.)b

Oral (birth control pills)

Intravaginal (rings)

Transdermal

Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy.

Progestogen-only hormonal contraception associated with inhibition of ovulation. (This
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol.)b

Oral

Injectable

Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy.
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation. (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol.)b

Intrauterine device.
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Intrauterine hormone-releasing system (IUS). (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol.)b,c

Bilateral tubal occlusion.

Vasectomized partner 
Having a vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used from 
Screening through 4 months after the last dose of mavacamten.
A vasectomy is a highly effective contraception method provided that the participant is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.

Sexual abstinence.
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

Continuous abstinence must begin at least 30 days prior to initiation of study therapy.

It is not necessary to use any other method of contraception when complete abstinence is 
elected.

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2.

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participant chooses to forego complete abstinence.

Periodic abstinence (including, but not limited to, calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from failure rates when contraceptive methods are used consistently and 
correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative 
methods of contraception should be utilized. For information specific to this study regarding permissibility of 
hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 7.7.4 PROHIBITED AND/OR 
RESTRICTED TREATMENTS of the protocol.
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies when hormone 
exposures from intrauterine devices do not alter contraception effectiveness. For information specific to this 
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study regarding permissibility of hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 
7.7.4 PROHIBITED AND/OR RESTRICTED TREATMENTS of the protocol.
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of > 1% per year when used consistently and correctly.

Male or female condom with or without spermicide. Male and female condoms cannot be used 
simultaneously.

Diaphragm with spermicide.

Cervical cap with spermicide.

Vaginal sponge with spermicide.

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action. (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited.)
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, postovulation methods).

Withdrawal (coitus interruptus).

Spermicide only.

LAM.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of pregnancy information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and Appendix 3.
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APPENDIX 5
PROHIBITED MEDICATIONS
Cardiotoxic Agents
Prior or concomitant treatment with cardiotoxic agents such as doxorubicin or similar agents is 
prohibited.
Disopyramide, cibenzoline, or ranolazine
Use of disopyramide, cibenzoline, or ranolazine is prohibited from 14 days before Screening 
assessments to the end of study (EOS).
Moderate and Potent CYP 2C19 Inhibitors and Potent CYP 3A4 Inhibitors
Potent and moderate CYP 2C19 inhibitors and potent CYP 3A4 inhibitors are prohibited from 
14 days before Screening assessments through the EOS. Examples are listed below. For any 
medication in question, ask the Sponsor/CRO medical monitor.
CYP 2C19 Inhibitors

Efavirenz (antiviral)

Etravirine (antiviral)

Fluconazole (antifungal)

Fluvoxamine (selective serotonin reuptake inhibitor [SSRI] / antidepressant)

Fluoxetine (SSRI / antidepressant)

Moclobemide (monoamine oxidase [MAO] inhibitor / antidepressant)

Omeprazole (proton pump inhibitor)

Esomeprazole (proton pump inhibitor)

Ticlopidine (platelet inhibitor)

Voriconazole (antifungal)
CYP 3A4 Inhibitors

Boceprevir (antiviral)

Ceritinib (kinase inhibitor)

Clarithromycin (antibiotic)

Cobicistat (GS-9350)

Conivaptan (diuretic)

Idelalisib (kinase inhibitor)

Indinavir (protease inhibitor)

Itraconazole (antifungal)

Josamycin (antibiotic)

Ketoconazole (antifungal)

LCL161 (cancer treatment)
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
Mibefradil (calcium channel blocker)

Mifepristone (antiprogestin)

Nefazodone (antidepressant)

Nelfinavir (protease inhibitor)

Posaconazole (antifungal)

Ribociclib (kinase inhibitor)

Ritonavir (protease inhibitor)

Saquinavir (protease inhibitor)

Telaprevir (antiviral)

Telithromycin (antibiotic)

Tipranavir (protease inhibitor)

Troleandomycin (antibiotic)

Tucatinib (kinase inhibitor)

Viekira Pak (antiviral)
St. John’s Wort
Use of St. John’s Wort is prohibited from 14 days before Screening assessments to EOS.
Biotin Supplements
Biotin supplements are prohibited from 14 days prior to screening assessments through the EOS
visit. Multivitamins that contain < 1000 mg QD of biotin are allowed during the study but must be 
stopped 24 hours prior to each study visit.
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APPENDIX 6
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING AND 
ADDITIONAL ASSESSMENTS REPORTING
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases of 
concurrent aspartate/alanine (AST/ALT) and total bilirubin (TBL) elevation according to the 
criteria specified in Section 9.2.7 (> 3 times upper limit of normal [ULN] for AST/ALT and 
> 2 times ULN for TBL in participants with no underlying liver disease and eligibility criteria 
requiring normal liver function at baseline) require the following:

The event is to be reported to Sponsor as an SAE within 24 hours of discovery or notification 
of the event (ie, before additional etiologic investigations have been concluded)

The appropriate CRF (eg, AE CRF) that captures information necessary to facilitate the 
evaluation of treatment-emergent liver abnormalities are to be completed and sent to Sponsor.
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Appendix 3.
Additional Clinical Assessments and Observation
All participants in whom investigational product(s) or protocol-required therapies is/are withheld 
(either permanently or conditionally) due to potential DILI or who experience AST/ALT 
elevations > 3 × ULN are to undergo a period of “close observation” until abnormalities return to 
normal or to the participant’s baseline levels. Assessments that are to be performed during this 
period include the following:

Repeat liver chemistries within 24 to 48 hours (ALT, AST, alkaline phosphatase [ALP], total 
bilirubin [TBL]); in cases of TBL > 2 × ULN or AST/ALT much greater than 3 × ULN, 
retesting is to be performed within 24 hours

For participants that are far away from the trial site, it may be difficult for the subjects to 
return to the trial site promptly. In this case, the participants should be retested locally, but 
normal laboratory ranges should be recorded, results should be made available to trial 
investigators immediately, and the data should be included in the case reports
Participants are to be monitored at least twice weekly; testing frequency may decrease to once per 
week or less if laboratory abnormalities stabilize or the investigational product(s) or 
protocol-required therapies have been discontinued AND the participant is asymptomatic.

Obtain prothrombin time/international normalized ratio, fractionated bilirubin, and any other 
potentially relevant laboratory evaluations of liver function or disease

Obtain complete blood count with differential to assess for eosinophilia

Obtain appropriate blood sampling for 
 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 as specified in Section 9.2.7.

Follow the participant until all laboratory abnormalities return to baseline or normal. The 
“close observation period” is to continue for a minimum of 4 weeks after investigational 
product(s) or protocol-required therapies discontinuation
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs.
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APPENDIX 7
MANAGEMENT OF PARTICIPANTS WHO ARE UNABLE TO 
ATTEND ONSITE STUDY VISITS (DUE TO COVID-19 OR 
OTHER PANDEMICS OR NATURAL DISASTERS)
The following provisions may be made to accommodate participants who are unable to attend on-
site study visits for scheduled assessments and dispensation of mavacamten:

Study visits may be performed at a remote location by a visiting health care service provider. 
Service providers must be approved by the Sponsor before performing study assessments.

Participants who are unable to be seen at the clinic or at home by a visiting health care service 
provider may be required to temporarily discontinue mavacamten.

Participants may be tested for COVID-19 at the discretion of the investigator and/or Sponsor.
Remote Health Assessment

Protocol-specified assessments listed below may be conducted in the participant's home by a 
visiting health care professional or via telemedicine.

NYHA may be assessed by the Principal Investigator via telemedicine

Physical examination may be done by a home health care professional who is a licensed 
NP/PA

 may be acquired at home by a qualified sonographer who has been certified by the 
echocardiography core lab.

ECG may be acquired by home health care professional

Holter Monitor may be applied and removed at participant's home by a home health care 
professional.

Phlebotomy may be done by a home health care professional
Under certain circumstances the site may choose to contract with a community-based facility (with 
Sponsor/CRO medical monitor approval) for the above assessments (eg, vital signs, ECG, 
echocardiography upon certification by core echocardiography lab, application and removal of 
Holter).
Drug Dispensation

Mavacamten may be shipped by Direct-to-Subject Study Drug Shipment (Section 7.5.2)
Temporary Discontinuation of Study Drug
Participants in Treatment Period for Primary Analysis (Day 1 through Week 30)
Under unusual circumstances such as a pandemic or natural disaster, if participants in the first 30 
weeks of the study (Day 1 through Week 30) cannot be monitored for safety within 1 week of their 
scheduled study assessment, as they cannot be seen at the site or by a home health care provider, 
the participant will be contacted by the site at the end of the 1-week period and instructed to stop 
taking mavacamten.
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Participants who discontinue mavacamten should be contacted by the site every 2 to 4 weeks from 
the time of discontinuing mavacamten to assess for AEs and to document concomitant medications 
until the next study visit.
When the participant can return to the study site, he/she will receive a new participant ID and 
undergo rescreening to re-enter the study. All screening assessments need to be repeated.

Participants will restart study drug (mavacamten 2.5 mg QD) at Day 1 and resume study visits 
from Day 1.

Participants who do not qualify based on re-screening assessments, on Principal Investigator 
consultation with the Sponsor/CRO Medical Monitor, may be scheduled for repeat screening 
at a later time. There is no limit to the number of times re-screening can occur when the 
participant discontinued IP due to a pandemic or natural disaster.
Participants in Long-Term Treatment Period (Week 30 through Week 138)
Under unusual circumstances such as a Pandemic or Natural Disaster, if participants in the long-
term treatment period of the study (Week 30 through Week 138) cannot be monitored for safety 
within 1 week of their scheduled study assessment, as they cannot be seen at the site or by a home 
health care provider, the participant will be contacted by the site at the end of the 1-week period 
and instructed to stop taking mavacamten.
Participants who discontinue mavacamten should be contacted by the site every 2 to 4 weeks from 
the time of discontinuing mavacamten to assess for AEs and to document concomitant medications 
until the next study visit.
When the participant can return to the study site, he/she will receive a new participant ID and 
undergo re-screening to re-enter the study. All screening assessments need to be repeated.

Resume mavacamten at the dose they were taking when they temporarily discontinued, 
following completion of an unscheduled safety visit.

Resume study visits at time (T) + x weeks (where T is the study week at discontinuation and x 
is the number of weeks discontinued).

Participants who have discontinued and resumed treatment according to these guidelines may 
repeat the discontinuation/resumption cycle as often as necessary.

Participants who do not qualify based on re-screening assessments, on Principal Investigator 
consultation with the Sponsor/CRO Medical Monitor, may be scheduled for repeat screening 
at a later time. There is no limit to the number of times re-screening can occur when the 
participant discontinued IP due to a pandemic or natural disaster.
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APPENDIX 8
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for the Protocol Amendment 02, 23-Mar-2022
This amendment corrects findings
. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 02
Section Number 
& Title
Description of Change
Brief Rationale
6.2 Exclusion 
Criteria, 2) 
Prior/Concomitan
t Therapy, c) 
c) Removal of “non” from 
non-dihydropyridine 
Correction of typo. Combination 
treatment with beta blockers with 
dihydropyridine calcium channel 
blockers is permitted.
All
Minor typographical errors 
corrected throughout
Clarification
Overall Rationale for the Protocol Amendment 01, 17-Mar-2022
The main reason for revising the protocol 
. The revised 
protocol applies to all future participants of the study.
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01
Section Number 
& Title
Description of Change
Brief Rationale
Title Page
Clinical Scientist
Bristol-Myers Squibb 
Company
Route 206 & Province Line 
Road
Lawrenceville, NJ 08543
Phone: 
email: 
Updated name and contact information 
for Clinical Scientist
Table 2-1: 
Screening 
Procedural 
Outline 
(CV027004)
Removed SARS-CoV-2 
Serology Test
SARS-CoV-2 serology test no longer 
required
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01
Section Number 
& Title
Description of Change
Brief Rationale
5.1.2.1 Treatment 
Period for 
Primary Analysis
Removed exception from 
criteria for permanent 
treatment discontinuation. 
To avoid ambiguity, study drug is 
required to be discontinued, regardless of 
potential confounding factors, when 
LVEF ≤30%.
6.1 Inclusion 
Criteria, 4) 
Reproductive 
Status; Appendix 
4 Women of 
Childbearing 
Potential 
Definitions and 
Methods of 
Contraception

Note: 
Intravaginal 
and 
transdermal 
combined 
hormonal contraception are 
not approved by Japan 
Health 
Authority. 
Also, 
progestogen-only hormonal 
contraception 
is 
not 
approved by Japan Health 
Authority.
Added to clarify 
6.2 Exclusion 
Criteria, 1) 
Medical 
Conditions, e) 

Has 
paroxysmal 
atrial 
fibrillation 
with 
atrial 
fibrillation present per the 
investigator’s evaluation of 
the participant’s ECG at the 
time of Screening.
Removal of ‘intermittent’ to be 
consistent with JCS guideline for 
Cardiac Arrhythmias. 
6.2 Exclusion 
Criteria, 2) 
Prior/Concomitan
t Therapy, c) and 
d)
c) Current treatment (within 14 
days prior to Screening) or 
planned treatment during 
the 
study 
with 
a 
combination 
of 
beta 
blockers and verapamil or a 
combination 
of 
beta 
blockers 
and 
diltiazem. 
Combination 
treatment 
with beta blockers and non-
dihydropyridine 
calcium 
channel 
blockers 
is 
allowed.
d) For individuals on any beta 
blockers or any calcium 
channel blockers, any dose 
adjustment 
of 
these 
c) Added text to clarify that combination 
of beta blockers + non-dihydropyridine 
calcium channel blockers are prohibited 
but combination with dihydropyridine 
calcium channel blockers are allowed
d) added “any” for clarification
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01
Section Number 
& Title
Description of Change
Brief Rationale
medications < 14 days prior 
to 
Screening 
or 
any 
anticipated 
change 
in 
treatment regimen during 
the first 30 weeks of the 
study.
6.2 Exclusion 
Criteria 3), c) 
Timing of SARS infection 
updated to 30 days of 
screening. 
Participants with history of SARS-CoV-
2 infection greater than 30 days from 
Screening will be eligible. 
6.4.1 Meals and 
Dietary 
Restrictions

Refrain from consumption 
of 
Seville 
oranges, 
grapefruit 
or 
grapefruit 
juice and quinine (eg, tonic 
water) from Day 1 before 
the 
start 
of 
study 
intervention until after the 
final follow-up visit. 
Clarification. 
Table 7.4.1.1-1 
and Table 7.4.1.2-
1
Updated Valsalva LVOT 
gradient
Updates made to clarify LVOT gradient. 
7.7.2 Background 
HCM Therapy
Added collection of COVID-
19 vaccination status of all 
participants
To ensure understanding of COVID-19 
medical history. 
8.1.3 Criteria for 
Temporary 
Treatment 
Discontinuation
Updated to clarify language on 
temporary dose 
discontinuation.
Added “will” and “or” to clarify 
language of temporary discontinuation 
criteria 
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CV027004
BMS-986427
Mavacamten
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 01
Section Number 
& Title
Description of Change
Brief Rationale
8.1.4 Criteria for 
Permanent 
Treatment 
Discontinuation
Updated to specify 
discontinuation required if 
LVEF ≤ 30%.  
To avoid ambiguity, study drug is 
required to be discontinued, regardless 
of potential confounding factors, when 
LVEF ≤30%.
9.4.4 Clinical 
Safety Laboratory 
Assessments; 
Table 9.8.1 
Biomarker 
Assessments; 
9.10 Other 
Assessments;  
Removal of SARS-CoV-2 
Serology.
Blood samples for SARS-CoV-2 
Serology are no longer required.
9.7.1 HCM 
Genotyping
Redundant text removed. 
Clarification. 
All
Minor typographical errors 
corrected throughout. 
Clarification. 
Protocol Amendment No.: 03
Date: 18-Oct-2022
143
4.0
Approved
930177446
4.0
v
Approved
1.0
v