Conditions: Non-obstructive Hypertrophic Cardiomyopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 59
Healthy volunteers: no

Brief summary:
This is a multicenter, exploratory, randomized, double-blind study of the administration of mavacamten in 60 participants with symptomatic nHCM randomized to receive a 16-week course of mavacamten doses titrated to achieve 1 of 2 target drug concentrations.

Detailed description:

Arms:
arm 1: Active Treatment for participants with base target trough concentration arm 2: Active Treatment for participants with higher target trough concentration arm 3: Placebo Group

Interventions: intervention 1: mavacamten intervention 2: Placebo
Intervention descriptions: intervention 1: MYK-461 intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
Cover Page for Study Protocol 
 
Sponsor Name: MyoKardia, Inc. 
NCT Number: NCT03442764 
Sponsor Trial ID: MYK-461-006 (MAVERICK-HCM) 
Study Title: A Randomized, Double-blind, Placebo-controlled, Concentration-guided, 
Exploratory Study of Mavacamten (MYK-461) in Patients with Symptomatic Non-Obstructive 
Hypertrophic Cardiomyopathy (nHCM) and Preserved Left Ventricular Ejection Fraction 
Document Description: Study Protocol (Amendment 1.0) 
Document Date: 04 April 2018 


 
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CLINICAL STUDY PROTOCOL 
Protocol Number: 
MYK-461-006 (MAVERICK-HCM) 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, 
Concentration-guided, Exploratory Study of Mavacamten 
(MYK-461) in Patients with Symptomatic Non-obstructive 
Hypertrophic Cardiomyopathy (nHCM) and Preserved Left 
Ventricular Ejection Fraction 
Indication: 
Hypertrophic Cardiomyopathy 
Phase: 
2 
Investigational 
Medicinal Product: 
Mavacamten (MYK-461) 
Sponsor: 
MyoKardia, Inc. 
 
 
Key Sponsor Contacts: 
Amy Sehnert, MD 
Medical Monitor 
 
 
 
 
 
 
Original Protocol 
Date: 
04 December 2017 
Amendment 1 Date: 
04 April 2018 
 
Confidentiality Statement 
This document contains trade secrets or otherwise confidential and/or proprietary information of 
MyoKardia, Inc. Access to and use of this information is strictly limited and controlled by 
MyoKardia, Inc. Acceptance of this document constitutes agreement by the recipient that the contents 
will be not be copied, distributed, or otherwise disclosed to third parties, and will not be used in any 
way, except as expressly authorized by MyoKardia, Inc. 
 
 


 
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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES TABLE 
Protocol Amendment 1: 04 April 2018 
This amendment is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment 
 
 
 
 
 
Section(s) 
Summary of Change 
Reason(s) for Change 
Title page 
• Changed the title of clinical 
operations contact to “Associate 
Director” 
• Replaced the name and contact 
information
 
 
 
• 
 
 
 
• 
 
Entire document 
• Moved Figure 1 Study Schema 
and Table 1 Schedule of Study 
Procedures immediately 
following Synopsis 
• Deleted Section 5.5 Withdrawal 
of Participants and replaced with 
Section 10 Treatment 
Discontinuation and Withdrawal 
From Study 
 
 
) 
• Reorganized and updated 
Section 11 (formerly Section 10) 
Evaluation, Recording, and 
Reporting of Adverse Events 
(
 
 
 
 
 
 
 


 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Synopsis; Table 1 
(including footnotes); 
Section 4; Section 9.1; 
Section 12.2.2 
• 
 
 
• Removed CCS chest pain grading 
scale assessment 
• 
 
 
 
 
 
 
 
-
-
 
 
Synopsis (Inclusion 
Criteria); Section 5.2 
• Deleted “initial diagnosis or” 
from inclusion criterion 4 
• Added “and distinctly measurable 
from the LVOT gradient” to 
inclusion criterion 8 
 
Synopsis (Exclusion 
Criteria); Section 5.3 
• Added exclusion criteria 
regarding phenocopy diseases 
(exclusion criterion 4) and atrial 
fibrillation (exclusion criteria 8 
and 9) 
• Deleted former exclusion 
criterion 7 
• Changed several exclusion 
criteria (exclusion criteria 10, 13, 
14, 23) 
• 
 
  
 
 
 
 
-
-
 
 
 
 
Synopsis (Safety 
Endpoints); 
Section 12.2.1 
• Added “Safety” to Synopsis row 
name and Section 12.2.1 heading 
• Added “AESIs” to list of safety 
endpoints 
 
 
 
Synopsis (Sample Size 
and Statistical 
Considerations); 
Section 12.1 
Changed “95% confidence 
intervals” to “effect size estimates” 
 
 
Figure 1 Study Schema Removed stress echo at Week 16 
 
Table 1 Schedule of 
Study Procedures; 
Section 9.2.1 
 
 
 
 
 
 
 
 
 
 
 
Table 1 Schedule of 
Study Procedures 
Added row for TSH 
 
 
 
Table 1 Schedule of 
Study Procedures 
Added IMP administered at site at 
Week 16 
 
 
 
 


 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Table 1 Schedule of 
Study Procedures 
Changed footnotes e, h, o, q, r, s 
 
 
 
 
 
Section 1.2; Section 1.3 Updated text 
 
 
 
Section 2.1 
• 
 
 
-
-
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
Section 2.2 
Updated dosing scheme 
 
 
Section 4 
 
 
 
 
Section 4.2 
Changed “will be” to “is” 
 
 
Sections 7.4.1, 7.4.2, 
7.4.3, 7.6, 14.2.2 
Replaced “mavacamten” with 
“study drug” in headings and text, 
as applicable 
 
 
 
 
Section 7.5 
Revised language and inserted 
Subsection 7.5.1 
 
 
Section 7.6 (including 
Section 7.6.1) 
Updated overdose text 
 
 
 
Section 7.7.3; 
Appendix 2 
 
 
 
 
 
 
Section 9.2.2.1 
 
 
 
Section 9.2.3 
Changed “Plasma” to “Serum” 
 
 
Section 9.3.3 
• Deleted triplicate 12-lead ECG 
• Reworded so that ECG is 
conducted predose on Day 1 
 
 
Section 9.3.4 
Updated language 
 
 


 
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Section(s) 
Summary of Change 
Reason(s) for Change 
Section 9.3.5 
Updated language 
 
 
Section 12.3.6.2 
 
 
 
 
Section 14.1.2 
Added ECG machines and PRO 
devices to list of study supplies 
 
 
Throughout document 
Style changes (eg, spaces around 
mathematical operators) (Note: 
these are not shown in track 
changes since they do not affect 
clinical operations or patient 
safety.) 
 
 
 
Abbreviations: AESI, adverse event of special interest; AMA, American Medical Association; 
CCS, Canadian Cardiovascular Society; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; 
IDMC, Independent Data Monitoring Committee; IMP, investigational medicinal product; LVOT, left 
ventricular outflow tract; NT-proBNP, N-terminal pro b-type natriuretic peptide; PRO, patient-reported 
outcomes; TSH, thyroid-stimulating hormone. 


 
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PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-blind, Placebo-controlled, 
Concentration-guided, Exploratory Study of Mavacamten 
(MYK-461) in Patients with Symptomatic Non-obstructive 
Hypertrophic Cardiomyopathy (nHCM) and Preserved Left 
Ventricular Ejection Fraction 
Study Number 
MYK-461-006 (MAVERICK-HCM) 
Study Phase 
2 
Number of Centers 
Approximately 35 sites in the United States 
Objective 
• 
To evaluate the safety and tolerability of a 16-week course of 
mavacamten in individuals with symptomatic nHCM 
 
• 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
-
-
 
 
 
 
 
 
 
  
 
 
 
 
 
 
• 
 
 
Study Design 
This is a multicenter, exploratory, randomized, double-blind study of 
the administration of mavacamten in 60 participants with 
symptomatic nHCM randomized to receive a 16-week course of 
mavacamten doses titrated to achieve 1 of 2 target drug 
concentrations (Group 1: ~200 ng/mL; Group 2: ~500 ng/mL) or 
placebo once daily (QD). Dose adjustments will be based on PK 
parameters. Assessments include safety, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Number of 
Participants 
Approximately 60, with approximately 20 participants in each of the 
3 treatment groups 
Study Treatment 
Participants will be randomized via an interactive response system to 
3 groups in a 1:1:1 ratio: 2 active treatment groups and 1 matching 
placebo. Participants in the 2 active treatment groups start at a dose of 
5 mg QD and will undergo dose adjustment at Week 6 based on 
plasma concentration of mavacamten in samples taken at the Week 4 
visit. Participants in the placebo group will undergo the same 
assessments in order to preserve the blind. Target trough 
concentration is approximately 200 ng/mL for active treatment 
(Group 1) and approximately 500 ng/mL for active treatment (Group 
2). Dosing will continue to Week 16. During the study, participants 
who are treated for their hypertrophic cardiomyopathy (HCM) 
condition (eg, beta blocker or calcium channel blocker) should 
receive a stable dose of such treatment for at least 2 weeks prior to 
Screening, and every effort should be made to keep such treatment 
unchanged (ie, at the same dose) throughout the entire study duration 
until the final end of study visit at Week 24. 
Doses of mavacamten used in this study will be 2.5, 5, 10, and 15 mg. 
Randomization will be stratified according to current treatment with 
beta blocker (yes or no) and type of exercise testing (treadmill or 
bicycle). Study drug will be administered as 1 capsule QD by mouth. 
Study Duration 
The study duration for any individual participant will be 28 weeks 
(± 7 days); this includes a 4-week screening period, a 16-week 
treatment period, and an 8-week post-treatment follow-up period. 
Inclusion Criteria 
Each participant must meet the following criteria to be included in 
this study: 
1. Able to understand and comply with the study procedures, 
including CPET, understand the risks involved in the study, and 
provide written informed consent according to federal, local, and 
institutional guidelines before the first study-specific procedure 
2. Is at least 18 years old at Screening 
3. Body weight is greater than 45 kg at Screening 
4. Diagnosed with nHCM (hypertrophied and non-dilated left 
ventricle in absence of systemic or other known cause) consistent 
with current American College of Cardiology 
Foundation/American Heart Association and European Society of 
Cardiology guidelines, ie, the participant must meet at least 1 of 
the 2 following criteria at the time of Screening: 
• 
Left ventricular (LV) wall thickness ≥ 15 mm, or 
• 
LV wall thickness ≥ 13 mm with a positive family history of 
HCM 
5. Has documented left ventricular ejection fraction ≥ 55% at the 
Screening visit as determined by the echocardiography central 
laboratory 
6. Has adequate acoustic windows to enable accurate transthoracic 


 
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echocardiograms 
7. Left ventricular outflow tract (LVOT) peak gradient at rest AND 
during Valsalva AND post-exercise < 30 mmHg as determined by 
the echocardiography central laboratory 
8. If intracavitary gradient is present and distinctly measurable from 
the LVOT gradient, then maximal intracavitary gradient at rest 
AND during Valsalva AND post-exercise < 30 mmHg as 
determined by the echocardiography central laboratory 
9. Has New York Heart Association (NYHA) Class II or III 
symptoms at Screening 
10. Has an elevated NT-proBNP at rest (> 300 pg/mL) at Screening 
11. Has safety laboratory parameters (chemistry, hematology, 
coagulation, and urinalysis) within normal limits (according to 
the central laboratory reference range) at Screening; however, a 
participant with safety laboratory parameters outside normal 
limits may be included if he or she meets all of the following 
criteria: 
• 
The safety laboratory parameter outside normal limits is 
considered by the investigator to be clinically unimportant 
• 
If there is an alanine aminotransferase or aspartate 
aminotransferase result, the value must be < 3 × the upper 
limit of the laboratory reference range 
• 
The body size–adjusted estimated glomerular filtration rate is 
≥ 30 mL/min/1.73 m2 
12. Female participants must not be pregnant or lactating and, if 
sexually active, must be using one of the following acceptable 
birth control methods from the Screening visit through 3 months 
after the last dose of study drug. Hormonal contraceptives are not 
considered highly effective contraception for this study because 
mavacamten could reduce the effectiveness of hormonal 
contraceptives. 
• 
Double-barrier method (eg, male using a condom and female 
using a diaphragm or cervical cap) 
• 
Barrier plus nonhormonal contraception (eg, male using a 
condom and female using a nonhormonal intrauterine device 
or nonhormonal intrauterine system) 
• 
Female is surgically sterile for 6 months or postmenopausal 
for 2 years. Permanent sterilization includes hysterectomy, 
bilateral oophorectomy, bilateral salpingectomy, and/or 
documented bilateral tubal occlusion at least 6 months prior to 
Screening. Females are considered postmenopausal if they 
have had amenorrhea for at least 2 years or more following 
cessation of all exogenous hormonal treatments and follicle-
stimulating hormone levels are in the postmenopausal range 
13. Male participants with sexual partners must agree to use condoms 
for the duration of the study and for 3 months after the last dose 
of study medication in order to prevent passing mavacamten to 
the partner in the ejaculate 


 
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Exclusion Criteria 
A participant who meets any of the following exclusion criteria may 
not participate in this study: 
1. Previously participated in a clinical study with mavacamten 
2. Hypersensitivity to mavacamten or any of the components of the 
mavacamten formulation 
3. Participated in a clinical trial where the participant received any 
investigational drug (or is currently using an investigational 
device) within 30 days prior to Screening or 5 times the 
respective elimination half-life (whichever is longer) 
4. Has a known infiltrative or storage disorder causing cardiac 
hypertrophy that mimics nHCM, such as Fabry disease, 
amyloidosis, or Noonan syndrome with LV hypertrophy 
5. Has any medical condition that precludes upright exercise stress 
testing 
6. Has a history of syncope or a history of sustained ventricular 
tachyarrhythmia with exercise within the past 6 months 
7. Has a history of resuscitated sudden cardiac arrest at any time or 
known appropriate implantable cardioverter defibrillator (ICD) 
discharge within 6 months prior to Screening 
8. Has paroxysmal, intermittent atrial fibrillation with atrial 
fibrillation present per the investigator’s evaluation of the 
participant’s electrocardiogram (ECG) at the time of Screening 
9. Has persistent or permanent atrial fibrillation not on 
anticoagulation for at least 4 weeks prior to Screening and/or is 
not adequately rate-controlled within 6 months prior to Screening 
(note: patients with persistent or permanent atrial fibrillation who 
are anticoagulated and adequately rate-controlled are allowed) 
10. Is currently treated with disopyramide or ranolazine (within 
14 days prior to Screening) or treatment with disopyramide or 
ranolazine is planned during the study 
11. For participants on beta blocker, verapamil, or diltiazem, any 
dose adjustment < 14 days before Screening (see Section 7.7.2) 
12. Currently treated or planned treatment during the study with a 
combination of beta blocker and verapamil or a combination of 
beta blocker and diltiazem 
13. Has been treated with invasive septal reduction (surgical 
myectomy or percutaneous alcohol septal ablation) within 
6 months prior to Screening (note: if a participant has had prior 
septal reduction therapy, the diagnostic wall thickness criteria and 
all other eligibility criteria must be met at time of Screening) 
14. Documented history of resting or post-exercise LVOT or 
intracavity gradient > 30 mmHg unless subsequently treated by 
septal reduction therapy 
15. Fridericia-corrected QT interval (QTcF) > 480 ms or any other 
ECG abnormality considered by the investigator to pose a risk to 
participant safety (eg, second-degree atrioventricular block type 
II) 


 
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16. Has documented obstructive coronary artery disease (> 70% 
stenosis in one or more epicardial coronary arteries) or 
myocardial infarction within the past 6 months 
17. Has known moderate or severe (as per the investigator’s 
judgment) aortic valve stenosis at Screening 
18. Has any acute or serious comorbid condition (eg, major infection 
or hematologic, renal, metabolic, gastrointestinal, or endocrine 
dysfunction) that, in the judgment of the investigator, could lead 
to premature termination of study participation or interfere with 
the measurement or interpretation of the efficacy and safety 
assessments in the study 
19. Has pulmonary disease that limits exercise capacity or systemic 
arterial oxygen saturation 
20. Positive serologic test at Screening for infection with human 
immunodeficiency virus, hepatitis C virus, or hepatitis B virus 
21. History of clinically significant malignant disease within 10 years 
of Screening: 
• 
Participants who have been successfully treated for 
nonmetastatic cutaneous squamous cell or basal cell 
carcinoma or have been adequately treated for cervical 
carcinoma in situ can be included in the study 
• 
Participants with other malignancies who are cancer-free for 
more than 10 years before Screening can be included in the 
study 
22. History or evidence of any other clinically significant disorder, 
condition, or disease (with the exception of those outlined above) 
that, in the opinion of the investigator or the medical monitor, 
would pose a risk to participant safety or interfere with the study 
evaluation, procedures, or completion 
23. Currently taking, or has taken within 14 days prior to Screening, a 
prohibited medication such as a cytochrome P450 (CYP) 2C19 
inhibitor (eg, omeprazole), a strong CYP 3A4 inhibitor, or St. 
John’s Wort (see APPENDIX 2 for more details) 
24. Prior treatment with cardiotoxic agents such as doxorubicin or 
similar (see APPENDIX 2) 
25. Unable to comply with the study requirements, including the 
number of required visits to the clinical site 
26. Employed by, or a relative of someone employed by MyoKardia, 
the investigator, or his/her staff or family 
Safety Endpoints 
• 
Frequency and severity of treatment-emergent adverse events, 
adverse events of special interest, and serious adverse events; 
laboratory abnormalities; vital signs; and cardiac rhythm 
abnormalities 
 
 
 
 
 
 
 
 
 
 
 


 
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-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
Sample Size and 
Statistical 
Considerations 
This study will include a total of approximately 60 participants, or 
approximately 20 participants per treatment group. Such a sample 
size will be sufficient to obtain sound variability estimates while 
yielding reasonable effect size estimates for future planning purposes. 
 
 


 
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Figure 1 
Study Schema 
 
Abbreviations: CPET, cardiopulmonary exercise testing; EOS, end of study; NT-proBNP, N-terminal pro 
b-type natriuretic peptide; PK, pharmacokinetic blood sample taken; QD, once daily; stress echo, stress 
echocardiography; TTE, transthoracic echocardiogram.


 
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Table 1 
Schedule of Study Procedures 
Assessmenta 
Screeningb 
Day -28 to 
Day -1 
Day 1 
Week 2 
(telephone 
call)c 
Week 
4c 
Week 
6c 
Week 
8c 
Week 10 
(telephone 
call)c 
Week 
12c 
Week 14 
(telephone 
call)c 
Week 
16c/ET 
Week 
24c/EOS 
General Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical historyd 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
AEsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ICD information downloadedf 
X 
 
 
 
 
 
 
 
 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination including height and 
weightg 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
ECGh 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Resting TTEi 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Post-exercise stress echocardiographyj 
X 
 
 
 
 
 
 
 
 
 
 
CPETk 
 
X 
 
 
 
 
 
 
 
X 
 
Accelerometer attachedl 
X 
 
 
 
 
 
 
X 
 
 
 
Apply cardiac monitoring skin patchm 
X 
 
 
 
 
 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Laboratory 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis panel, HIV test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Coagulation panel 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Chemistry 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
X 
Footnotes and abbreviations are defined on last page of table. 
Page 1 of 2 
 
 


 
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Table 1 
Schedule of Study Procedures (continued) 
Assessmenta 
Screeningb 
Day -28 to 
Day -1 
Day 1 
Week 2c 
(telephone 
call) 
Week 
4c 
Week 
6c 
Week 
8c 
Week 10 
(telephone 
call)c 
Week 
12c 
Week 14 
(telephone 
call)c 
Week 
16c/ET 
Week 
24c/EOS 
Laboratory (continued) 
 
 
 
 
 
 
 
 
 
 
 
hs-cardiac troponin I 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
NT-proBNPo 
Xo 
Xo 
 
X 
 
X 
 
X 
 
Xo 
X 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
FSHp /Serum pregnancy test (women)q 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)q 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Symptom Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Xv 
 
 
 
 
 
Xw 
 
Xw 
Xw 
Xw 
 
Xx 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Investigational Medical Product 
 
 
 
 
 
 
 
 
 
 
 
IMP QD 
 
 
 
 
 
 
 
 
 
 
 
IMP administered at site 
 
X 
 
 
 
 
 
 
 
X 
 
IMP compliancey 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Abbreviations: AE, adverse event; BP, blood pressure; CPET, cardiopulmonary exercise testing; DNA, deoxyribonucleic acid; ECG, electrocardiogram; 
eCRF, electronic case report form; EOS, end of study; 
-
; ET, early termination; FSH, follicle-stimulating hormone; 
HCM, hypertrophic cardiomyopathy; 
, 
; HIV, human immunodeficiency virus; HR, heart rate; 
hs, high-sensitivity; ICD, implantable cardioverter-defibrillator; ICF, informed consent form; IMP, investigational medicinal product; 
 
; LVOT, left ventricular outflow tract; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart 
Association; 
 
 
; PK, pharmacokinetic; 
PRO, patient-reported outcomes; QD, once daily; TSH, thyroid-stimulating hormone; TTE, transthoracic echocardiography. 


 
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a 
Preferred order of assessments is symptom questionnaires; the following 3 assessments in any order: ECG, vital signs, and TTE; pre-exercise blood draws; 
exercise test; and post-exercise blood draws. 
b 
Screening may require more than 1 visit to accommodate all of the study procedures. 
c 
All post−Day 1 study visits have a window of ± 7 days. At Weeks 2, 10, and 14, participants will be contacted by telephone to collect AE and concomitant 
medication data. 
d 
Changes in baseline conditions from once the ICF is signed are recorded on the medical history eCRF unless the change is related to a study procedure, 
which is then considered an AE. All changes that occur after the administration of the IMP are recorded as AEs.  
e 
At Screening, ET (if applicable), Week 16 (end of treatment), and Week 24 (end of study), complete vital signs including temperature, HR, respiratory rate, 
and BP will be obtained. At all other onsite visits except Week 6, only HR and BP are required. If PK sampling is conducted at a visit, vital signs should be 
collected before PK sampling. Vital signs should be taken with the participant in the same position at all visits. BP should be taken via an automated recorder 
after the participant rests for at least 5 minutes. 
f 
For participants who have ICDs, information including rhythm strips and events will be downloaded from the ICDs. 
g 
At Screening, Week 16, and Week 24, a complete physical examination will be conducted, including a neurological examination. At Week 4, Week 8, and 
Week 12, an abbreviated cardiopulmonary physical examination will be conducted, with other systems assessed as directed by interval history. Physical 
examinations will also include height (at Screening only) and weight (at all onsite visits at which a physical examination is performed). 
h 
12-lead ECGs will be performed at Screening and all onsite visits except for the Week 6 visit after 10 minutes of rest. Each time an ECG is completed, a 
10-second paper ECG will be obtained and maintained in the study participant’s source documentation. On Day 1, an ECG will be performed predose. 
i 
Resting TTE should be performed prior to post-exercise stress echocardiography or CPET. Instantaneous peak LVOT gradient at rest and provoked peak 
LVOT gradient (Valsalva maneuver) will be assessed only at Screening. 
j 
After a 4-hour fast, participants will undergo a standard symptom-limited exercise test by standardized treadmill or bicycle ergometer. Instantaneous peak 
LVOT gradient will be assessed immediately post-exercise by TTE. 
k 
CPET by standardized treadmill or bicycle ergometer will be performed on both Day 1 and at Week 16/ET prior to dosing. CPET is done after a 4-hour fast. 
Obtain CPET with study participant in the same position at Week 16 as done on Day 1. 
l 
The accelerometer is to be distributed during Screening and at the Week 12 visit and retrieved at the Day 1 and Week 16 visits. 
m 
The cardiac monitoring adhesive skin patch is to be applied during Screening and at the Week 12 visit and retrieved at the Day 1 and Week 16 visits. 
n 
Blood samples for PK will be collected at all post-Screening onsite visits except for the Day 1 and Week 6 visits. The time of each blood draw will be 
recorded. At Week 16, a PK sample will be collected before dosing as well as within 2 hours postdose. On other PK sampling days, the PK blood samples 
can be taken at any time that best facilitates conduct of all scheduled study procedures. The date and time of the last dose of IMP taken prior to the PK 
sample collection will be recorded. 
o 
At Screening, the blood draw for NT-proBNP will occur prior to post-exercise stress echocardiography. At the Day 1 and Week 16 visits, the blood draw for 
NT-proBNP will be obtained both prior to and immediately after CPET. 
p 
FSH testing at Screening for postmenopausal women to confirm postmenopausal status. 
q 
Pregnancy testing for all females of childbearing potential. Conduct serum test at Screening and a urine pregnancy test at all other visits shown; conduct 
serum test if a urine test is positive. At Week 20, a urine pregnancy test will be conducted at home. 


 
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r 
Separate consent is required for HCM genotyping. Note that if a participant with a prior HCM clinical genotype test that was positive for pathogenic 
HCM-causing mutation(s) consents to provide their results, then no further genotype assessment will be performed. However, participants who have not 
been tested, participants who have tested negative for pathogenic HCM-causing mutation(s) on clinical panels, and participants who have a positive HCM 
genotype result but cannot provide the results or will not consent to provide the results may consent to have blood drawn on Day 1 prior to the first dose of 
IMP for assessment of HCM genotype. 
s 
Participants may also consent separately to have blood drawn prior to dosing on Day 1 for assessment of pharmacogenetics and potentially additional DNA 
sequencing. 
t 
Participants will have blood samples drawn on Day 1 and Week 16 prior to dosing and at Week 24 for potential exploratory biomarker analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
y 
All participants will return their IMP dosing containers to the site for capsule counts. Refer to the Pharmacy Manual for details. 


 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ......................................2 
Protocol Amendment 1: 04 April 2018 ................................................................................2 
PROTOCOL SYNOPSIS ..........................................................................................................6 
TABLE OF CONTENTS .........................................................................................................17 
LIST OF TABLES ...................................................................................................................21 
LIST OF FIGURES .................................................................................................................21 
LIST OF ABBREVIATIONS ..................................................................................................22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
STUDY OBJECTIVES ..........................................................................................31 
3.1 
Objective ..........................................................................................................31 
 
 
 
 
 
 
4 
OVERALL STUDY DESIGN AND PLAN ..........................................................32 
4.1 
Study Duration .................................................................................................33 
4.2 
Independent Data Monitoring Committee .......................................................33 
5 
SELECTION AND WITHDRAWAL OF STUDY POPULATION.....................34 
5.1 
General Study Population and Clinical Sites ...................................................34 
5.2 
Inclusion Criteria .............................................................................................34 
5.3 
Exclusion Criteria ............................................................................................35 
5.4 
Screening and Enrollment ................................................................................37 
6 
RANDOMIZATION AND BLINDING PROCEDURES.....................................38 
6.1 
Randomization .................................................................................................38 
6.2 
Study Blinding .................................................................................................38 
6.3 
Methods for Unblinding ...................................................................................38 
7 
STUDY TREATMENT .........................................................................................39 
7.1 
Formulation, Packaging, and Labeling of Study Drug ....................................39 
7.2 
Administration and Schedule of Study Drug ...................................................39 


 
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7.3 
Treatment Compliance .....................................................................................39 
7.4 
Hepatotoxicity Stopping and Rechallenge Rules .............................................39 
7.4.1 
Criteria for Permanent Withholding of Study Drug Due to 
Potential Hepatotoxicity.......................................................................40 
7.4.2 
Criteria for Conditional Withholding of Study Drug Due to 
Potential Hepatotoxicity.......................................................................41 
7.4.3 
Criteria for Rechallenge of Study Drug After Potential 
Hepatotoxicity ......................................................................................41 
7.5 
Guidelines for the Management of Exaggerated Pharmacologic Effect 
(Systolic Dysfunction), Higher Than Expected Plasma Concentration, or 
Excessive QT Prolongation..............................................................................41 
7.5.1 
Management of Double-blind Treatment in the Case of 
LVEF ≤ 30% at Study Site ...................................................................42 
7.6 
Overdose ..........................................................................................................42 
7.6.1 
Reporting and Follow-up of Overdose ................................................43 
 
 
 
 
 
 
 
 
 
 
8 
RISKS AND PRECAUTIONS ..............................................................................44 
8.1 
General .............................................................................................................44 
8.2 
Pregnancy .........................................................................................................44 
8.2.1 
Avoidance of Pregnancy ......................................................................44 
8.2.2 
Restrictions for Male Participants ........................................................44 
8.2.3 
Acceptable Forms of Contraception ....................................................44 
8.2.4 
Reporting and Follow-up of Pregnancies ............................................45 
9 
STUDY ASSESSMENTS AND PROCEDURES .................................................46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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9.3 
Safety Assessments ..........................................................................................49 
9.3.1 
Medical History ...................................................................................50 
9.3.2 
Physical Examination...........................................................................50 
9.3.3 
12-lead ECG.........................................................................................50 
9.3.4 
Cardiac Monitoring Skin Patch ............................................................50 
9.3.5 
Vital Signs ............................................................................................51 
9.3.6 
Other Safety Assessments ....................................................................51 
9.4 
Participant Restrictions During this Study .......................................................51 
9.5 
Study Procedures by Visit ................................................................................52 
9.6 
Visit Scheduling ...............................................................................................52 
10 
TREATMENT DISCONTINUATION AND WITHDRAWAL FROM 
STUDY ..................................................................................................................53 
10.1 
Treatment Discontinuation...............................................................................53 
10.1.1 
Temporary Treatment Discontinuation ................................................53 
10.1.2 
Permanent Treatment Discontinuation ................................................53 
10.1.3 
Criteria for Permanent Treatment Discontinuation ..............................53 
10.1.4 
Management of Participants After Permanent Treatment 
Discontinuation ....................................................................................54 
10.2 
Withdrawal from Study....................................................................................55 
10.2.1 
Withdrawal of Consent for Ongoing Study Participation ....................55 
10.2.2 
Replacement of Participants Who Withdraw from the Study ..............55 
11 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS ................................................................................................................56 
11.1 
Definitions........................................................................................................56 
11.1.1 
Adverse Event ......................................................................................56 
11.1.2 
Serious Adverse Event .........................................................................57 
11.2 
Adverse Event Reporting and Descriptions .....................................................58 
11.2.1 
Reporting Period and Follow-up ..........................................................58 
11.2.2 
Recording and Assessing Adverse Events ...........................................59 
11.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) .......................60 
12 
STATISTICAL METHODS ..................................................................................61 
12.1 
Determination of Sample Size .........................................................................61 
12.2 
Study Endpoints ...............................................................................................61 
12.2.1 
Safety Endpoints ..................................................................................61 
 
 
 
 
 
 
12.3 
Statistical Analysis ...........................................................................................62 


 
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12.3.1 
Analysis Populations ............................................................................62 
12.3.2 
General Considerations ........................................................................62 
12.3.3 
Participant Disposition .........................................................................63 
12.3.4 
Demographics and Baseline Characteristics ........................................63 
12.3.5 
Extent of Study Treatment Exposure and Compliance ........................63 
 
 
 
 
 
 
 
12.3.8 
Safety Analyses ....................................................................................64   
12.3.9 
Interim Analysis ...................................................................................68 
 
 
 
13 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS ........................69 
13.1 
Compliance Statement .....................................................................................69 
13.2 
Informed Consent.............................................................................................69 
13.3 
Ethics Committee .............................................................................................69 
14 
ADMINISTRATIVE PROCEDURES ..................................................................71 
14.1 
Sponsor’s Responsibilities ...............................................................................71 
14.1.1 
Participant Confidentiality ...................................................................71 
14.1.2 
Study Supplies .....................................................................................72 
14.1.3 
Investigator Training ............................................................................72 
14.1.4 
Ongoing Communication of Safety Information During the Study.....72 
14.1.5 
Study Monitoring .................................................................................73 
14.1.6 
Study Auditing and Inspecting.............................................................73 
14.2 
Investigator’s Responsibilities .........................................................................73 
14.2.1 
Screening Log ......................................................................................73 
14.2.2 
Study Drug Accountability ..................................................................73 
14.2.3 
Reporting and Recording of Study Data ..............................................73 
14.2.4 
Source Data and Source Documents ....................................................74 
14.2.5 
Participant Identification Information..................................................75 
14.2.6 
Records Retention ................................................................................75 
14.2.7 
Protocol Deviations ..............................................................................75 
14.2.8 
Blood Sample Collection/Storage ........................................................75 
14.3 
Clinical Trial Insurance....................................................................................76 
14.4 
Protocol Amendments and Study Administrative Letters ...............................76 
15 
DATA QUALITY ASSURANCE .........................................................................77 
16 
ADMINISTRATIVE CONSIDERATIONS ..........................................................78 
16.1 
Use of Computerized Systems .........................................................................78 
16.2 
Study Records ..................................................................................................78 
17 
PUBLICATION .....................................................................................................80 


 
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APPENDIX 1 
LABORATORY ASSESSMENTS .....................................................83 
 
 
 
APPENDIX 3 
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING 
AND ADDITIONAL ASSESSMENTS REPORTING .......................85 
APPENDIX 4 
INVESTIGATOR’S SIGNATURE .....................................................87 
 
 
LIST OF TABLES 
Table 1 
Schedule of Study Procedures ...................................................................13 
 
 
 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema.............................................................................................12 
 


 
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LIST OF ABBREVIATIONS 
A 
peak velocity of late transmitral flow 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CI 
confidence interval 
CPET 
cardiopulmonary exercise test or testing 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
E 
peak velocity of early diastolic transmitral flow 
eꞌ 
peak velocity of early diastolic septal and lateral mitral annular motion 
EC 
ethics committee; refers to an IRB or IEC or equivalent 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
-
 
 
EOS 
end of study 
ET 
early termination 
FDA 
The United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HCM 
hypertrophic cardiomyopathy 
 
 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICD 
implantable cardioverter-defibrillator 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 


 
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IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IXRS 
interactive response system 
 
 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
LVOT 
left ventricular outflow tract 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
nHCM 
non-obstructive hypertrophic cardiomyopathy 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
oHCM 
obstructive hypertrophic cardiomyopathy 
PD 
pharmacodynamic(s) 
 
 
 
 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcomes 
PT 
preferred term 
QD 
once daily 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reactions 
TBL 
total bilirubin 


 
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TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
TTE 
transthoracic echocardiography, transthoracic echocardiogram 
ULN 
upper limit of normal 
US 
United States 
VCO2 
carbon dioxide production 
VE 
volume expired 
VO2 
oxygen uptake 


 
 
-
-
-
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
-
-
-
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
-
 
 
 


 
 
-
-
-
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
-
-
-
 
  
 
 
 


 
 
-
-
-
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
-
-
-
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
−
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3 
STUDY OBJECTIVES 
3.1 
Objective 
The objective of this study is: 
• To evaluate the safety and tolerability of a 16-week course of mavacamten in individuals 
with symptomatic nHCM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
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4 
OVERALL STUDY DESIGN AND PLAN 
This is a Phase 2, multicenter, exploratory, randomized, double-blind study to evaluate the 
safety, tolerability, preliminary efficacy, PD, and PK of 2 target drug concentrations of 
mavacamten compared with placebo in participants with symptomatic nHCM. 
Approximately 60 participants with symptomatic nHCM will be enrolled. Participants will be 
randomized in a 1:1:1 ratio to 1 of 2 active treatment groups or matching placebo group 
(Figure 1). Randomization will be stratified according to current treatment with beta blocker 
(yes or no) and type of exercise testing (treadmill or bicycle). Participants will be treated for 
16 weeks and then followed up approximately 8 weeks after the last dose of study drug. At 
Week 6, all participants will undergo blinded dose adjustment based on Week 4 assessments 
(see Section 2.2 for details). Participants who are treated for their HCM condition (eg, beta 
blocker or calcium channel blocker) should receive a stable dose of such treatment for at 
least 2 weeks prior to Screening, and every effort should be made to keep such treatment 
unchanged (ie, at the same dose) throughout the entire study duration until the EOS visit at 
Week 24. 
During the Screening process, participants will undergo a variety of general, 
cardiopulmonary, laboratory, 
, patient-reported outcomes (PRO), and 
symptom assessments as detailed in Table 1. Participants will receive their first dose of study 
drug on Day 1. Participants will then undergo a variety of assessments as noted in Table 1 
every 2 weeks through Week 16. Assessments will be conducted at the clinical site at Weeks 
4, 6, 8, 12, and 16; assessments will be conducted via telephone call at Weeks 2, 10, and 14. 
At Week 24, participants will undergo EOS procedures as described in Table 1. 
 
 
 
 
. 
Data from these PRO assessments will not be made available to the investigators and other 
site personnel throughout the study. Participants will first be informed of this when they fill 
out the consent form that is required in order to participate in the trial. The form will include 
information explaining that the PRO information gathered via the device is not shared with 
their healthcare provider and they should therefore report any concerning symptoms directly 
to their physician. Participants will then be reminded of this every time they go to complete 
the assessment on their handheld device. When the participant logs onto his/her handheld 
device to complete the assessments, a message screen will be shown advising the participant 
to consult his/her healthcare provider if he/she has any concerning symptoms. The participant 
will not be able to continue with the PRO assessments until he/she has acknowledged that 
he/she has read a provided message that any symptoms, health issues, or other concerns 
he/she is having may need to be discussed with his/her healthcare team. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4.1 
Study Duration 
The expected study duration is approximately 28 weeks: up to 4 weeks for Screening and 
24 weeks (± 7 days) for study conduct, including the 8-week posttreatment follow-up period. 
4.2 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will meet at regular intervals to review 
study data. The role of the IDMC will be to act in an advisory capacity to the Sponsor with 
respect to safeguarding the interest of study participants, assessing interim safety data, and 
advising the Sponsor and investigators on important emerging study conduct issues. The 
IDMC may formulate recommendations in relation to the evaluation procedures and 
methodologies being employed to survey and detect potential safety signals. Meeting 
frequency and membership is described in the IDMC Charter. 


 
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5 
SELECTION AND WITHDRAWAL OF STUDY POPULATION 
5.1 
General Study Population and Clinical Sites 
Approximately 60 participants with symptomatic nHCM are expected to enroll in this study 
at up to 35 clinical sites in the US. 
5.2 
Inclusion Criteria 
Each participant must meet the following criteria to be enrolled in this study. 
1. Able to understand and comply with the study procedures, including cardiopulmonary 
exercise testing (CPET), understand the risks involved in the study, and provide written 
informed consent according to federal, local, and institutional guidelines before the first 
study-specific procedure 
2. Is at least 18 years old at Screening 
3. Body weight is greater than 45 kg at Screening 
4. Diagnosed with nHCM (hypertrophied and non-dilated left ventricle in absence of 
systemic or other known cause) consistent with current American College of Cardiology 
Foundation/American Heart Association and European Society of Cardiology guidelines, 
ie, the participant must meet at least 1 of the 2 following criteria at the time of Screening: 
• 
LV wall thickness ≥ 15 mm, or 
• 
LV wall thickness ≥ 13 mm with a positive family history of HCM 
5. Has documented LVEF ≥ 55% at the Screening visit as determined by the 
echocardiography central laboratory 
6. Has adequate acoustic windows to enable accurate transthoracic echocardiograms (TTEs) 
7. LVOT peak gradient at rest AND during Valsalva AND post-exercise < 30 mmHg as 
determined by the echocardiography central laboratory 
8. If intracavitary gradient is present and distinctly measurable from the LVOT gradient, 
then maximal intracavitary gradient at rest AND during Valsalva AND post-exercise 
< 30 mmHg as determined by the echocardiography central laboratory 
9. Has NYHA Class II or III symptoms at Screening 
10. Has an elevated NT-proBNP at rest (> 300 pg/mL) at Screening 
11. Has safety laboratory parameters (chemistry, hematology, coagulation, and urinalysis) 
within normal limits (according to the central laboratory reference range) at Screening; 
however, a participant with safety laboratory parameters outside normal limits may be 
included if he or she meets all of the following criteria: 
• The safety laboratory parameter outside normal limits is considered by the 
investigator to be clinically unimportant 
• If there is an alanine aminotransferase or aspartate aminotransferase result, the value 
must be < 3 × the upper limit of the laboratory reference range 
• The body size–adjusted estimated glomerular filtration rate is ≥ 30 mL/min/1.73 m2 


 
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12. Female participants must not be pregnant or lactating and, if sexually active, must be 
using one of the following acceptable birth control methods from the Screening visit 
through 3 months after the last dose of study drug. Hormonal contraceptives are not 
considered highly effective contraception for this study because it is unknown if 
mavacamten reduces the effectiveness of hormonal contraceptives. 
• Double-barrier method (eg, male using a condom and female using a diaphragm or 
cervical cap) 
• Barrier plus nonhormonal contraception (eg, male using a condom and female using a 
nonhormonal intrauterine device [IUD] or nonhormonal intrauterine system [IUS]) 
• Female is surgically sterile for 6 months or postmenopausal for 2 years. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, 
and/or documented bilateral tubal occlusion at least 6 months prior to Screening. 
Females are considered postmenopausal if they have had amenorrhea for at least 
2 years or more following cessation of all exogenous hormonal treatments and 
follicle-stimulating hormone levels are in the postmenopausal range 
13. Male participants with sexual partners must agree to use condoms for the duration of the 
study and for 3 months after the last dose of study medication in order to prevent passing 
mavacamten to the partner in the ejaculate 
 
5.3 
Exclusion Criteria 
A participant who meets any of the following criteria will be excluded from the study. 
1. Previously participated in a clinical study with mavacamten 
2. Hypersensitivity to mavacamten or any of the components of the mavacamten 
formulation 
3. Participated in a clinical trial where the participant received any investigational drug (or 
is currently using an investigational device) within 30 days prior to Screening or 5 times 
the respective elimination half-life (whichever is longer) 
4. Has a known infiltrative or storage disorder causing cardiac hypertrophy that mimics 
nHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy 
5. Has any medical condition that precludes upright exercise stress testing 
6. Has a history of syncope or a history of sustained ventricular tachyarrhythmia with 
exercise within the past 6 months 
7. Has a history of resuscitated sudden cardiac arrest at any time or known appropriate 
implantable cardioverter defibrillator (ICD) discharge within 6 months prior to Screening 
8. Has paroxysmal, intermittent atrial fibrillation with atrial fibrillation present per the 
investigator’s evaluation of the participant’s electrocardiogram (ECG) at the time of 
Screening 
9. Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks 
prior to Screening and/or is not adequately rate-controlled within 6 months prior to 


 
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Screening (note: patients with persistent or permanent atrial fibrillation who are 
anticoagulated and adequately rate-controlled are allowed) 
10. Is currently treated with disopyramide or ranolazine (within 14 days prior to Screening) 
or treatment with disopyramide or ranolazine is planned during the study 
11. For participants on beta blocker, verapamil, or diltiazem, any dose adjustment < 14 days 
before Screening (see Section 7.7.2) 
12. Currently treated or planned treatment during the study with a combination of beta 
blocker and verapamil or a combination of beta blocker and diltiazem 
13. Has been treated with invasive septal reduction (surgical myectomy or percutaneous 
alcohol septal ablation) within 6 months prior to Screening (note: if a participant has had 
prior septal reduction therapy, the diagnostic wall thickness criteria and all other 
eligibility criteria must be met at time of Screening) 
14. Documented history of resting or post-exercise LVOT or intracavity gradient > 30 mmHg 
unless subsequently treated by septal reduction therapy 
15. QTcF > 480 ms or any other ECG abnormality considered by the investigator to pose a 
risk to participant safety (eg, second-degree atrioventricular block type II) 
16. Has documented obstructive coronary artery disease (> 70% stenosis in one or more 
epicardial coronary arteries) or myocardial infarction within the past 6 months 
17. Has known moderate or severe (as per the investigator’s judgment) aortic valve stenosis 
at Screening 
18. Has any acute or serious comorbid condition (eg, major infection or hematologic, renal, 
metabolic, gastrointestinal, or endocrine dysfunction) that, in the judgment of the 
investigator, could lead to premature termination of study participation or interfere with 
the measurement or interpretation of the efficacy and safety assessments in the study 
19. Has pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation 
20. Positive serologic test at Screening for infection with human immunodeficiency virus, 
hepatitis C virus, or hepatitis B virus 
21. History of clinically significant malignant disease within 10 years of Screening: 
• Participants who have been successfully treated for nonmetastatic cutaneous 
squamous cell or basal cell carcinoma or have been adequately treated for cervical 
carcinoma in situ can be included in the study 
• Participants with other malignancies who are cancer-free for more than 10 years 
before Screening can be included in the study 
22. History or evidence of any other clinically significant disorder, condition, or disease 
(with the exception of those outlined above) that, in the opinion of the investigator or the 
medical monitor, would pose a risk to participant safety or interfere with the study 
evaluation, procedures, or completion 
23. Currently taking, or has taken within 14 days prior to Screening, a CYP 2C19 inhibitor 
(eg, omeprazole), a strong CYP 3A4 inhibitor, or St. John’s Wort (see APPENDIX 2 for 
more details) 
24. Prior treatment with cardiotoxic agents such as doxorubicin or similar (see 
APPENDIX 2) 


 
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25. Unable to comply with the study requirements, including the number of required visits to 
the clinical site 
26. Employed by, or a relative of someone employed by MyoKardia, the investigator, or 
his/her staff or family 
 
5.4 
Screening and Enrollment 
An informed consent form (ICF) must be signed and dated by the participant before any 
study-specific tests or procedures may be performed. 
Each participant will be assigned a unique identification number when informed consent has 
been obtained. The identification number will be assigned based on information obtained 
from an interactive response system (IXRS). Participants will be considered enrolled once an 
identification number has been assigned. The identification number will be used to identify 
the participant throughout the study and should appear on all study-related documentation. 
Numbers will not include identifiable information. The investigator will ensure that informed 
consent is obtained from each participant before any study-specific procedures are 
performed. 
Participants that fail to meet all inclusion criteria or present with an exclusion criterion may 
be re-screened. Refer to the Study Reference Manual for re-screening criteria and procedures. 


 
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6 
RANDOMIZATION AND BLINDING PROCEDURES 
6.1 
Randomization 
Participants who meet the inclusion/exclusion criteria will be randomized via an IXRS to 1 of 
3 groups in a 1:1:1 ratio: 2 active treatment groups and 1 matching placebo group. 
Randomization will be stratified according to current treatment with beta blocker (yes or no) 
and type of exercise testing (treadmill or bicycle). 
6.2 
Study Blinding 
Participants will be randomized to 1 of 3 groups via the IXRS. All participants receive either 
5 mg mavacamten or matching placebo from Day 1 to Week 6. Blinded dose adjustment (2.5, 
5, 10, or 15 mg mavacamten or placebo) via the IXRS will begin at Week 6 based on PK 
measurements at Week 4. Study drug administration will occur in a double-blind manner via 
the IXRS such that the investigator, site staff, the pharmacist, and the participant will not 
know which study drug is being administered. 
In addition, the Sponsor, the central and core laboratories, and clinical site monitors will be 
blinded to assigned treatment. Echocardiography results (eg, LVEF) performed at clinic 
visits will be blinded to the investigator and study staff. The 4 different doses of mavacamten 
and matching placebo will be identical in appearance in order to preserve the blind. Study 
drug (2.5, 5, 10, or 15 mg mavacamten or matching placebo) will be labeled with a unique 
identifying number that will be assigned to a participant through the IXRS. 
The pharmacovigilance team will be unblinded for suspected unexpected serious adverse 
reaction (SUSAR) reporting. The IDMC may also review unblinded safety and efficacy data. 
6.3 
Methods for Unblinding 
Unblinding by the investigator independently of the Sponsor also may occur if an AE or 
toxicity necessitates identification of the medication for the welfare of the participant. Please 
refer to the IXRS Manual for the unblinding process and contact information. 


 
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7 
STUDY TREATMENT 
Study drug is defined as mavacamten or placebo. 
All randomized study participants will receive either mavacamten (5 mg from Day 1 to 
Week 6 and one of a range of doses [2.5, 5, 10, or 15 mg] from Week 6 to Week 16) or 
matching placebo (Day 1 to Week 16) in a double-blind manner. 
7.1 
Formulation, Packaging, and Labeling of Study Drug 
Mavacamten capsules and matching placebo have the same appearance. The study drug 
presentation is size 2, blue opaque capsules printed with a yellow band on the body and black 
band on the cap. Each capsule contains white to off-white powder. The active capsules are 
supplied in 4 strengths: 2.5, 5, 10, and 15 mg. 
Mavacamten active and placebo capsules have been manufactured according to current Good 
Manufacturing Practice (cGMP) regulations. They will be supplied in high-density 
polyethylene bottles with induction seals and child resistant caps at 30 count per bottle. All 
study drug will be labeled according to applicable local regulatory guidelines. 
The mavacamten active and placebo capsules must be stored at 2°C to 25°C (36°F to 77°F) 
in the packaging supplied by MyoKardia. Study medication at the investigational site will be 
stored in a secure area with access limited to authorized study personnel. 
7.2 
Administration and Schedule of Study Drug 
Study drug will be supplied to participants via the IXRS in 30-count high-density 
polyethylene bottles that are appropriately labeled. The participants will be instructed to store 
their supply of study drug capsules and bottles in a cool, dry place. 
Participants will take study drug as directed by the physician. Participants should be 
instructed to take the study drug under fasting conditions (≥ 8 hours) at approximately the 
same time every day (± 4 hours). Study drug should be taken with approximately 8 ounces of 
water. If the dosing window is missed, the participant should not take study drug that day. 
Participants should never take 2 doses of study drug within an 8-hour period. 
7.3 
Treatment Compliance 
Compliance with study drug will be monitored by capsule count at Weeks 4, 6, 8, 12, and 16 
(Table 1). Refer to the Pharmacy Manual for details. 
7.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Participants with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL], or 
international normalized ratio) or signs/symptoms of hepatitis may meet the criteria for 
withholding of study medication or other protocol-required therapies. Withholding is either 


 
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permanent or conditional depending on the clinical circumstances discussed below (as 
specified in the US FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation, July 2009). 
7.4.1 
Criteria for Permanent Withholding of Study Drug Due to Potential 
Hepatotoxicity 
Study drug should be discontinued permanently and the participant should be followed 
according to the recommendations in APPENDIX 3 for possible drug-induced liver injury 
(DILI) if all the criteria below are met: 
• TBL > 2 × upper limit of normal (ULN) or international normalized ratio > 1.5 
• AND increased AST or ALT if the baseline value was < ULN and AST or ALT elevation 
is > 3 × ULN 
• AND no other cause for the combination of laboratory abnormalities is immediately 
apparent. Important potential causes for abnormal AST/ALT or TBL values include, but 
are not limited to, the following: 
◦ 
Obstructive gallbladder or bile duct disease 
◦ 
Viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella) 
◦ 
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right-sided heart failure 
◦ 
Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
◦ 
Heritable disorders causing impaired glucuronidation (eg, Gilbert syndrome); 
α-1 antitrypsin deficiency 
◦ 
Autoimmune hepatitis 
◦ 
Nonalcoholic steatohepatitis or other fatty liver disease 
 
If an alternative cause for hepatotoxicity is identified or less stringent conditions developed 
than what is noted above, the investigator will determine whether study drug and other 
protocol-required therapies should be permanently or temporarily discontinued based on 
participant population and/or severity of the hepatotoxicity or event, as deemed appropriate 
for the safety of the participant. 


 
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7.4.2 
Criteria for Conditional Withholding of Study Drug Due to Potential 
Hepatotoxicity 
For participants who do not meet the criteria for permanent withholding of study medication 
outlined above, study drug should be withheld if ANY of the following criteria are met, and 
the participant should be evaluated for DILI: 
• Elevation of either AST or ALT, regardless of baseline AST or ALT value, if: 
◦ 
> 8 × ULN at any time 
◦ 
> 5 × ULN and < 8 × ULN for ≥ 2 weeks 
◦ 
> 5 × ULN and < 8 × ULN and unable to adhere to enhanced monitoring schedule 
• OR: clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant pain/tenderness, fever, nausea, vomiting, jaundice, 
rash or eosinophilia > 5%). If such signs or symptoms are coupled with ALT or AST 
elevations > 3 × ULN, study medication should be withheld 
• OR: TBL > 3 × ULN at any time 
• OR: ALP > 8 × ULN at any time 
 
Study drug should be withheld pending an investigation into alternative causes of DILI. If 
study medication is withheld, the participant should be followed according to 
recommendations in APPENDIX 3 for possible DILI. Rechallenge may be considered if an 
alternative cause, such as acute hepatitis B infection, is discovered and the laboratory 
abnormalities resolve to normal or baseline (Section 7.4.3). 
7.4.3 
Criteria for Rechallenge of Study Drug After Potential Hepatotoxicity 
The decision to rechallenge the participant should be discussed and unanimously agreed by 
the investigator, IDMC, and Sponsor. 
If signs or symptoms recur with rechallenge, then study drug will be permanently 
discontinued. Participants who clearly meet the criteria for permanent discontinuation (as 
described in Section 7.4.1) should never be rechallenged. 
7.5 
Guidelines for the Management of Exaggerated Pharmacologic Effect 
(Systolic Dysfunction), Higher Than Expected Plasma Concentration, or 
Excessive QT Prolongation 
If during the treatment period a participant has a resting LVEF ≤ 45%, plasma drug 
concentration ≥ 1000 ng/mL, or QTcF ≥ 500 ms (as determined by the echocardiography 
central laboratory, PK analysis laboratory, or ECG core laboratory, respectively), it will be 
communicated to the investigator and Sponsor that a stopping criterion has been met. Upon 
receipt of this information, the study site/investigator will contact the participant by 


 
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telephone and instruct the participant to discontinue study drug and return for the next 
scheduled onsite study visit or within 2 weeks, whichever is earlier. After the participant 
discontinues study drug, the participant will be encouraged to undergo early termination (ET) 
and EOS assessments (see Section 10.1.4). To maintain the study blind, a participant in either 
of the other 2 treatment groups may be randomly selected via the IXRS to similarly 
discontinue study drug. 
If a participant experiences heart failure related to systolic dysfunction, no further study drug 
should be administered and administration of therapeutic doses of a β-adrenergic agonist 
(eg, 5 to 10 µg/kg/min dobutamine infusion) should be considered. Additional supportive 
measures, eg, intravenous volume supplementation and/or the use of arterial vasoconstrictor 
agents (α-adrenergic agonists) could complement the use of a β-adrenergic agonist. Aside 
from this specific advice regarding the role of a β-adrenergic agonist, appropriate care will be 
determined by the treating medical personnel. 
New or worsening heart failure associated with systolic dysfunction is one of the criteria for 
permanent treatment discontinuation (Section 10.1.3) and should be subsequently managed 
as described in Section 10.1.2 and Section 10.1.4. 
7.5.1 
Management of Double-blind Treatment in the Case of LVEF ≤ 30% at 
Study Site 
Results of TTE performed by study site sonographers at each scheduled visit following 
randomization should be kept blinded to the investigator and other study site personnel. An 
exception may occur if LVEF ≤ 30% is measured at the site. Under these circumstances, the 
sonographer should review and re-measure the findings with at least one other nonstudy 
professional qualified in echocardiography assessment who is not the investigator 
(eg, echocardiography laboratory director, other experienced sonographer, or nonstudy 
cardiologist). If the result is confirmed (LVEF ≤ 30%), then the investigator will be 
immediately notified and study drug will be discontinued. 
LVEF ≤ 30%, as measured by local site sonography, is one of the criteria for permanent 
treatment discontinuation (Section 10.1.3). As this finding will lead to the investigator being 
unblinded, it should be subsequently managed as described in Section 10.1.2 and 
Section 10.1.4. 
7.6 
Overdose 
An overdose is defined as taking more capsules of study drug than directed. An overdose 
may be suspected by the investigator or spontaneously reported by the participant. An 
overdose may be symptomatic or asymptomatic. 
In the event of suspected overdose, the investigator should contact the medical monitor. No 
further study drug should be administered. The participant should be closely monitored 
clinically for AEs/SAEs, with supportive measures undertaken as clinically indicated. If 
necessary, corrective measures such as initiation of inotropic support with adrenergic agents, 


 
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levosimendan, and/or PDE III inhibitors and other supportive measures, as described in the 
2013 American College of Cardiology Foundation/American Heart Association Guideline for 
the Management of Heart Failure (
 
 
) and in the 2016 European Society of 
Cardiology Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 
(
 
 
 
 
 should be implemented. 
7.6.1 
Reporting and Follow-up of Overdose 
If a participant should experience an overdose, the investigator will report the overdose to the 
medical monitor within 24 hours, even if there are no signs or symptoms associated with the 
overdose in the participant. Follow-up on the participant’s condition will be conducted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
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8 
RISKS AND PRECAUTIONS 
8.1 
General 
Based on nonclinical data and the available clinical data, the most likely risks are those 
associated with higher exposures potentially resulting in an excessive decrease in LVEF. 
This could result in the development or worsening of signs or symptoms of systolic heart 
failure or reduced cardiac output. 
Safety testing in other mammalian species has demonstrated that dose-limiting toxicity is 
related to exaggerated pharmacologic effect and not to off-target adverse effects. For 
overdose, see Section 7.6. 
8.2 
Pregnancy 
8.2.1 
Avoidance of Pregnancy 
Women of childbearing potential must use appropriate methods of birth control as listed in 
Section 8.2.3. Women of nonchildbearing potential are defined as women who are 
permanently (surgically) sterilized or are postmenopausal. Permanent sterilization includes 
hysterectomy, bilateral oophorectomy, and bilateral tubal occlusion or ligation at least 
6 months prior. Women are considered postmenopausal if they have had amenorrhea for at 
least 2 years or more following cessation of all exogenous hormonal treatments and 
follicle-stimulating hormone levels are in the postmenopausal range. 
8.2.2 
Restrictions for Male Participants 
Male participants with sexual partners should use condoms for the duration of the study and 
for 3 months after the last dose of study drug in order to prevent passing mavacamten to the 
partner in the ejaculate. 
Male participants should be advised not to donate sperm for 3 months after the last dose of 
study drug. 
8.2.3 
Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those that result in a low failure rate 
(< 1% per year) when used consistently and correctly. From the time of Screening through 
3 months after the last dose of study drug, participants should practice true abstinence or use 
effective means of contraception as follows: 
• Double-barrier method (eg, male using a condom and female using a diaphragm or 
cervical cap) 
• Barrier (eg, male using a condom) plus nonhormonal contraception (female using a 
nonhormonal IUD or IUS) 
• Female is surgically sterile or postmenopausal as defined in Section 8.2.1. 


 
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8.2.4 
Reporting and Follow-up of Pregnancies 
All pregnancies in female participants and female partners of male participants receiving at 
least 1 dose of study drug will be reported if they occur anytime from first dose to 3 months 
after the last dose of study drug. The investigator is responsible for informing MyoKardia 
within 24 hours of knowledge of the pregnancy even if no AE has occurred. The participant 
will be asked to provide information on the outcome of the pregnancy, including premature 
termination. Spontaneous miscarriage and congenital abnormalities will be reported as SAEs. 


 
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9 
STUDY ASSESSMENTS AND PROCEDURES 
The investigator is responsible for ensuring that all staff involved in the study are familiar 
and comply with the content of this section. 
The following describes the study procedures to be performed during the study. Additional 
details are provided in Table 1 of this document. When several assessments are to be 
conducted at the same time point, the preferred order of assessments is ECG, vital signs, PK, 
and then TTE. The order of assessments may vary slightly at specific time points (eg, 1 hour 
postdose) to facilitate the most contemporaneous performance of the required assessments. 
Unscheduled or additional safety assessments may be performed if necessary in the opinion 
of the investigator. 
For assessments that require the participants to be in a semi-recumbent or supine position, 
assessments should be conducted with participants in the same position at all time points. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
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-
 
 
 


 
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9.3 
Safety Assessments 
Safety will be assessed throughout the study. Safety assessments include medical history, 
physical examinations, ECGs, vital signs, observed and participant-reported AEs, and safety 
laboratory results. Any abnormal findings judged by the investigator to be clinically 
important will be recorded as an AE. 


 
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9.3.1 
Medical History 
A complete medical history will be recorded at the Screening visit, which will include 
evaluation (past or present) of the following: general, head and neck, eyes, ears, nose, throat, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, gynecological/urogenital, 
musculoskeletal/extremities, skin, neurological/psychiatric, endocrine/metabolic, 
hematologic/lymphatic, allergies/drug sensitivities, past surgeries, substance abuse, or any 
other diseases or disorders as well as participation in clinical studies (study medication 
and/or device or other therapy). 
9.3.2 
Physical Examination 
At selected visits, a complete physical examination will be conducted including a 
neurological examination (gross motor and deep tendon reflexes), height (Screening only) 
and weight, and assessment of the following: general appearance, skin, head and neck, 
mouth, lymph nodes, thyroid, abdomen, musculoskeletal, cardiovascular, neurological, and 
respiratory systems. At all other visits, an abbreviated cardiopulmonary physical examination 
will be conducted, with other systems assessed as directed by interval history. 
Height (cm) and body weight (kg) will be measured at Screening, and body mass index 
(kg/m2) will be calculated. Participants will be required to remove their shoes and wear 
clothing as specified by the clinical site. Weight will also be collected at all subsequent onsite 
visits. 
9.3.3 
12-lead ECG 
Twelve-lead ECG evaluations will be performed after 10 minutes of rest at Screening and at 
all onsite study visits except the Week 6 visit. All ECG data will be sent to a central cardiac 
laboratory. 
On Day 1, ECG will be performed predose 
The investigator will judge the overall interpretation as normal or abnormal with clinical 
significance. The investigator will review the ECG and correlate abnormal findings with any 
other clinical findings, participant’s medical history, and laboratory data to determine the 
clinical importance of the finding. 
The investigator may add extra 12-lead ECG safety assessments if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason. These 
assessments should be recorded as an unscheduled assessment. 
9.3.4 
Cardiac Monitoring Skin Patch 
At 2 time points during the study, participants will wear a small device to collect HR and 
rhythm data (Table 1). The self-contained device attaches to the skin using medical adhesive 
and contains surface electrodes, internal electronics to capture a continuous single lead ECG 
waveform, an accelerometer to capture physical activity, sufficient solid state memory to 


 
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store data over multiple days, and a battery to power the device. Two sequential patches will 
be worn for approximately 7 days (14 days total). Following a period of data collection, the 
device will be transported to a core laboratory where the continuous ECG waveforms and 
activity record stored on the device will be uploaded for analysis. The analysis will provide 
full disclosure capabilities for HR, heart rhythm, and physical activity over the period during 
which the device was properly applied and functioning. The device will be used to explore 
the pattern of HR and heart rhythm before and during treatment with study drug. 
9.3.5 
Vital Signs 
Vital signs, including temperature, HR, respiratory rate, and blood pressure (BP), will be 
obtained at Screening, ET (if applicable), Week 16 (end of treatment), and Week 24 (EOS). 
At all other onsite visits except Week 6, only HR and BP are required. If PK sampling is 
conducted at a visit, vital signs should be collected before PK sampling. Vital signs should be 
taken with the participant in the same position at all visits. BP should be taken via an 
automated recorder after the participant rests for at least 5 minutes. 
Vital signs will be taken prior to dosing. Refer to the Study Reference Manual for additional 
details. 
9.3.6 
Other Safety Assessments 
Refer to Section 11.2.2 for information on AE assessment and Section 7.7.2 for concomitant 
therapy assessments. 
Safety laboratory results will be assessed in an ongoing manner. A central safety laboratory 
will be used. Laboratory parameters are provided in APPENDIX 1. 
9.4 
Participant Restrictions During this Study 
The following restrictions apply for the specified times during the study period. If a 
participant does not comply with these restrictions or tests positive in any laboratory tests 
(eg, pregnancy), he or she may be excluded or withdrawn from the study. 
• Starting 72 hours prior to the first dose until the final follow-up visit, participants should 
not engage in unaccustomed intensive exercise except during protocol-specified exercise 
tests 
• Starting at Screening, participants will be required to abstain from blood or plasma 
donation until 3 months after the final study visit 
• Starting on Day 1 until the final follow-up visit, participants will be asked to abstain from 
grapefruit or grapefruit juice, Seville oranges, and quinine (eg, tonic water) 
• Contraception requirements are discussed in Section 8.2 
 


 
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9.5 
Study Procedures by Visit 
Study procedures are presented by visit in Table 1. Every effort should be made to avoid 
protocol deviations. 
At the investigator’s discretion, unscheduled visits may be conducted for the assessment of 
AEs, physical examinations, vital signs, laboratory tests, ECGs, and/or TTEs. All 
information collected from unscheduled visits will be recorded on the eCRF and included in 
the clinical database. 
9.6 
Visit Scheduling 
All visits should occur within the visit window (± 7 days). If an evaluation is missed, 
reschedule and perform it as close as possible to the original date. 


 
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10 
TREATMENT DISCONTINUATION AND WITHDRAWAL FROM 
STUDY 
In general, every effort should be made to keep a participant on double-blind treatment for as 
long as possible during the study unless a safety concern arises. Treatment discontinuation 
may either be temporary or permanent, and if treatment discontinuation is permanent, the 
degree to which a study participant withdraws can vary (see Section 10.1.4). Each of these 
circumstances is described below. 
10.1 
Treatment Discontinuation 
10.1.1 
Temporary Treatment Discontinuation 
Temporary treatment discontinuation may be considered by the investigator in the case of an 
AE/SAE or for another reason. 
As a general rule, any discontinuation of study drug should be initially considered temporary 
unless permanent treatment discontinuation is mandated by the protocol (see Section 10.1.3). 
In the case of discontinuation for an AE/SAE, the investigator should make a best effort to 
resume study drug as soon as practically possible, assuming there are no safety concerns 
(ie, the investigator is satisfied that in his or her medical judgment, the study drug is unlikely 
to be responsible for the event concerned). 
All temporary treatment interruptions should be recorded in the eCRF. 
10.1.2 
Permanent Treatment Discontinuation 
After a temporary treatment discontinuation, if a safety concern has not resolved or stabilized 
or the investigator suspects that study drug is responsible, the investigator may consider a 
treatment discontinuation as permanent. The investigator should make a best effort to contact 
the monitoring team before considering any treatment discontinuation as permanent. 
Permanent treatment discontinuation should be considered a last resort. Every effort should 
be made to collect important safety data if feasible and the study participant agrees. 
In all cases, participants should be encouraged to discuss stopping study drug with the 
investigator or the investigator’s designee so that questions can be addressed, concomitant 
therapy can be adjusted if needed, and a follow-up assessment be arranged. 
Any permanent treatment discontinuation should be recorded in the eCRF. 
10.1.3 
Criteria for Permanent Treatment Discontinuation 
The following reasons will lead to permanent treatment discontinuation: 
• Safety threshold being met (see Section 7.5) 


 
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• Pregnancy 
• New or worsening heart failure associated with systolic dysfunction 
• Any breaking of the study blind requested by the investigator 
• Continued administration of study drug is considered by the investigator to be detrimental 
to the participant’s safety or well-being 
• If all the criteria are met for possible DILI (see Section 7.4.1) 
• The participant requests to discontinue study drug 
• The Sponsor requests that the participant permanently discontinues study drug 
 
10.1.4 
Management of Participants After Permanent Treatment Discontinuation 
If a participant permanently discontinues treatment prior to Week 16 (end of treatment), the 
participant will be asked to undergo an ET visit as soon as possible after stopping study drug, 
undergoing the procedures normally planned for the Week 16 visit, including CPET. 
Subsequently, every effort will be made to have the participant return to the site at the times 
corresponding to his or her remaining scheduled visits (ie, until the end of the study at 
Week 24), or through the recovery or stabilization of any AE to be followed as specified in 
this protocol, whichever comes last. 
Under circumstances of permanent treatment discontinuation, study participants can: 
• Withdraw from treatment (permanent treatment discontinuation) and agree to participate 
in the ET and EOS visits 
• Withdraw from treatment (permanent treatment discontinuation) and agree to participate 
in the ET visit 
• Withdraw from treatment (permanent treatment discontinuation) and all follow-up (see 
Section 10.2) 
 
In case of difficulties to comply and return for all study visits through Week 24, every effort 
should be made to have the participant return for as many study visits as possible, especially 
the Week 16 visit with CPET. 
For participants who do not withdraw consent for ongoing study participation but fail to 
return to the site, the investigator should make every effort to contact the participant 
(eg, contacting participant’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, particularly vital status. 
Attempts to contact such participants must be documented in the participant’s records 


 
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(eg, number of attempts and dates of attempted telephone contact and receipt for sending a 
registered letter). 
10.2 
Withdrawal from Study 
10.2.1 
Withdrawal of Consent for Ongoing Study Participation 
Participants may withdraw from the study before study completion if they decide to do so, at 
any time and for any reason. Withdrawal of consent for treatment (permanent treatment 
discontinuation) described above should be distinguished from withdrawal of consent for 
ongoing study participation with scheduled visits and from withdrawal of consent for 
non-participant contact follow-up (eg, medical records check). 
Participants who withdraw from the study should be explicitly asked about the reason and the 
contribution of any possible AE(s) that led to their decision, and any AE information elicited 
should be documented. The participant may withdraw consent verbally or in writing. If the 
consent is withdrawn verbally, the site should document it appropriately. Preferably the 
participant should withdraw consent in writing and, if the participant or the participant’s 
representative refuses or is physically unavailable, the site should document and sign the 
reason for the participant’s failure to withdraw consent in writing. 
All study withdrawals should be recorded by the investigator in the appropriate eCRF and in 
the participant’s medical records when considered as confirmed. The date of the withdrawal 
and the reason should be documented. 
The statistical analysis plan (SAP) will specify how these participants lost to follow-up will 
be considered for their primary endpoints. 
Participants who have withdrawn from the study cannot be re-randomized (treated) in the 
study. Their inclusion and treatment numbers must not be reused. 
10.2.2 
Replacement of Participants Who Withdraw from the Study 
Participants who withdraw from the study after receiving an initial dose of treatment will not 
be replaced. If a participant withdraws after randomization and before dosing, that participant 
may be replaced. The replacement participant will undergo the same stratification procedure 
as a new participant; no special replacement randomization schedule is necessary. 


 
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11 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS 
11.1 
Definitions 
11.1.1 
Adverse Event 
An AE is any untoward medical occurrence or the deterioration of a pre-existing medical 
condition (other than the condition that is being treated by the study) associated with the use 
of a study medication in humans, whether or not it is considered related to the study 
medication. An AE (also referred to as an adverse experience) can therefore be any 
unfavorable and unintended sign (eg, tachycardia, enlarged liver, clinically important 
abnormal laboratory result or diagnostic procedure), participant-reported symptom 
(eg, nausea, chest pain), or evidence of any disease activity temporally associated with the 
use of a study medication, whether or not related to the study medication. 
In clinical studies, an AE can include an undesirable medical condition occurring at any time 
after the participant has signed informed consent, including run-in or washout periods, even 
if no specific treatment has been administered. 
Preexisting medical conditions (other than natural progression of the disease being studied) 
judged by the investigator or participant to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period will be reported as 
AEs or SAEs as appropriate. 
Imaging-based assessments of a decrease in contractility are not considered AEs unless 
associated with symptoms or signs of clinical concern on the part of the investigator. Such 
events should be categorized as an AE defined in terms of those symptoms or signs. 
An AE or SAE can also be a complication that occurs as a result of protocol-mandated 
procedures (eg, invasive procedures such as biopsies). 
For MyoKardia to collect additional information about clinically important laboratory results 
or diagnostic tests (eg, blood, ECG, imaging), at a minimum, the following abnormalities 
should be captured on the AE eCRF: 
• Any test result that meets the definition of an SAE (see Section 11.1.2) 
• Any clinically important test abnormality that suggests a disease and/or organ toxicity is 
worsening or is new (eg, > 3 × deviation from the upper or lower limit of the analyzing 
laboratory reference range, or as otherwise specified in the protocol) 
• Any test abnormality that requires the participant to have study medication discontinued 
or interrupted in the clinical judgment of the investigator 


 
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• Any test abnormality that requires the participant to receive specific corrective therapy, 
close observation, more frequent follow-up assessment, or further diagnostic 
investigation 
 
The term AE is used generally to include any AE whether serious or nonserious. 
11.1.1.1 
Events That Do Not Meet the Definition of Adverse Event 
Events that do not meet the definition of AE include the following: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
• Medical or surgical procedure (eg, endoscopy, appendectomy, device implantation): 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) 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
 
11.1.2 
Serious Adverse Event 
An SAE is an AE that fulfills one or more of the following criteria in the opinion of the 
investigator or MyoKardia: 
• Results in death 
• Is immediately life-threatening (places the participant at immediate risk of death from the 
event as it occurred) 
• Requires in-participant hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical 


 
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judgment, it may require medical or surgical intervention to prevent one of the outcomes 
listed above 
 
11.2 
Adverse Event Reporting and Descriptions 
11.2.1 
Reporting Period and Follow-up 
11.2.1.1 
Adverse Events 
AEs will be assessed from the time the participant provides informed consent through the 
duration of the study. Preexisting medical conditions that increase in severity from the first 
dose of study medication will be reported as AEs. Preexisting medical conditions that 
increase in severity after providing informed consent but before the first dose of study 
medication will be reported as medical history. 
Any AEs that are unresolved at the participant’s last visit in the study will be followed by the 
investigator until resolved or stabilized and are considered irreversible, or the participant has 
died. 
MyoKardia retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
11.2.1.2 
Serious Adverse Events 
All SAEs occurring during the treatment-emergent period (defined as the period from the 
first administration of study drug to 56 days [8 weeks] after the last administration of study 
drug) regardless of causality will be reported by the investigator or designee to MyoKardia or 
its designee within 24 hours of knowledge of the event. All follow-up information for 
previously reported SAEs will also be reported to MyoKardia or its designee within 24 hours 
of knowledge. SAEs occurring after informed consent is signed but before the first dose of 
study drug is administered will be reported as SAEs only if they are considered related to the 
protocol or study procedure. 
SAE reporting instructions are provided in the Study Reference Manual. 
11.2.1.3 
Adverse Events of Special Interest 
Overdose, pregnancy, and LVEF ≤ 30% (as determined by local site−read echocardiogram) 
are considered adverse events of special interest (AESIs). Pregnancy includes the pregnancy 
of a female participant or the pregnancy of a partner of a male participant during the study up 
to 3 months after the last dose of study drug. 
If an AESI occurs, this event must be reported to MyoKardia within 24 hours of knowledge 
of the event. A pregnancy will be followed until the final outcome, and a live birth will be 
followed for 6 months after the birth. 


 
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11.2.2 
Recording and Assessing Adverse Events 
11.2.2.1 
Description 
All AEs spontaneously reported by the participant or reported in response to the open 
question from the study personnel “Have you had any health problems since you were last 
asked?”, or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms (eg, anemia, not low hemoglobin). However, if a diagnosis is 
known and there are other signs or symptoms that are not generally part of the diagnosis, the 
diagnosis and each sign or symptom will be recorded separately. 
Death is an outcome and not the name of the event. In this situation, the event that led to the 
death is the name of the event. If the cause of death is unknown, “found dead” is an 
acceptable description. 
11.2.2.2 
Relationship to Study Treatment 
The investigator should assess causality by answering either “yes” or “no” to the question “Is 
there a reasonable possibility that the event may have been caused by the investigational 
medicinal product [IMP]/study medication?” 
The following factors can be used in consideration of causality assessment: 
• Challenge/rechallenge: Did the event abate after study medication was reduced or 
interrupted? Did the event reappear after study medication was reintroduced? 
• Temporal relationship and time to onset plausibility 
• Confounding risk factors 
• Amount and duration of study drug exposure 
• Concomitant medications 
 
11.2.2.3 
Severity 
Severity can be assessed as follows: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
• Life-threatening (urgent intervention indicated) 


 
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• Fatal (event led to death) 
 
It is important to distinguish between category (AE vs SAE) and intensity (mild, 
moderate, or severe) of AEs. 
Severity is a measure of intensity, whereas seriousness is defined by the criteria in 
Section 11.1.2. 
An AE of severe intensity need not necessarily be considered serious. For example, nausea 
that persists for several hours may be considered severe nausea but not an SAE. On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be an SAE. 
11.3 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SUSARs are SAEs that qualify for mandatory expedited reporting to regulatory authorities 
where the SAE is suspected to be caused by the study treatment and is considered unexpected 
(ie, not defined as expected in the current IB, clinical protocol, or approved labeling for 
marketed products). In this case, MyoKardia or its designee may be required per regulatory 
requirements to unblind the participant to determine treatment assignment. Only specified 
MyoKardia pharmacovigilance staff members or designees will have access to the unblinded 
information in order to meet regulatory requirements and report to the relevant regulatory 
authority(ies). A blinded report describing the SUSAR will be sent to all investigators. Each 
investigator must then notify his/her ethic committee (EC) of the blinded SUSAR as required 
by local regulatory authorities and in accordance with their EC policy. 


 
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12 
STATISTICAL METHODS 
12.1 
Determination of Sample Size 
This study will include a total of approximately 60 participants, or approximately 
20 participants per treatment group. Such a sample size will be sufficient to obtain sound 
variability estimates while yielding reasonable effect size estimates for future planning 
purposes. 
12.2 
Study Endpoints 
12.2.1 
Safety Endpoints 
• Frequency and severity of treatment-emergent AEs, AESIs, and SAEs; laboratory 
abnormalities; vital signs; and cardiac rhythm abnormalities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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12.3 
Statistical Analysis 
Before database lock, final SAPs for clinical data and PK data will be prepared that contain 
full details of all planned analyses. The analyses presented here represent an outline of the 
intended methodology. 
12.3.1 
Analysis Populations 
Four analysis populations are defined in this study: 
• Intention-to-treat (ITT) Population: all randomized participants regardless of whether 
they receive study drug, with analyses conducted according to the randomized treatment 
assignment 
• Safety Analysis Population: all randomized participants who receive at least 1 dose of 
study drug, with analyses conducted by actual treatment received 
• PK Analysis Population: all randomized participants who receive at least 1 dose of study 
drug and have at least 1 evaluable mavacamten plasma drug concentration 
• PK/PD Analysis Population: all randomized participants who receive at least 1 dose of 
study drug, have at least 1 evaluable mavacamten plasma drug concentration, and have 
post-Baseline PD data; at least one 1 post-baseline PD data point must coincide 
temporally with an evaluable mavacamten plasma drug concentration 
 
12.3.2 
General Considerations 
Descriptive summary statistics for continuous variables will include the number of 
participants, mean, standard deviation (SD) or standard error, median, minimum, and 
maximum. Nominal categorical variables will be summarized using counts and percentages. 
Ordinal variables may be analyzed as if they were continuously scaled. Confidence intervals 
at 95% and first and third quartiles may be presented as well. 


 
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12.3.3 
Participant Disposition 
The number and percentage of participants who complete and discontinue as well as reasons 
for early discontinuation will be presented. 
12.3.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. Treatment 
groups may be simultaneously compared to confirm that the randomization process generated 
3 homogeneous groups prior to treatment. 
12.3.5 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
The duration of study drug exposure is defined as last dose date – first dose date + 1 day, 
regardless of intermittent discontinuations. 
A given administration will be considered noncompliant if the participant did not take the 
planned dose of treatment as required by the protocol. No imputation will be performed for 
participants with missing or incomplete data. 
Treatment compliance and above-planned and under-planned dosing percentages will be 
summarized descriptively (number [n], mean, SD, median, minimum, and maximum). The 
participants with compliance < 80% will be fully described and summarized. In addition, 
number and percentage of participants with at least 1 dosing administration will be given, as 
well as the number and percentage of participants with 0, (0, 20%), and > 20% under-planned 
dosing administrations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
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12.3.8 
Safety Analyses 
All safety analyses will be performed on the Safety population using the following common 
rules: 
• The baseline value is defined generally as the last available value before the first 
administration of study drug 
• For quantitative safety parameters based on central laboratory measurements, descriptive 
statistics will be used to summarize results and change from baseline values by visit and 
treatment group; said changes may be presented in shift tables or scattergrams 
• The analysis of the safety variables will be descriptive and no hypothesis testing is 
planned 
 
The safety analysis will focus on the treatment-emergent period, which is defined as the time 
from the first administration of study drug to the last administration of study drug + 56 days. 


 
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12.3.8.1 
Adverse Events 
AEs will be mapped to system organ classes and preferred terms 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 (n) and percentage (%) of 
participants experiencing at least one treatment-emergent AE (TEAE) by system organ class 
(SOC) and preferred term (PT). Multiple occurrences of the same event in the same 
participant will be counted only once in the tables. The denominator for computation of 
percentages is the safety population within each treatment group. 
Adverse event incidence tables will be provided by treatment group for all types of TEAEs: 
all TEAEs, all treatment-emergent SAEs and all TEAEs leading to permanent treatment 
discontinuation. 
Potential drug-induced liver injury 
The incidence of liver-related AEs will be summarized by treatment group. The selection of 
PTs will be based on standardized MedDRA query hepatic disorder. 
Deaths 
The following deaths summaries will be generated: 
• Number and percent of participants who died by study period (TEAE, on-study) 
summarized on the safety population by treatment received 
• Death in non-randomized participants or randomized and not treated participants 
• TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
investigator) by primary SOC and PT showing number and percent of participants 
 
Pregnancy 
The following pregnancy summaries will be generated: 
• Number of participants or partners of participants who became pregnant summarized by 
treatment received 
• Outcomes of the pregnancies and analysis of the outcomes 


 
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• TEAE experienced during the pregnancy by primary SOC and PT showing the number 
and percent of participants 
 
Overdose 
The following summaries for reports of overdose will be generated: 
• Number of participants who experienced overdose summarized by treatment received 
• Analysis of the cause and occurrence of the overdose 
• TEAE experienced during the overdose by primary SOC, high-level group term, 
high-level term, and PT showing the number and percent of participants 
 
12.3.8.2 
12-lead Electrocardiogram 
The RR, PR, QRS, and QT intervals will be measured and read by a central laboratory. HR 
will be calculated as 60/(RR × 1000) (with RR expressed in msec) and rounded to the nearest 
integer. 
Correction for Heart Rate 
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. 
Each individual ECG QT value will be corrected for HR. The measured QT data will be 
corrected for HR using QTcF as per the following formulae/method (with QT, RR and QTc 
expressed in msec): 
Fridericia’s Correction: 
 
ECG Numeric Variables 
HR, PR, QRS, and QTcF will be summarized using descriptive statistics. The change from 
baseline of these ECG parameters at each time point will be listed for each participant. For 
each time point of measurement, the changes from baseline will be summarized using 
descriptive statistics. 
Categorical Analysis 
The incidence count and percentage of participants with any postdose QTcF values of 
> 450 msec, > 480 msec, and > 500 msec will be tabulated for all participants. Participants 
with QTc values > 500 msec will be listed with corresponding baseline values, ∆QTcF, and 


 
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baseline and treatment HR. The incidence count and percentage of participants with ∆QTcF 
increase from baseline of > 30 msec and > 60 msec will be tabulated. 
Morphology Findings 
New ECG morphologies for each participant not present on any ECG at baseline for that 
participant will be summarized for all observation time points combined. 
The number and percentage of participants having T-wave morphology changes and/or the 
occurrence of abnormal U-waves that represent the appearance or worsening of the 
morphological abnormality from baseline will be reported. 
Concentration-QTc Analyses 
A concentration-QTc regression analysis, based on data collected from the ECG recordings 
after drug administration and concentration values for each participant at each matching time 
point, will be performed. The concentration-ECG relationship will be first evaluated by some 
descriptive plots to investigate any potential delayed or sustained effects and explore the 
shape of the relationship. Then, linear or nonlinear models will be implemented to estimate 
the slope and 95% CI of the relationship. Predictions at selected concentration values will be 
computed within the model. 
12.3.8.3 
Laboratory Data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of 
all laboratory variables (laboratory values and changes from baseline) may be calculated for 
each visit (baseline and post-baseline time points) and presented by treatment group. 
Listings of participants with laboratory values that are out of the reference range will be 
produced. Shift tables reflecting changes from baseline may be presented in lieu of 
descriptive statistics of changes from baseline. 
Potential drug-induced liver injury 
The liver function tests, namely ALT, AST, ALP, and TBL, are used to assess possible 
drug-induced liver toxicity. 
A graph of distribution of peak values of ALT versus peak values of TBL will be presented. 
Note that the ALT and TBL values are presented on a logarithmic scale. The graph will be 
divided into 4 quadrants with a vertical line corresponding to 3 × ULN for ALT and a 
horizontal line corresponding to 2 × ULN for TBL. 
The normalization (to ≤ 1 × ULN or return to baseline if baseline > ULN) of elevated liver 
function tests will be summarized by categories of elevation (3 × ULN, 5 × ULN, 10 × ULN, 
20 × ULN for ALT and AST, 1.5 × ULN for ALP, and 1.5 × ULN and 2 × ULN for TBL), 
with the following categories of normalization: never normalized, normalized after 
permanent discontinuation of study drug. Note that a participant will be counted only under 


 
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the maximum elevation category (1-3 × ULN, 3-5 × ULN, 5-10 × ULN, 10-20 × ULN, 
> 20 × ULN). 
12.3.8.4 
Vital Signs Data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of 
all vital signs variables (values and changes from baseline) may be calculated for each visit 
(baseline and post-baseline time points) and presented by treatment group. 
Shift tables reflecting changes from baseline may be presented in lieu of descriptive statistics 
of changes from baseline. 
12.3.8.5 
Other Safety Analyses 
Abnormal physical examination results will be listed. Concomitant medications will be 
summarized. 
12.3.9 
Interim Analysis 
No interim analysis is planned. 
 
 
 
 
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13 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
13.1 
Compliance Statement 
This study will be conducted in accordance with the International Council for Harmonisation 
(ICH) GCP guidelines; US Title 21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, 
and 312; European Union GCP; cGMP; the principles enunciated in the Declaration of 
Helsinki; and all human clinical research regulations in the countries where the study is to be 
conducted. 
13.2 
Informed Consent 
The ICFs used for the study must comply with the Declaration of Helsinki, US 21 CFR 
Part 50, ICH GCP guidelines, and any other local regulations. The investigator, or a person 
delegated by the investigator, must explain the medical aspects of the study including the 
nature of the study and the treatment, orally and in writing, in such a manner that the 
potential participant is aware of potential benefits and risks. Potential participants must be 
informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. Participants, or a legal guardian if the participant is unable to, must 
give informed consent in writing. 
Prior to participation in any study-related procedures, participants must sign and date an 
EC-approved written ICF in a language the participant can understand. The informed consent 
process must be conducted, documented in the source document (including the date), and the 
form must be signed before the participant undergoes any study-specific procedures. 
The language in the written information about the study should be as nontechnical as 
practical and should be understandable to the potential participant. Before informed consent 
is obtained, the investigator should provide the potential participant ample time and 
opportunity to inquire about the study and to decide whether or not to participate. 
All questions about the study should be answered to the satisfaction of the participant. The 
written ICF should be signed and personally dated by the participant and by the person who 
conducts the informed consent discussion. All participants will receive a copy of his/her 
signed and dated ICF. 
13.3 
Ethics Committee 
The term EC used in this document refers to an Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) or equivalent. The EC must review and, if appropriate, 
approve the following documents, as applicable: 
• Study protocol and amendment(s) 
• Written ICF(s) and consent form updates 
• Participant recruitment procedures/documents (eg, advertisements) 


 
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• Written information to be provided to participants 
• IB and available safety information (Note: ECs do not approve IBs but are responsible for 
acknowledging receipt) 
• Information about payments and compensation available to participants 
 
The EC approval must be in writing, clearly identifying the study (by protocol date and/or 
version), the documents reviewed, including informed consent, and date of the review. The 
investigator has the responsibility to provide MyoKardia with the written EC approval prior 
to initiating any study-related procedures. 
The investigator also has the responsibility to inform the EC of the following according to 
the EC’s policy: 
• All SUSARs (as described in Section 11.3) 
• Any new information that may affect adversely the safety of the participants or the 
conduct of the trial 
• Protocol deviations 
• A synopsis of the study report upon study completion 
 
Documentation of subsequent reviews of the study must also be forwarded to MyoKardia. 


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


 
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14.1.3 
Investigator Training 
All clinical sites will have a center-specific study initiation meeting to ensure the center staff 
understands the protocol, study requirements and procedures, and data capture processes. 
This training will take place before the first participant is enrolled. Each clinical site will be 
provided with information regarding GCP and regulations specific to the conduct of the 
clinical studies. Each clinical site will be responsible for ensuring that new team members are 
adequately trained and the training is documented. 
14.1.4 
Ongoing Communication of Safety Information During the Study 
MyoKardia will provide the investigator(s) with documentation of SAEs from this study and 
other studies that are related to mavacamten study medication and are unexpected (refer to 
Section 11.3), as appropriate. The investigator(s) must forward this documentation to the EC 
as described in Section 11.3. 
MyoKardia will also notify the investigator(s) about any other significant safety findings that 
could alter the safety profile of the IMP from what is described in the protocol and 
significantly affect the safety of participants, affect the conduct of the study, or alter the EC’s 
opinion about the continuation of the study. 


 
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14.1.5 
Study Monitoring 
MyoKardia will monitor this clinical study through remote data checks and monitoring visits 
to check the adequacy of clinical site staff and facilities, and to ensure adherence to the 
protocol, study procedures, and applicable regulations. The clinical site monitor will also 
assess proper eCRF completion and source document retention. The investigator(s) and 
clinical site staff are expected to provide adequate space for monitoring visits and to allocate 
sufficient time to permit adequate review of the study’s progress. The investigator(s) will 
permit study-related monitoring, audits, EC review, and regulatory inspection(s), providing 
direct access to source data/documents and study-related facilities (eg, pharmacy, diagnostic 
laboratories). 
14.1.6 
Study Auditing and Inspecting 
MyoKardia may audit the study conduct, compliance with the protocol, and accuracy of the 
data in 1 or more clinical sites. 
The investigator(s)/institution(s) will permit study-related monitoring, audits and inspections 
by MyoKardia, EC, government regulatory authority(ies), and MyoKardia’s quality 
assurance personnel or its designees by providing direct access to source data/documents 
after appropriate notification from MyoKardia. 
14.2 
Investigator’s Responsibilities 
14.2.1 
Screening Log 
The investigator must keep a record that lists all participants who signed an informed consent 
and the reason for noninclusion if the potential participant does not ultimately enroll and 
receive IMP. 
14.2.2 
Study Drug Accountability 
The investigator must ensure that the study drug at the investigational site is kept secured and 
accounted for with access limited to only those individuals authorized by the investigator. 
The investigator, his/her designee, or pharmacist must also maintain adequate records of 
distribution, dispensing, and destruction of all study drug at the end of the study. The study 
drug records must be readily available for inspection by the site monitor and/or auditor. Only 
those sites with institutional, local, state, or federal restrictions in the destruction of material 
will be allowed to return study drug to the depot. No study drug can be destroyed or returned 
to depot until the clinical site monitor has verified the accuracy of the study drug records at 
the clinical site. 
14.2.3 
Reporting and Recording of Study Data 
Data will be captured and compiled using procedures developed by MyoKardia or designee. 
Electronic data capture (EDC) technology will be used for this study. Clearly record all 
requested study data on the eCRF and other forms as required. Whenever possible, record the 


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


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


 
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25Apr2006) and European Medicines Agency’s Reflection Paper on Pharmacogenomic 
Samples, Testing and Data Handling. 
14.3 
Clinical Trial Insurance 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating 
clinical sites upon request. 
14.4 
Protocol Amendments and Study Administrative Letters 
Study procedures will not be changed without the mutual agreement of the investigator and 
MyoKardia. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the 
study protocol. 
The amendment should be approved by the EC and the appropriate regulatory authority(ies), 
before implementation, as appropriate. Local requirements should be followed for revised 
protocols. 
If a protocol amendment requires a change to the ICF, the EC will need to approve the 
revised ICF before the revised form is used. 
If there are nonsubstantial changes such as clarification of statement or corrections to 
obvious errors/typos/inconsistencies in the protocol, or change to logistical or administrative 
aspects, then MyoKardia may issue an Administrative Letter. If local regulations require any 
administrative change, it will be communicated to or approved by the EC. 


 
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15 
DATA QUALITY ASSURANCE 
Quality assurance and quality control systems will be implemented and maintained per 
Standard Operating Procedures by MyoKardia, as appropriate, to ensure that this clinical 
study is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, ICH E6 GCP: consolidated guidance and the applicable 
regulatory requirements. 


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


 
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to, the protocol, eCRFs, AE reports, participant source data (original records or certified 
copies), correspondence with health authorities and EC, consent forms, investigator’s 
curriculum vitae, monitor visit logs, laboratory reference ranges and laboratory certification 
or quality control procedures, and laboratory director curriculum vitae. 
The eCRF must be completed at the time of, or shortly after the participant’s visit or upon 
receipt of test results. Information will be provided to clinical site staff on the proper way to 
complete the eCRF. 
A copy of each participant’s eCRF will be maintained by the investigator. 


 
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17 
PUBLICATION 
The data and results of the study will be owned solely by MyoKardia and shall be 
confidential information of MyoKardia, participant to the investigator’s publication rights, all 
as outlined in the agreement between the investigator/institution and MyoKardia regarding 
the conduct of the clinical study (the “Clinical Study Agreement”). It is understood by the 
investigator that MyoKardia may use the information developed in this study in connection 
with the development of MyoKardia’s proprietary IMP and, therefore, may disclose such 
information as necessary or useful to other clinical investigators or regulatory agencies. To 
allow for the use of the information derived from the study, the investigator understands that 
he/she has an obligation to provide and disclose all study results and all data developed 
during this study to MyoKardia. 
Any publication or presentation of the results or data of this clinical study by the investigator 
may only be made in strict compliance with the provision of the Clinical Study Agreement. 
The investigator understands that it is not MyoKardia’s intention to prevent publication of 
the data generated in the study; rather, MyoKardia reserves the right to control the form and 
timing of such publication for commercial reasons and desires to confirm the scientific 
accuracy of such information prior to such publication or presentation.


 
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APPENDIX 1 
LABORATORY ASSESSMENTS 
The following safety laboratory parameters will be measured by the central laboratory: 
Hematology/Coagulation 
Serum Chemistry 
Urinalysisa 
• CBC, including differential 
count 
• Sodium 
• Specific gravity 
• Potassium 
• pH 
• Platelet count 
• Chloride 
• Protein 
• INR 
• Bicarbonate 
• Glucose 
• aPTT 
• Calcium 
• Leukocyte esterase 
 
• Magnesium 
• Blood 
 
• BUN 
 
 
• Creatinine 
 
 
• ALP 
 
 
• ALT 
 
 
• AST 
 
 
• Total bilirubin 
 
 
• CPKb 
 
 
• Glucose 
 
 
• Protein 
 
 
• Albumin 
 
ALT, alanine aminotransferase; ALP, alkaline phosphatase; aPTT, activated partial thromboplastin time; 
AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; CPK, creatine 
phosphokinase; INR, international normalized ratio. 
a 
Urine microscopy will be performed if there is a significant abnormality in the dipstick. 
b 
If CPK is high, troponin I will be performed and reported. 
 
At the investigator’s discretion, safety laboratory assessments may be repeated on Day -1 to 
confirm study eligibility before dosing of study medication. 
The following nonsafety laboratory parameters will be measured at Screening: 
• Hepatitis panel (hepatitis B virus and hepatitis C virus) 
• Human immunodeficiency virus test 
• Follicle-stimulating hormone 
• Thyroid-stimulating hormone 


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


 
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• Obtain appropriate blood sampling for pharmacokinetic (PK) analysis if it has not already 
been collected. 
• Obtain a more detailed history of the following: 
◦ 
Prior and/or concurrent diseases or illness 
◦ 
Exposure to environmental and/or industrial chemical agents 
◦ 
Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-type 
reactions, fatigue, nausea, vomiting, and fever 
◦ 
Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
◦ 
Concomitant medications (including nonprescription medicines and herbal and 
dietary supplements) 
• Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A, B, C, 
D, E, Epstein-Barr virus, herpes simplex virus, etc.); evaluate for other potential causes of 
DILI, including but not limited to non-alcoholic steatohepatitis, hypoxic/ischemic 
hepatopathy, and biliary tract disease. 
• Obtain gastroenterology or hepatology consult. 
• Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider 
these tests in cases of concurrent transaminase and TBL elevation as specified in 
Section 7.4. 
• Follow the participant until all laboratory abnormalities return to baseline or normal. The 
“close observation period” is to continue for a minimum of 4 weeks after investigational 
product(s) or protocol-required therapies discontinuation. 
 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding eCRFs. 


 
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APPENDIX 4 
INVESTIGATOR’S SIGNATURE 
I have read and understood the contents of the clinical protocol, MYK-461-006, A 
Randomized, Double-blind, Placebo-controlled, Concentration-guided, Exploratory Study of 
Mavacamten (MYK-461) in Patients with Symptomatic Non-obstructive Hypertrophic 
Cardiomyopathy (nHCM) and Preserved Left Ventricular Ejection Fraction, and I agree to 
the following: 
• To assume responsibility for the proper conduct of this clinical study at this clinical site 
and to conduct the study in compliance with this protocol, any future amendments and 
with any other study conduct procedures provided by MyoKardia/designee. 
• That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practices (GCP) and all other applicable regulatory requirements to obtain 
written and dated approval for the Ethics Committee (EC; eg, Institutional or Central 
Review Board [IRB] or Independent Ethics Committee [IEC]) for the study protocol, 
written informed consents, consent form updates, study participant recruitment 
procedures and any other written information to be provided to the study participants 
before initiating this clinical study. 
• Not to implement any changes to, or deviations from the protocol without prior 
agreement from MyoKardia and review and documented approval from the EC, except to 
eliminate an immediate hazard to the study participants, or when change(s) involves only 
logistical or administrative aspects of the clinical study. 
• To permit direct monitoring and auditing by MyoKardia or MyoKardia’s representatives 
and inspection by the appropriate regulatory authority(ies). 
• That I am thoroughly familiar with the appropriate use of the Investigational Medicinal 
Product (IMP) and other study medication(s) (if applicable), as described in this protocol, 
and any other information provided by MyoKardia or designee, including, but not limited 
to the current Investigator’s Brochure (IB) or equivalent document and marketed 
prescription information (if applicable). 
• To provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically and safely. 
• To ensure that all persons assisting in this study are adequately informed about the 
protocol, IMP/study medication(s) and their clinical study-related duties and functions. 
 
 
Signed: ____________________________________ 
Date: ___________________ 
(sign name with credentials) 
Printed Name: ______________________________ 

SAP_001.pdf: 
 
 
 
 
 
Cover Page for Statistical Analysis Plan 
 
Sponsor Name: MyoKardia, Inc. 
NCT Number: NCT03442764 
Sponsor Trial ID: MYK-461-006 (MAVERICK-HCM) 
Study Title: A Randomized, Double-blind, Placebo-controlled, Concentration-guided, 
Exploratory Study of Mavacamten (MYK-461) in Patients with Symptomatic Non-Obstructive 
Hypertrophic Cardiomyopathy (nHCM) and Preserved Left Ventricular Ejection Fraction 
Document Description: Statistical Analysis Plan (Version 1.0) 
Document Date: 28 August 2019 


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STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
MYK-461-006 (MAVERICK-HCM) 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, 
Concentration-guided, Exploratory Study of Mavacamten 
(MYK-461) in Patients with Symptomatic Non-obstructive 
Hypertrophic Cardiomyopathy (nHCM) and Preserved Left 
Ventricular Ejection Fraction 
Indication: 
Hypertrophic Cardiomyopathy 
Phase: 
2 
Investigational 
Medicinal Product: 
Mavacamten (MYK-461) 
Sponsor: 
MyoKardia, Inc. 
 
 
Protocol Version 
Date 
Amendment 1 
April 4, 2018 
SAP Version  
Date 
Version 1.0 
August 28, 2019 
Author 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains trade secrets or otherwise confidential and/or proprietary information of 
MyoKardia, Inc. Access to and use of this information is strictly limited and controlled by 
MyoKardia, Inc. Acceptance of this document constitutes agreement by the recipient that the contents 
will be not be copied, distributed, or otherwise disclosed to third parties, and will not be used in any 
way, except as expressly authorized by MyoKardia, Inc. 
 
 




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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................5 
 
 
2. 
STUDY OBJECTIVES ................................................................................................8 
2.1. 
Primary Objective .........................................................................................................8 
 
 
 
 
3. 
OVERALL STUDY DESIGN AND PLAN .................................................................9 
3.1. 
Study Duration ............................................................................................................10 
3.2. 
Independent Data Monitoring Committee ..................................................................10 
3.3. 
Treatment Withholding and Discontinuation .............................................................10 
4. 
RANDOMIZATION AND BLINDING PROCEDURES .........................................10 
4.1. 
Randomization ............................................................................................................10 
4.2. 
Study Blinding ............................................................................................................10 
4.3. 
Methods for Unblinding .............................................................................................11 
5. 
DETERMINATION OF SAMPLE SIZE ...................................................................11 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................11 
6.1. 
Study Endpoints ..........................................................................................................13 
6.2. 
Analysis Populations ..................................................................................................14 
6.3. 
Covariates and Subgroups ..........................................................................................14 
6.4. 
Missing data ................................................................................................................15 
6.5. 
Multiplicity Control ....................................................................................................15 
7. 
SUBJECT DISPOSITION ..........................................................................................16 
7.1. 
Demographics and Baseline Characteristics ...............................................................16 
7.2. 
Extent of Study Treatment Exposure and Compliance ...............................................16 
7.3. 
Protocol Deviations ....................................................................................................16 
 
 
 
 
 
 
 
 
 
 


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13. 
SAFETY ANALYSES ...............................................................................................24 
13.1. 
Adverse Events ...........................................................................................................24 
13.2. 
12-lead Electrocardiogram ..........................................................................................25 
13.3. 
Safety Laboratory Data ...............................................................................................26 
13.4. 
Vital Signs Data ..........................................................................................................27 
13.5. 
Cardiac Rhythm Monitoring (including Holter Monitor) ...........................................27 
13.6. 
Other Safety Analyses ................................................................................................27 
 
 
15. 
INTERIM ANALYSIS ...............................................................................................27 
16. 
SUMMARY OF CHANGES FROM PROTOCOL DEFINED ANALYSES ...........28 
 
 
APPENDIX A. ...............................................................................................................................31 
 
 


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LIST OF ABBREVIATIONS 
A 
peak velocity of late transmitral flow 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CI 
confidence interval 
CPET 
cardiopulmonary exercise test or testing 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
E 
peak velocity of early diastolic transmitral flow 
eꞌ 
peak velocity of early diastolic septal and lateral mitral annular motion 
EC 
ethics committee; refers to an IRB or IEC or equivalent 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
 
EOS 
end of study 
ET 
early termination 
FDA 
The United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HCM 
hypertrophic cardiomyopathy 
 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICD 
implantable cardioverter-defibrillator 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 


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IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IXRS 
interactive response system 
 
LLOQ 
lower limit of quantification 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
LVOT 
left ventricular outflow tract 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
nHCM 
non-obstructive hypertrophic cardiomyopathy 
NSVT 
non-sustained ventricular tachycardia 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
oHCM 
obstructive hypertrophic cardiomyopathy 
PD 
pharmacodynamic(s) 
 
 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcomes 
PT 
preferred term 
QD 
once daily 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SRT 
septal reduction therapy 
SUSAR 
suspected unexpected serious adverse reactions 


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TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
TTE 
transthoracic echocardiography, transthoracic echocardiogram 
ULN 
upper limit of normal 
US 
United States 
VCO2 
carbon dioxide production 
VE 
volume expired 
VO2 
oxygen uptake 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of a 16-week course 
of mavacamten in individuals with symptomatic nHCM. 
 
 
 
 
 
 
 
 
 


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3. 
OVERALL STUDY DESIGN AND PLAN 
This is a Phase 2, multicenter, exploratory, randomized, double-blind study to evaluate the 
safety, tolerability, preliminary efficacy, PD, and PK of 2 target drug concentrations of 
mavacamten compared with placebo in patients with symptomatic nHCM.  
Approximately 60 patients with symptomatic nHCM will be enrolled. Patients will be 
randomized in a 1:1:1 ratio to receive a 16-week course of mavacamten doses titrated to achieve 
1 of 2 target drug concentrations (Group 1: ~200 ng/mL; Group 2: ~500 ng/mL) or placebo once 
daily (QD). Randomization will be stratified according to current treatment with beta blocker 
(yes or no) and type of exercise testing (treadmill or bicycle). Patients will be treated for 
16 weeks and then followed up approximately 8 weeks after the last dose of study drug. At 
Week 6, all patients will undergo blinded dose adjustment based on Week 4 assessments. 
Patients who are treated for their HCM condition (eg, beta blocker or calcium channel blocker) 
should receive a stable dose of such treatment for at least 2 weeks prior to Screening, and every 
effort should be made to keep such treatment unchanged (ie, at the same dose) throughout the 
entire study duration until the EOS visit at Week 24. 
During the Screening process, patients will undergo a variety of general, cardiopulmonary, 
laboratory, exploratory biomarker, patient-reported outcomes (PRO), and symptom assessments. 
Patients will receive their first dose of study drug on Day 1. Patients will then undergo a variety 
of assessments every 2 weeks through Week 16. Assessments will be conducted at the clinical 
site at Weeks 4, 6, 8, 12, and 16; assessments will be conducted via telephone call at Weeks 2, 
10, and 14. At Week 24, patients will undergo EOS procedures. 
PRO questionnaires will be completed either on paper or on an electronic device provided to 
each patient during the Screening period or on an app installed on the patient’s own electronic 
device.  
 
 
 
 


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3.1. 
Study Duration 
The expected study duration is approximately 28 weeks: up to 4 weeks for Screening and 
16 weeks (± 7 days) for study conduct, and 8-week posttreatment follow-up period. 
3.2. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will meet at regular intervals to review 
study data. The role of the IDMC will be to act in an advisory capacity to the Sponsor with 
respect to safeguarding the interest of study patients, assessing interim safety data, and advising 
the Sponsor and investigators on important emerging study conduct issues. The IDMC may 
formulate recommendations in relation to the evaluation procedures and methodologies being 
employed to survey and detect potential safety signals. Meeting frequency and membership is 
described in the IDMC Charter. 
3.3. 
Treatment Withholding and Discontinuation 
Patients with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL], or international 
normalized ratio) or signs/symptoms of hepatitis may meet the criteria for withholding of study 
medication or other protocol-required therapies. Withholding is either permanent or conditional 
depending on the clinical circumstances discussed in the protocol. 
Patients with exaggerated pharmacologic effect (systolic dysfunction), higher than expected 
plasma concentration, or excessive QT prolongation, may discontinue study treatment as 
described in the protocol  
4. 
RANDOMIZATION AND BLINDING PROCEDURES 
4.1. 
Randomization 
Patients who meet the inclusion/exclusion criteria will be randomized via an IXRS to 1 of 3 
groups in a 1:1:1 ratio: 2 active treatment groups and 1 matching placebo group. Randomization 
will be stratified according to current treatment with beta blocker (yes or no) and type of exercise 
testing (treadmill or bicycle). 
4.2. 
Study Blinding 
Patients will be randomized to 1 of 3 groups via the IXRS. All patients receive either 5 mg 
mavacamten or matching placebo daily from Day 1 to Week 6. Blinded dose adjustment (to 2.5, 


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5, 10, or 15 mg mavacamten or placebo daily) via the IXRS will begin at Week 6 based on PK 
measurements at Week 4. Study drug administration will occur in a double-blind manner via the 
IXRS such that the investigator, site staff, the pharmacist, and the patient will not know which 
study drug is being administered. 
In addition, the Sponsor, the central and core laboratories, and clinical site monitors will be 
blinded to assigned treatment. Echocardiography results (eg, LVEF) performed at clinic visits 
will be blinded to the investigator and study staff. The 4 different doses of mavacamten and 
matching placebo will be identical in appearance in order to preserve the blind. Study drug (2.5, 
5, 10, or 15 mg mavacamten or matching placebo) will be labeled with a unique identifying 
number that will be assigned to a patient through the IXRS. 
Members of the pharmacovigilance team will be unblinded for suspected unexpected serious 
adverse reaction (SUSAR) reporting. The IDMC may also review unblinded safety and efficacy 
data. 
4.3. 
Methods for Unblinding 
Unblinding by the investigator independently of the Sponsor also may occur if an AE or toxicity 
necessitates identification of the medication for the welfare of the patient. Please refer to the 
IXRS Manual for the unblinding process. 
5. 
DETERMINATION OF SAMPLE SIZE 
This study will include a total of approximately 60 patients, or approximately 20 patients per 
treatment group. Such a sample size will be sufficient to obtain sound variability estimates while 
yielding reasonable effect size estimates for future planning purposes. 
6. 
GENERAL STATISTICAL CONSIDERATIONS 
The primary analysis will be conducted through the 16-week treatment period. Data collected 
through this timepoint will be cleaned and locked prior to analysis.  
Once all subjects have completed their Week 24/EOS visit, all data will be cleaned and locked, 
and analyses using this data will be used to inform study objectives relating to follow-up safety 
and reversibility of drug effect.  
SAS® version 9.4 or higher will be used for statistical analyses, tabulations and graphical 
presentations. 
In general, descriptive summaries will be presented by treatment group [placebo, Group 1, Group 
2, and overall active]. Summaries of continuous variables will utilize the number of subjects (N), 
mean, standard deviation (SD), median, minimum and maximum. Descriptive summaries for 
categorical variables will utilize counts and percentages.  Unless otherwise stated, denominators 
for percentages will be the number of patients in the analysis population with non-missing 
variable of interest for the column of interest.   
The between-group comparisons focus on the comparative performance of Group 1 (target 
concentration of ~200 ng/mL) vs placebo and Group 2 (target concentration of ~500 ng/mL) vs 


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placebo. An overall active vs placebo comparison will also be conducted where appropriate. Any 
statistical test will be conducted at a two-sided significance level of 0.05 using the exact method 
unless otherwise stated. 
In general, baseline is defined as the last non-missing result on or before the first dose date, and 
time where applicable. For certain data types (e.g., accelerometer, PROs, cardiac rhythm 
monitoring, etc.), special considerations may be required; please refer to the specific data section 
for details. Unless otherwise noted, non-safety (ie. efficacy, PD) information displayed “by visit” 
will utilize analysis visits as defined by the analysis visit window as opposed to the visits at 
which the information was collected (ie. nominal visit).  Data collected at unscheduled or early 
termination visits will also be mapped to analysis visits. The analysis day for purposes of the 
visit windows are derived as follows (reference date is the study drug initiation date for the 
safety population or the randomization date for the ITT population):  
 If date of information is missing, analysis day cannot be calculated and leave as 
missing  
 If date of information < reference date, analysis day = analysis date – reference date.  
If date of information >= reference date, analysis day = (analysis date – reference 
date) + 1  
Safety information will be summarized by the nominal visit (per protocol), and unscheduled 
visits will be presented in listings only.   
The visit windows for efficacy and PD assessments will be as follows, unless otherwise noted in 
the specific data sections below: 
Table 1: 
Analysis Windows 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Day 1 (Baseline*) 
Screening <= analysis day <=1 
1 
Week 4 
15 < analysis day <= 42  
28 
Week 8 
43 <= analysis day <= 70 
56 
Week 12 
71 <= analysis day <= 98 
84 
Week 16 
99 <= analysis day <= 126 
112 
Week 24 
155 <= analysis day <= 182 
168 
Note: CPET only collected on Day 1 and Week 16. 
* Per the baseline definition in this section. 
 
When more than one result is available within the same analysis visit, the result collected closest 
to the target visit day will be used for analysis. If two values tie as closest to the time point (for 
example, one value is before and the other value is after the target day), then the latest value will 
be selected as the analysis value. If for a specific analysis window, the last collected time point 
has 2 or more values collected, for continuous and ordinal (scale) data, the average among these 
results will be derived. If the data are categorical (eg, Yes/No) then the clinically ‘worse’ 
measurement will be affiliated with the visit of interest.  


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If a measurement does not fall into an analysis window it will not be included in efficacy 
summary. However, these measurements will be included in data listings and SAS data sets. 
6.1. 
Study Endpoints 
Safety Endpoints: 
 Frequency and severity of treatment-emergent AEs, AEs of special interest, and SAEs  
 Frequency of laboratory abnormalities  
 Change from baseline vital signs  
 Frequency of cardiac rhythm abnormalities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2. 
Analysis Populations 
Four analysis populations are defined in this study: 
 Intention-to-treat (ITT) Population: all randomized subjects regardless of whether 
they receive study drug, with analyses conducted according to the randomized 
treatment assignment 
 Safety Analysis Population: all randomized subjects who receive at least 1 dose of 
study drug, with analyses conducted by actual treatment received 
 PK Analysis Population: all randomized subjects who receive at least 1 dose of study 
 
 
 
 
 
 
6.3. 
Covariates and Subgroups 
The study is not adequately powered to detect treatment differences in any subgroup analysis.  
Any subgroup analyses performed will be considered exploratory.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4. 
Missing Data 
In general, no imputation of missing data will be done in the study unless specifically stated in 
this SAP.  For mixed model repeated measure analyses, missing data are handled by the model 
implicitly.  For responder analyses, if the patient’s responder status cannot be determined due to 
missing data, the patient will be treated as non-responder.  For other analyses, missing data will 
not be included in the analyses.   
Handling of Missing Data: 
 In general, missing result values will not be imputed unless otherwise specified. 
 For values below the lower limit of quantitation (LLOQ), 1/2 of LLOQ will be 
imputed unless otherwise specified.  
 In general, for missing or partial dates the following noted: 
o Start Dates: 
 If day is missing, then impute it to be the start of the month (e.g., 
01MMMYYYY), except if the month and year is equal to the first dose 
date month and year then impute the day to be the same day as the first 
dose date. 
 If month is missing, then impute it to be the start of the year (e.g., 
01JANYYYY), except if the year is equal to the first dose date year then 
impute the day and month to be the same as the first dose date. 
 If year is missing, then do not impute. 
o End Dates: 
 If day is missing, then impute it to be the end of the month (e.g., 
31MMMYYYY), except if the month and year is equal to the last 
assessment date month and year then the day should be imputed to the last 
assessment date day.   
 If month is missing, then impute it to be the end of the year (e.g., 
31DECYYYY), except if the year is equal to the last assessment date year 
then the day and month should be imputed to the last assessment date day 
and month.   
 If year is missing, then do not impute. 
6.5. 
Multiplicity Control 
Due to the exploratory nature of the study, multiplicity adjustment is not planned. 


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7. 
SUBJECT DISPOSITION 
The number and percentage of subjects who complete and discontinue the treatment and study as 
well as reasons for early discontinuation will be summarized by randomized treatment 
assignment using the ITT population. 
7.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by randomized 
treatment assignment using the ITT population.  
Body surface area (BSA) will be derived using the Du Bois method.  
CYP2C19 genotypes and phenotypes will be summarized as part of the baseline characteristics 
summary table and listing. 
7.2. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received 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. 
Compliance will be calculated based on the total cumulative dose received divided by the total 
planned cumulative dose. Imputation will be performed for subjects with missing or incomplete 
data. 
Treatment compliance and above-planned and under-planned dosing percentages will be 
summarized descriptively (number [n], mean, SD, median, minimum, and maximum). The 
subjects with compliance < 80% will be fully described and summarized. In addition, number 
and percentage of subjects with at least 1 dosing administration will be given, as well as the 
number and percentage of subjects with 0, 0 to 20%, and greater than 20% under-planned dosing 
administrations. 
Actual dose adjustments that occurred in the study and expected dose adjustments based on the 
criteria per protocol will be listed by subject and timepoint. Any inconsistencies will be flagged. 
7.3. 
Protocol Deviations 
Prior to database lock, all protocol deviations will be reviewed and confirmed by the Sponsor. 
All protocol deviations will be presented in a by-subject data listing. Important Protocol 
Deviations (IPD) (ie. CSR Reportable PDs) will be identified by the Sponsor and summarized in 
table.  ICH E3 defines important protocol deviations as a subset of protocol deviations that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject’s rights, safety, or well-being.   
 
 
 
 


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13. 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety population using the following common 
rules: 
 The baseline value is defined generally as the last available value before the first 
administration of study drug 
 The analysis of the safety variables will be descriptive, and no hypothesis testing is 
planned 
 The safety analysis will focus on the treatment-emergent period, which is defined as 
the time from the first administration of study drug to the last administration of study 
drug + 56 days. 
13.1. 
Adverse Events 
AEs will be mapped to system organ classes and preferred terms using the Medical Dictionary 
for Regulatory Activities (MedDRA v21.0). AEs will be monitored during the study and the data 
analyzed with respect to overall incidence as well as severity and potential relationship of AEs to 
study 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 (n) and percentage (%) of subjects 
experiencing at least one treatment-emergent AE (TEAE) by system organ class (SOC) and 
preferred term (PT). Multiple occurrences of the same event in the same patient will be counted 
only once in the tables. The denominator for computation of percentages is the safety population 
within each treatment group.  In addition, the adverse event incident table will also be presented 
by SOC, PT, and severity grade.  When there are multiple occurrences of the same event in the 
same patient, only the most severe one will be included in the tables.  
Adverse event incidence tables will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment-emergent serious AEs, drug related AEs, AEs of Special Interest (AESI; 
per protocol), all TEAEs leading to permanent treatment discontinuation, and all TEAEs leading 
to death.  
AE may also be summarized by Standardised MedDRA Queries (SMQs) deemed relevant based 
on AESIs and SAEs observed in the study. 
A by-subject listing of all AEs, SAEs, and TEAEs leading to treatment discontinuation will also 
be provided.   


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Deaths 
The following deaths summaries will be generated in a summary table and listed in a by-subject 
data listing: 
 Number and percent of subjects who died by study period (TEAE, on-study) 
summarized on the safety population by treatment received 
 Death in non-randomized subjects or randomized and not treated subjects 
 TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
investigator) by primary SOC and PT showing number and percent of subjects 
Pregnancy 
The following pregnancy information will be provided in a by-subject data listing: 
 Number of subjects or partners of subjects who became pregnant summarized by 
treatment received 
 Outcomes of the pregnancies and analysis of the outcomes 
 TEAE experienced during the pregnancy by primary SOC and PT showing the 
number and percent of subjects 
Overdose 
If overdoses occur, the following overdose information will be provided in a by-subject data 
listing: 
 Number of subjects who experienced overdose summarized by treatment received 
 Analysis of the cause and occurrence of the overdose 
 TEAE, if any, experienced during the overdose by primary SOC, high-level group 
term, high-level term, and PT showing the number and percent of subjects 
13.2. 
12-lead Electrocardiogram 
The RR, PR, QRS, and QT intervals will be measured and read by a central laboratory. HR will 
be calculated as 60/(RR × 1000) (with RR expressed in msec) and rounded to the nearest integer. 
Correction for Heart Rate 
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. Each 
individual ECG QT value will be corrected for HR. The measured QT data will be corrected for 
HR using QTcF as per the following formulae/method (with QT, RR and QTc expressed in 
msec): 
Fridericia’s Correction: 
 


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ECG Numeric Variables 
HR, PR, QRS, and QTcF will be summarized using descriptive statistics. The change from 
baseline of these ECG parameters at each time point will be listed for each patient. For each time 
point of measurement, the changes from baseline will be summarized using descriptive statistics. 
Categorical Analysis 
The incidence count and percentage of subjects with any postdose QTcF values of > 450 msec, 
> 480 msec, and > 500 msec will be tabulated for all subjects. Subjects with QTc values 
> 500 msec will be listed with corresponding baseline values, QTcF, and baseline and treatment 
HR. The incidence count and percentage of subjects with QTcF increase from baseline of 
> 30 msec and > 60 msec will be tabulated. 
Morphology Findings 
ECG morphologies for each patient will be listed. 
Concentration-QTc Analyses 
The concentration-QTc relationship will first be evaluated by a scatterplot of time-matched 
QTcF and concentration data to investigate any potential delayed or sustained effects and to 
explore the shape of the relationship. Linear or nonlinear mixed models may then be applied, if 
appropriate, to estimate the slope and 95% CI of the concentration-QTc relationship. For linear 
mixed effects models, concentration and sex will be included as fixed effects, subject as random 
effect, and compound symmetry will be implemented for the variance-covariance structure.   
13.3. 
Safety Laboratory Data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
safety laboratory tests (ie. hematology and chemistry panels) will be calculated for each visit 
(baseline and post-baseline time points) and presented by treatment group. 
Shift tables reflecting changes from baseline (i.e., normal to low, high, etc.) will be presented in 
lieu of descriptive statistics of changes from baseline. Listings of subjects 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 (alkaline phosphatase), and TBL (total 
bilirubin), will be 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 of subjects with elevated liver function tests will be summarized in a table by 
categories of elevation (3 × ULN, 5 × ULN, 10 × ULN, 20 × ULN for ALT and AST, 1.5 × ULN 
for ALP, and 1.5 × ULN and 2 × ULN for TBL), along with the following categories of 
normalization (to ≤ 1 × ULN or return to baseline if baseline > ULN): never normalized, 


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normalized after permanent discontinuation of study drug. Note that a patient will be counted 
only under the maximum elevation category (1-3 × ULN, 3-5 × ULN, 5-10 × ULN, 10-
20 × ULN, > 20 × ULN).  
If identified, the number of subjects with concurrent ALT/AST of 3 x ULN or higher, TBL of 2 x 
ULN or higher, and ALP below 2 x ULN (possible Hy’s Law cases) will also be summarized in 
this table and included in a by-subject listing as well.  
13.4. 
Vital Signs Data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
vital signs variables (values and changes from baseline) will be calculated for each visit (baseline 
and post-baseline time points) and presented by treatment group. 
Shift tables reflecting changes from baseline may be presented in lieu of descriptive statistics of 
changes from baseline. 
13.5. 
Cardiac Rhythm Monitoring (including Holter Monitor) 
The summary statistics (including mean, median, SD, minimum and maximum) of atrial 
fibrillation (AF), nonsustained ventricular tachycardia (NSVT) will be calculated for each visit 
(baseline and post-baseline time points) and presented by treatment group. For each cardiac 
event type, the number of subjects with at least one occurrence, the number of episodes per 
subject per day, and the duration of each episode will also be summarized. Additional parameters 
may be summarized as appropriate.  
13.6. 
Other Safety Analyses 
Abnormal physical examination results will be listed by subject, and clinical significance. 
Medical history, concomitant, and prior medications will be summarized in tables and listings.  
HCM history, including frequency of SRT (septal reduction therapy) will be summarized in a 
separate table by treatment and overall. 
The number of subjects who met each IMP stopping criteria per protocol will be summarized by 
treatment and overall. 
 
 
 
 
 
 
 
  
15. 
INTERIM ANALYSIS 
No interim analysis is planned. 


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16. 
SUMMARY OF CHANGES FROM PROTOCOL DEFINED 
ANALYSES 
 
 


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Biophysical J. 2012;102(3 suppl 1):613a-614a. Available at: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A.  
Figure 1: 
Study Schema 
 
Abbreviations: CPET, cardiopulmonary exercise testing; EOS, end of study; NT-proBNP, N-terminal pro b-type 
natriuretic peptide; PK, pharmacokinetic blood sample taken; QD, once daily; stress echo, stress echocardiography; 
TTE, transthoracic echocardiogram.


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Table 1: Schedule of Study Procedures 
Assessmenta 
Screeningb 
Day -28 to 
Day -1 
Day 
1 
Week 2 
(telephone 
call)c 
Week 
4c 
Week 
6c 
Week 
8c 
Week 10 
(telephone 
call)c 
Week 
12c 
Week 14 
(telephone 
call)c 
Week 
16c/ET 
Week 
24c/EOS 
General Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical historyd 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
AEsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ICD information downloadedf 
X 
 
 
 
 
 
 
 
 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination including 
height and weightg 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
ECGh 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Resting TTEi 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Post-exercise stress 
echocardiographyj 
X 
 
 
 
 
 
 
 
 
 
 
CPETk 
 
X 
 
 
 
 
 
 
 
X 
 
Accelerometer attachedl 
X 
 
 
 
 
 
 
X 
 
 
 
Apply cardiac monitoring skin 
patchm 
X 
 
 
 
 
 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Laboratory 
Hepatitis panel, HIV test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Coagulation panel 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 


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Table 1: Schedule of Study Procedures (cont’d) 
Assessmenta 
Screeningb 
Day -28 to 
Day -1 
Day 
1 
Week 2 
(telephone 
call)c 
Week 
4c 
Week 
6c 
Week 
8c 
Week 10 
(telephone 
call)c 
Week 
12c 
Week 14 
(telephone 
call)c 
Week 
16c/ET 
Week 
24c/EOS 
Laboratory (continued) 
Chemistry 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
X 
hs-cardiac troponin I 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
NT-proBNPo 
Xo 
Xo 
 
X 
 
X 
 
X 
 
Xo 
X 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
FSHp /Serum pregnancy test 
(women)q 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)q 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Symptom Assessments 
NYHA class 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
PRO Assessments 
KCCQ, EQ-5D 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Xv 
 
 
 
 
 
Xw 
 
Xw 
Xw 
Xw 
 
Xx 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Footnotes and abbreviations are defined on last page of table.  


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Table 1: Schedule of Study Procedures (cont’d) 
Assessmenta 
Screeningb 
Day -28 to 
Day -1 
Day 
1 
Week 2c 
(telephone 
call) 
Week 
4c 
Week 
6c 
Week 
8c 
Week 10 
(telephone 
call)c 
Week 
12c 
Week 14 
(telephone 
call)c 
Week 
16c/ET 
Week 
24c/EOS 
Investigational Medical Product 
IMP QD 
 
 
 
 
 
 
 
 
 
 
 
IMP administered at site 
 
X 
 
 
 
 
 
 
 
X 
 
IMP compliancey 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Abbreviations: AE, adverse event; BP, blood pressure; CPET, cardiopulmonary exercise testing; DNA, deoxyribonucleic acid; ECG, electrocardiogram; 
eCRF, electronic case report form; EOS, end of study; EQ-5D, Eu
; ET, early termination; FSH, follicle-stimulating hormone; 
HCM, hypertrophic cardiomyopathy; 
 HIV, human immunodeficiency virus; HR, heart rate; 
hs, high-sensitivity; ICD, implantable cardioverter-defibrillator; ICF, informed consent form; IMP, investigational medicinal product; 
 
 LVOT, left ventricular outflow tract; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart 
Association; 
e; PK, pharmacokinetic; 
PRO, patient-reported outcomes; QD, once daily; TSH, thyroid-stimulating hormone; TTE, transthoracic echocardiography. 
a 
Preferred order of assessments is symptom questionnaires; the following 3 assessments in any order: ECG, vital signs, and TTE; pre-exercise blood draws; 
exercise test; and post-exercise blood draws. 
b 
Screening may require more than 1 visit to accommodate all of the study procedures. 
c 
All postDay 1 study visits have a window of ± 7 days. At Weeks 2, 10, and 14, patients will be contacted by telephone to collect AE and concomitant 
medication data. 
d 
Changes in baseline conditions from once the ICF is signed are recorded on the medical history eCRF unless the change is related to a study procedure, 
which is then considered an AE. All changes that occur after the administration of the IMP are recorded as AEs.  
e 
At Screening, ET (if applicable), Week 16 (end of treatment), and Week 24 (end of study), complete vital signs including temperature, HR, respiratory rate, 
and BP will be obtained. At all other onsite visits except Week 6, only HR and BP are required. If PK sampling is conducted at a visit, vital signs should be 
collected before PK sampling. Vital signs should be taken with the patient in the same position at all visits. BP should be taken via an automated recorder 
after the patient rests for at least 5 minutes. 
f 
For patients who have ICDs, information including rhythm strips and events will be downloaded from the ICDs. 
g 
At Screening, Week 16, and Week 24, a complete physical examination will be conducted, including a neurological examination. At Week 4, Week 8, and 
Week 12, an abbreviated cardiopulmonary physical examination will be conducted, with other systems assessed as directed by interval history. Physical 
examinations will also include height (at Screening only) and weight (at all onsite visits at which a physical examination is performed). 
h 
12-lead ECGs will be performed at Screening and all onsite visits except for the Week 6 visit after 10 minutes of rest. Each time an ECG is completed, a 
10-second paper ECG will be obtained and maintained in the study patient’s source documentation. On Day 1, an ECG will be performed predose. 
i 
Resting TTE should be performed prior to post-exercise stress echocardiography or CPET. Instantaneous peak LVOT gradient at rest and provoked peak 
LVOT gradient (Valsalva maneuver) will be assessed only at Screening. 


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j 
After a 4-hour fast, patients will undergo a standard symptom-limited exercise test by standardized treadmill or bicycle ergometer. Instantaneous peak LVOT 
gradient will be assessed immediately post-exercise by TTE. 
k 
CPET by standardized treadmill or bicycle ergometer will be performed on both Day 1 and at Week 16/ET prior to dosing. CPET is done after a 4-hour fast. 
Obtain CPET with study patient in the same position at Week 16 as done on Day 1. 
l 
The accelerometer is to be distributed during Screening and at the Week 12 visit and retrieved at the Day 1 and Week 16 visits. 
m 
The cardiac monitoring adhesive skin patch is to be applied during Screening and at the Week 12 visit and retrieved at the Day 1 and Week 16 visits. 
n 
Blood samples for PK will be collected at all post-Screening onsite visits except for the Day 1 and Week 6 visits. The time of each blood draw will be 
recorded. At Week 16, a PK sample will be collected before dosing as well as within 2 hours postdose. On other PK sampling days, the PK blood samples 
can be taken at any time that best facilitates conduct of all scheduled study procedures. The date and time of the last dose of IMP taken prior to the PK 
sample collection will be recorded. 
o 
At Screening, the blood draw for NT-proBNP will occur prior to post-exercise stress echocardiography. At the Day 1 and Week 16 visits, the blood draw for 
NT-proBNP will be obtained both prior to and immediately after CPET. 
p 
FSH testing at Screening for postmenopausal women to confirm postmenopausal status. 
q 
Pregnancy testing for all females of childbearing potential. Conduct serum test at Screening and a urine pregnancy test at all other visits shown; conduct 
serum test if a urine test is positive. At Week 20, a urine pregnancy test will be conducted at home. 
r 
Separate consent is required for HCM genotyping. Note that if a patient with a prior HCM clinical genotype test that was positive for pathogenic 
HCM-causing mutation(s) consents to provide their results, then no further genotype assessment will be performed. However, patients who have not been 
tested, patients who have tested negative for pathogenic HCM-causing mutation(s) on clinical panels, and patients who have a positive HCM genotype result 
but cannot provide the results or will not consent to provide the results may consent to have blood drawn on Day 1 prior to the first dose of IMP for 
assessment of HCM genotype. 
s 
Patients may also consent separately to have blood drawn prior to dosing on Day 1 for assessment of pharmacogenetics and potentially additional DNA 
sequencing. 
t 
Patients will have blood samples drawn on Day 1 and Week 16 prior to dosing and at Week 24 for potential exploratory biomarker analysis. 
 
 
 
 
 
 
 
 
 
. 
y 
All patients will return their IMP dosing containers to the site for capsule counts. Refer to the Pharmacy Manual for details.