Conditions: Heart Failure With Reduced Ejection Fraction Dilated Cardiomyopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
The purpose of this Phase 1b/2a study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MYK-491 in patients with stable heart failure.

Detailed description:

Arms:
arm 1: Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo

Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo arm 2: Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo

Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo

Interventions: intervention 1: MYK-491 intervention 2: Placebo
Intervention descriptions: intervention 1: Single Ascending Dose and Multiple Ascending Dose of MYK-491 intervention 2: Single Ascending Dose and Multiple Ascending Dose of placebo

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
Randomized, Double-blind, Placebo-controlled, Two-Part, Adaptive Design Study of Safety, Tolerability, 
Preliminary Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of 
MYK-491 in Patients With Stable Heart Failure With Reduced Ejection Fraction 
 
 
NCT Number: NCT03447990 
 
Document Date (Date in which document was last revised): March 19, 2019 


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CLINICAL TRIAL PROTOCOL 
Protocol Number: 
MYK-491-003 (HF-SAD/MAD) 
Study Title: 
Randomized, Double-blind, Placebo-controlled, Two-Part, 
Adaptive Design Study of Safety, Tolerability, Preliminary 
Pharmacokinetics, and Pharmacodynamics of Single and 
Multiple Ascending Oral Doses of MYK-491 in Patients 
with Stable Heart Failure with Reduced Ejection Fraction 
Indication: 
Heart Failure with Reduced Ejection Fraction 
Phase: 
1b/2a 
Investigational Medicinal 
Product: 
MYK-491 
Sponsor: 
MyoKardia, Inc. 
333 Allerton Avenue 
South San Francisco, CA 94080 
EudraCT Number 
2018-002239-11 
Key Sponsor Contacts: 
Edition Number: 
5 
Release Date: 
19 March 2019 
Replaces Previous Edition 
Number: 
4 
Date: 
14 December 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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SYNOPSIS 
Sponsor: 
MyoKardia, Inc. 
Investigational Medicinal Product: 
MYK-491 
Study Title: 
Randomized, Double-blind, Placebo-controlled, Two-Part, Adaptive Design Study of 
Safety, Tolerability, Preliminary Pharmacokinetics, and Pharmacodynamics of Single and 
Multiple Ascending Oral Doses of MYK-491 in Patients with Stable Heart Failure with 
Reduced Ejection Fraction 
Study Number: 
MYK-491-003 
Study Phase: 1b/2a 
Primary Objective: 
To establish preliminary safety and tolerability of single- and multiple-ascending oral 
doses of MYK-491 in ambulatory patients with stable heart failure with reduced ejection 
fraction (HFrEF) 
Secondary Objectives: 
• To establish preliminary human pharmacokinetics (PK) of MYK-491 after single- 
and multiple-ascending oral doses of MYK-491 in patients with HFrEF 
• To determine changes in left ventricular stroke volume [LVSV] derived from left 
ventricular outflow tract-velocity time integral [LVOT-VTI]), left ventricular 
ejection fraction (LVEF) and change in left ventricular fractional shortening 
[LVFS] with MYK-491 after ascending single and multiple doses compared with 
Baseline and placebo as measured by transthoracic echocardiography (TTE) 
• To determine changes in systolic ejection time (SET) with MYK-491 after 
ascending single and multiple doses compared with Baseline and placebo as 
measured by TTE 
• To determine changes in pharmacodynamics (PD) dose/concentration effects 
(change in LVSV [derived from LVOT-VTI], LVEF, LVFS) with MYK-491 
compared with Baseline and placebo after ascending single and multiple doses, as 
measured by TTE 
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Main Criteria for Inclusion: 
Inclusion Criteria: 
This study is to be performed in patients with HFrEF due to any etiology. Each patient 
must meet the following criteria to be included in this study: 
1. Able to understand and comply with the study procedures, understand the risks 
involved in the study, and provide written informed consent according to 
federal, local, and institutional guidelines before the first study-specific 
procedure. 
2. Men or women 18 to 80 years of age at the Screening visit. 
3. Body mass index (BMI) 18 to 40 kg/m2, inclusive, at the Screening visit and all 
required assessments can be reliably performed. 
4. Sinus rhythm or stable atrial pacing with mean resting heart rate (HR) 50-95 
beats per minute (bpm), inclusive. (Patient will be ineligible to dose if, on 
Day 1, the predose HR measurement is ≥ 95 bpm. Heart rate is the mean of 
3 measurements taken 1 minute apart. A single measurement would not make a 
patient ineligible). 
5. Has stable, chronic HFrEF of moderate severity as defined by all of the 
following: 
• For the first 3 patients in each multiple-ascending dose (MAD) cohort 
testing a new (higher) daily dose: documented LVEF 25% to 35% during 
Screening (as confirmed by ECHO Central Lab) 
• For other patients in the MAD Cohorts (and all patients in SAD Cohorts): 
documented LVEF 15% to 35% during Screening (as confirmed by ECHO 
Central Lab) 
• LVEF must be confirmed with second screening ECHO to be performed at 
least 7 days after initial screening ECHO.  Results of both must meet 
inclusion criteria and must be received from core lab prior to dosing.  In the 
event of extended screening windows due to SRC reviews, effort should be 
made to ensure second ECHO is near planned time of randomization. 
• Chronic medication for the treatment of heart failure consistent with current 
guidelines that has been given at stable doses for ≥ 2 weeks with no plan to 
modify during the study. This includes treatment with at least one of the 
following unless not tolerated or contraindicated: beta-blocker, angiotensin 
converting enzyme (ACE) inhibitor/angiotensin receptor blocker 
(ARB)/angiotensin receptor neprilysin inhibitor (ARNI) 
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6. Female patients must not be pregnant or lactating. Male patients (including men 
who have had vasectomies), as there may be a risk of drug being secreted in the 
ejaculate, should use barrier methods for the duration of the study and for 
3 months after the last dose of study medication. All patients, if sexually active, 
must be using one of the following highly-effective birth control methods from 
the Screening visit through 3 months after the last dose of investigational 
medicinal product (IMP): 
• Hormonal contraception associated with inhibition of ovulation, intrauterine 
device (IUD), or intrauterine hormone-release system (IUS) plus barrier 
(eg, male using condom or female using diaphragm or cervical cap). 
• Vasectomy plus barrier.  
• Female is surgically sterile for 6 months or postmenopausal for 1 year. 
Permanent sterilization includes hysterectomy, bilateral oophorectomy, 
bilateral salpingectomy, and/or documented bilateral tubal occlusion at least 
6 months prior to Screening. Females are considered postmenopausal if 
they have had amenorrhea for at least 1 year or more following cessation of 
all exogenous hormonal treatments, and follicle-stimulating hormone (FSH) 
levels are in the postmenopausal range. 
• Male patients with postmenopausal partners. 
Exclusion Criteria: 
Patients who meet any of the following criteria will be excluded from the study. 
1. Inadequate echocardiographic acoustic windows. 
2. Any of the following ECG abnormalities (a) QTcF > 480 ms (Fridericia’s 
correction, not attributable to pacing or prolonged QRS duration, average of 
triplicate Screening ECGs) or (b) second-degree atrioventricular block type II 
or higher in a patient who has no pacemaker. 
3. Hypersensitivity to MYK-491 or any of the components of the MYK-491 
formulation. 
4. Active infection as indicated clinically as determined by the investigator. 
5. History of malignancy of any type within 5 years prior to Screening, with the 
exception of the following surgically excised cancers occurring more than 
2 years prior to Screening: in situ cervical cancer, nonmelanomatous skin 
cancers, ductal carcinoma in situ, and nonmetastatic prostate cancer. 
6. Positive serologic test at Screening for infection with human immunodeficiency 
virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). 
7. Hepatic impairment (defined as alanine aminotransferase [ALT]/ aspartate 
aminotransferase [AST] > 3 times upper limit of normal [ULN] and/or total 
bilirubin [TBL] > 2 times ULN). 
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8. Severe renal insufficiency (defined as current estimated glomerular filtration 
rate [eGFR] < 30 mL/min/1.73m2 by simplified Modification of Diet in Renal 
Disease equation [sMDRD]). 
9. Serum potassium < 3.5 or > 5.5 mEq/L. 
10. Any persistent out-of-range safety laboratory parameters (chemistry, 
hematology, urinalysis), considered by the investigator and medical monitor to 
be clinically significant. 
11. History or evidence of any other clinically significant disorder, condition, or 
disease (including substance abuse) that, in the opinion of the investigator or 
MyoKardia physician would pose a risk to patient safety or interfere with the 
study evaluation, procedures, completion, or lead to premature withdrawal from 
the study. 
12. Participated in a clinical trial in which the patient received any investigational 
drug (or is currently using an investigational device) within 30 days prior to 
Screening, or at least 5 times the respective elimination half-life (whichever is 
longer). 
13. Previous participation in a clinical trial with MYK-491, with the exception that 
patients that participated or were screen failures in one part of this trial may 
participate in the other part, ie patients may enroll in Part 1 (SAD) followed by 
Part 2 (MAD) or Part 2 (MAD) followed by Part 1 (SAD), with the following 
caveats: 
• If the patient has an ongoing adverse event (AE), has had a serious adverse 
event (SAE), or has met any stopping criteria, the investigator should 
contact the Sponsor prior to enrolling the patient in a subsequent cohort. 
• Patients must have at least 1 week washout after the end of MAD dosing 
prior to SAD dosing, or at the end of SAD dosing prior to MAD dosing. 
• Patients do not need to rescreen if MAD screening occurred within 
12 weeks of the first SAD dosing, or if SAD screening occurred within 
12 weeks of the first MAD dosing. Investigators should verify that patients 
are clinically stable and no exclusions have occurred during the interim; if 
> 12 weeks have elapsed or there is clinical instability, then patients should 
be rescreened. 
14. Unable to comply with the study restrictions/requirements, including, in 
particular, the number of required overnight stays at the clinical site. 
15. Is employed by, or is a first-degree relative of someone employed by, 
MyoKardia or Sanofi, the investigator, or his/her staff or family. 
16. At Screening, symptomatic hypotension, or systolic blood pressure (BP) 
> 170 mmHg or < 90 mmHg, or diastolic BP > 95 mmHg, or HR < 50 bpm. 
Heart rate and BP will be the mean of 3 measurements taken at least 1 minute 
apart. 
17. Current angina pectoris. 
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18. Recent (< 90 days) acute coronary syndrome. 
19. Coronary revascularization (percutaneous coronary intervention [PCI] or 
coronary artery bypass graft [CABG]) within the prior 3 months. 
20. Recent (< 90 days) hospitalization for heart failure, use of chronic IV inotropic 
therapy or other cardiovascular event (e.g., cerebrovascular accident). 
21. Uncorrected severe valvular disease. 
22. Elevated troponin I (> 0.15 ng/mL) at Screening, based on Central Laboratory 
assessments. Note: Central Laboratory Troponin I assay ULN is 0.03 ng/mL. 
23. Presence of disqualifying cardiac rhythms that would preclude study ECG or 
echocardiographic assessments, including: (a) Current atrial fibrillation, (b) 
recent (< 2 weeks) persistent atrial fibrillation, or (c) frequent premature 
ventricular contractions. Note: Patients with active cardiac resynchronization 
therapy (CRT) or pace-maker (PM) are eligible if initiated at least 2 months 
prior with no plan to change CRT or PM settings during the study. 
24. A life expectancy of < 6 months. 
Study Treatment: 
Part 1-Single, ascending doses (SAD Cohorts): Each patient will be enrolled into either 
Cohort 1 or Cohort 2. Four to 8 patients will first be enrolled into Cohort 1 and then up to 
8 patients will be enrolled into Cohort 2. The Safety Review Committee (SRC) will 
determine the number of patients enrolled into each cohort. Patients enrolled in Cohort 1 
will participate in 3 to 4 dosing periods, while patients enrolled in Cohort 2 will participate 
in 2 to 4 dosing periods. For both cohorts, patients will receive sequential, ascending single 
oral doses of MYK-491 and a randomly assigned period with matching placebo. For 
Cohort 1, all patients will receive the first dose of MYK-491, which will be 175 mg, and 
the second dose of MYK-491, which will be 350 mg. Some patients in Cohort 1 may 
receive a third dose of MYK-491, given open label, that will be determined by the SRC 
after review of data from the first 2 doses. The SRC will select the number of dosing 
periods and the doses that will be administered to patients enrolled in Cohort 2 based on 
review of safety and PK/PD data from Cohort 1 and any other newly available MYK-491 
data. Doses may be split into 2 aliquots. Patients will receive the placebo in random order 
along with the doses of active drug (see Figure 1). Sequential dosing for an individual 
patient can occur after a minimum period of 5 days and a maximum period of 14 days 
from the time of the ingestion of the previous dose, except for the open-label dose in 
Cohort 1 which will be completed after the SRC meets and provides dosing instructions. 
Further details are available in Section 4.4.1. 
Part 2—Multiple, ascending doses (MAD Cohorts): The duration of dosing with blinded 
study drug will be 9 days. All patients will initially receive placebo twice a day (BID) in 
single-blinded manner for 2 days (Days 1 through 2). Patients will then be randomized to 
receive either placebo or active MYK-491 for 7 days (Days 3 through 9). Patients will be 
enrolled into sequential, dose-escalation cohorts with a low dose (Dose-Escalation 
Cohort A), medium dose (Dose-Escalation Cohort B), or high dose (Dose-Escalation 
Cohort C). The same dose will be given to all patients in a single cohort randomized to 
active drug. Based on prior testing, the low dose to be given in the first Cohort (Cohort A) 
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is intended to be at the lower end of the exposure range that produces a discernable 
pharmacodynamic effect in order to ensure safety and evaluate steady-state PK.
 
 
 
 
The low dose of MYK-491 for Cohort A will be 75 mg administered orally every 12 hours. 
 
 The planned medium dose of MYK-491 for Cohort B will be 
 every 12 hours. The planned high dose of MYK-491 for Cohort C will be 
 
every 12 hours. The actual medium and high doses will be determined and confirmed by 
the SRC after data from prior cohorts are reviewed. Dose escalation between cohorts will 
not exceed a 2-fold increase in dose from the prior cohort if the prior cohort demonstrated 
acceptable safety and tolerability. 
In addition, optional Cohorts D and E, and possible additional cohorts, may be enrolled to 
evaluate the feasibility of a once daily dosing regimen given for 7 days or to explore 
additional every day (QD) or BID dosing regimens. The total daily dose for the optional 
cohorts will not exceed a total daily dose already evaluated in this study, 
 
. 
Note: For Cohorts A, B and C testing a BID regimen, only one dose (active or placebo) 
will be given in the morning on Day 9 (Dosing Day 7) to allow for 72 hours of serial 
PK/PD assessments. 
Number of Patients Planned: 
Part 1-Single, ascending doses (SAD Cohorts): Enrollment of at least 4 and no more 
than 8 patients are planned for Cohort 1, with 1 patient randomized to each sequence of 
dose escalation and placebo administration (see Figure 1). For Cohort 2, 4 patients are 
planned, and no more than 8 patients will be enrolled, with up to 2 patients randomized to 
each sequence of dose escalation. 
There will be an option for the SRC to expand Cohort 1 or Cohort 2 to meet study 
objectives. Decision to expand the number of patients or not will be made by the SRC. 
Two additional patients may be enrolled as replacements for drop-outs in each cohort, so 
the maximum number of patients that may be enrolled, including cohort expansions, will 
be approximately 32. 
Part 2-Multiple, ascending doses (MAD Cohorts): Enrollment of a total of a minimum 
of 24 patients is planned, with 8 patients enrolled the low-dose group (Cohort A), 
8 patients enrolled in the medium-dose group (Cohort B), and 8 patients enrolled in the 
high-dose group (Cohort C). The SRC may expand any cohort up to 24 patients. In 
addition, the initial planned size of Cohorts D and E, and possible additional cohorts, will 
be 8 patients each. The final total sample size for Part 2 will not exceed 96 patients. In 
addition, up to 2 additional patients may be enrolled per cohort as replacements for drop-
outs or patients non-evaluable for PK-PD at steady state. 
Cohorts will be randomized 3:1 to each sequence of active drug and placebo 
administration.  
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Number/Location of Investigational Sites: 
Approximately 18 sites in North America and Europe 
Study Duration: 
The overall expected study duration is approximately 24 months. 
Part 1-Single, ascending doses (SAD Cohorts): Each patient is expected to be in the 
study no more than 77 days: up to 28 days for Screening plus up to 42 days for dosing 
including 7 days for follow up after the last dose (or longer if clinically indicated). Patients 
returning for an additional dosing period in Cohort 1 may have prolonged participation. 
Patients will be resident at the clinical site for each dosing period, each consisting of 
check-in on Day -1, dosing the following morning (Day 1) followed by ~24 hours of serial 
PD and ~48 hours of serial PK assessments, followed by discharge the following morning 
(Day 3). An additional outpatient plasma PK sample will be taken on the morning of Day 4 
at 72 hours postdose. 
Part 2: Multiple, ascending doses (MAD Cohorts): Patients are expected to be in the 
study no more than 56 days: up to 28 days for Screening plus up to 28 days for (a) 
scheduling (b) 11 days of dosing and associated assessments, and (c) 7 days of follow up 
after the last dose (or longer if clinically indicated). Patients who are in Screening while 
dosing is on hold due to SRC meeting may have participation extended to allow dosing to 
be scheduled after SRC has convened. While waiting for a cohort to open to patients with 
LVEF < 25%, these patients may be in Screening up to 12 weeks (if the patient remains 
stable) while the SRC convenes. 
Total time in the study may be longer for patients who participate in both Part 1 (SAD) and 
Part 2 (MAD). 
Study Design: 
This is a two-part study. Part 1 will evaluate single-ascending doses of MYK-491 (SAD 
Cohorts) and Part 2 will evaluate multiple, ascending doses of MYK-491 (MAD Cohorts). 
Note: Part 2 (MAD portion) of the study is planned to start before Cohort 2 of Part 1 (SAD 
Cohort) is complete. If a patient at a site qualifies for enrollment in either Part 1 (SAD) or 
Part 2 (MAD), Part 2 (MAD) will generally take priority; however, a patient may enroll in 
both, ie Part 1 (SAD) followed by Part 2 (MAD) or Part 2 (MAD) followed by Part 1 
(SAD). In such cases, sites should consult with the monitoring team to discuss details. 
Part 1-Single, ascending doses (SAD Cohorts): This is a randomized, crossover, double-
blind (DB), placebo-controlled, two-cohort, sequential ascending (oral) single-dose study 
in ambulatory patients with heart failure. All patients will receive placebo and 2 or 3 active 
doses of MYK-491. Each patient will undergo sequential, single-dose treatment events 
separated by no fewer than 5 days and no more than 14 days. Patients in Cohort 1 may also 
return for a fourth dosing period (open label) after the SRC reviews available data and 
recommends the dose. Patients enrolled prior to the implementation of Amendment 1 may 
be offered the opportunity to return for the open-label period. Patients who return for this 
additional period must sign the amended informed consent form (ICF). Patients in 
Cohort 2 may participate in 2-4 dosing periods, based on SRC decision. Patients will be 
randomized to 1 of the different dosing sequences outlined in Figure 1. Multiple patients 
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can be dosed at the same time or during the same week depending on administrative issues, 
ie, capacity and scheduling. 
For each dosing period, patients will be admitted to the clinical site on Day -1, (the day 
before dosing). Patients will be assessed for absence of exclusion criteria (eg, new lab 
abnormalities based on local labs and/or conditions that indicate the patient is clinically 
unstable). They will receive MYK-491 or placebo in the morning of Day 1 followed by 
serial PK and PD assessments, as well as serial safety assessments. Patients will be 
discharged on Day 3 (ie, ~48 hours following Day 1 dosing). An additional outpatient 
plasma PK sample will be taken on the morning of Day 4 at 72 hours postdose. 
Before administering a dose, the investigator or the subinvestigator will review all 
available safety data, including vital signs, safety laboratory values including locally 
assayed troponin concentrations, TTEs, ECGs, and ECG telemetry. Dosing with DB 
treatment will take place at the same time each of the dosing days. Background 
concomitant medications, including diuretic if applicable, should also be administered at 
same time each of the dosing day. Prior to dosing, any patient with a predose resting HR 
≥ 95 bpm will be considered ineligible and not treated. HR is the mean of 3 measurements. 
A full PK profile and multiple TTEs and ECGs will be obtained at Baseline and after each 
dose. Patients will return for a final safety Follow-up visit 7 days (±1 day) following the 
last dose. 
During the study, the patients should continue to ingest their medications for the treatment 
of their congestive heart failure and other medical conditions at the same doses and as 
close to the same times as usual. 
Part 2: Multiple, ascending doses (MAD Cohorts): This is a randomized, parallel-group, 
DB, placebo-controlled, adaptive design, sequential ascending (oral) multiple-dose study 
in stable patients with heart failure. Three MAD Cohorts (A, B, C) are initially planned 
(with additional optional cohorts) with 8 patients each (2 placebo, 6 active). An SRC will 
review results from each cohort and will determine the dose and confirm initial sample size 
for the subsequent cohort. Additionally, the first 3 patients in each cohort must have a 
≥ 25% LVEF; the SRC will review preliminary safety data from these patients and decide 
whether to open cohort enrollment to patients with LVEF < 25%. 
After Screening and qualification, patients will be confined to a clinical testing facility 
from Day 1 (Check-in) to Day 11. This includes an initial 2-day placebo dosing period 
(Days 1-2), followed by a 7-day randomized treatment period (Days 3-9) and 48 hours of 
monitoring following the last dose of study drug (Days 10-11). An additional outpatient 
plasma PK sample will be taken on the morning of the day following discharge at 72 hours 
after the last dose (Day 12). 
Note: Confinement is not required for patients with an implantable cardioverter 
defibrillator (ICD): Patients with an ICD may reside for some or all of the period from 
Day 1 to Day 12 in close proximity to the Clinical Testing Unit, eg, at a hotel, provided 
they can return for all study drug dosing and all study assessments, including but not 
limited to all serial PK and TTEs. Alternatively, patients may be visited by a home health 
nurse for selected study drug administration and for any assessments that can be performed 
away from the clinical site. 
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Each patient will initially receive placebo BID for 2 days (Days 1-2) in single-blinded 
manner (“run-in” during acclimatization to confinement in the Clinical Testing Unit) prior 
to receiving the randomized DB study drug treatment on Day 3. All patients will then 
receive either placebo or active MYK-491 for 7 days (Days 3-9). More than one patient 
can be dosed in a cohort at the same time or during the same week depending on 
administrative issues, i.e., capacity and scheduling. 
Patients will be dosed twice daily (every 12 hours). Doses may occur ± 2 hours from 
scheduled dosing times as long as doses are separated by at least 10 hours and by no more 
than 14 hours. The exception to the twice daily dosing is on Day 9 (last dose of 
randomized DB study drug treatment). On Day 9, a single morning dose will be 
administered followed by 72 hours of PK and PD assessments. 
Before each dosing event, all available safety data from the previous days will be reviewed 
(for non-confined patients, if a home health nurse is utilized, the nurse and site will be in 
daily communication to ensure safety). Dosing of DB treatment will take place at 
approximately the same time each day.  
A full PK profile and multiple TTEs and ECGs will be obtained on Days 3 and 9 
(corresponding to first and last day of DB treatment respectively) before and after the 
morning dose.  In case of premature permanent treatment discontinuation, perform end-of-
treatment visit (same assessments as Day 9) as close as possible to last DB dose (ie, on day 
of last dose or next day). 
Patients will return for a Follow-up visit 7 days following the last dose of study drug. In 
case of premature permanent treatment discontinuation, perform end-of-treatment visit 
(same assessments as Day 9) as close as possible to last DB dose (ie, on day of last dose or 
next day). 
Note: Screening may continue during planned and unplanned SRC meetings. The protocol-
specified Screening window may be extended to account for delays due to SRC meetings. 
Recommendations by the SRC will include, but not be limited to: (a) evaluation of dose-
modification and dose stopping criteria, (b) doses to be given in specified cohorts, (c) size 
of specified cohorts and (d) modification of the number and timing of PK and PD 
assessments (see Section 4.4.1). 
Study Assessment and Procedures: Efficacy Assessments: 
There are no therapeutic efficacy assessments in this study. Pharmacodynamic assessments 
will serve as surrogates for efficacy. 
Pharmacokinetic Assessments: 
For each cohort, blood samples to measure MYK-491 
 plasma 
concentration will be drawn on each dosing day predose and postdose at serial timepoints 
as defined in the schedule of assessments. After review of the data, the SRC may decide 
that up to 2 additional blood samples should be obtained after each dosing period, or the 
timing of the samples should be modified to allow for acquisition of robust PK profiles. 
 
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Pharmacodynamics Assessments: 
The PD effect of MYK-491 will be evaluated throughout this study by serial TTE 
examination in accordance with a standardized imaging protocol at Screening, before first 
DB dose (on Day 1, Day 2, and Day 3 morning predose), during DB treatment (Day 3 to 
Day 9), and during follow up (Day 10, Day 11) at defined timepoints (predose and/or 7h 
postdose) as defined in the schedule of assessments. The intent is to obtain a TTE at a 
timepoint close to the anticipated peak effect following each dose based on the PK profile. 
Throughout the study, in order to minimize variability of cardiac loading conditions for 
detecting changes in TTE assessments from DB treatment, every effort should be made to 
maintain stable background HF treatment and to administer such treatments (including 
diuretic as applicable) at the same time every day throughout the duration of the study. 
After review of the data, the SRC may decide to obtain up to 2 additional TTEs for each 
dosing period or the timing of the TTEs may be modified to obtain robust PD profiles. The 
primary echocardiographic variables of interest are LVSV (derived from LVOT-VTI), 
LVEF, LVFS, and SET. The sonographers will be trained and certified to perform the TTE 
by the Imaging Core Laboratory. 
 
 
 
 
Safety Assessments: 
Serum troponin and ECGs will be obtained as part of the Screening visit, before and/or 
after dosing on selected days. Refer to Schedule of Events for timing. 
Safety assessments include medical history, physical examinations, SET as determined by 
TTE, 12-lead ECGs, continuous ECG monitoring by (a) telemetry, (b) Holter monitor 
recording or (c) equivalent technology, vital signs, observed and patient-reported AEs, 
serum troponin concentrations, and safety laboratory tests. Any abnormal findings judged 
by the investigator to be clinically relevant will be recorded as AEs. 
Suspected ischemic events, new or worsening episodes of ventricular arrhythmias and 
troponin elevations will be sent for review by a Central Safety Adjudication Committee 
(see Section 4.5). 
Statistical Analyses: 
General Considerations: 
Clinical data will be analyzed separately for the SAD and MAD parts of the study. In 
Part 1, the placebo dosing periods will be pooled across cohorts to form a placebo group. 
Placebo subjects from all MAD Cohorts will be pooled to form one combined placebo 
group for analyses. No formal statistical hypothesis testing will be performed. Descriptive 
summary statistics for continuous variables will include the number of participants, mean, 
standard deviation (SD), median, 1st and 3rd quartiles, minimum, and maximum. 
Categorical variables will be summarized using counts and percentages. The 95% 
confidence intervals may be presented as well. 
Safety Analyses: 
SET, as determined by TTE, will be assessed using summary statistics. Observations and 
change from Baseline will be summarized by treatment at each timepoint and the 
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maximum change from Baseline will be determined for each patient.
 
 
 
 
The number of patients with abnormal and/or rising troponin levels (taking into account 
potential troponin elevation at Baseline) will be determined. 
Continuous ECG recordings by telemetry or Holter monitor (or equivalent) will be used to 
assess the nature, frequency, and severity of any ventricular arrhythmias or other 
significant cardiac rhythm abnormalities. 
AEs, ECGs, vital signs, and laboratory values will be analyzed using descriptive statistics. 
Pharmacokinetic Analyses: 
The PK population will include all patients who receive MYK-491, have detectable plasma 
concentration data, and have no major or critical protocol deviations related to IMP (eg, 
incomplete ingestion of the drug, vomiting up to 8 hours after drug administration). In 
addition, a single plasma sample near the predicted time of maximum observed plasma 
concentration (Tmax) of MYK-491 will be evaluated to confirm lack of circulating MYK-
491 for the dosing period(s) when the patients received placebo. 
Plasma concentration 
 data for MYK-491 will be summarized using 
descriptive statistics, including mean or geometric mean, as appropriate, SD, median, 
minimum and maximum values, and coefficient of variation (CV%). Other PK parameters 
include (but are not limited to) maximum observed plasma drug concentration (Cmax), Tmax, 
area under the plasma concentration-time curve over the dosing interval (AUC0-t), 
AUC0-12, AUC0-24, AUC0-inf after the single dose on Day 1 in Part1 or Days 3 and 9 in 
Part 2 (in appropriate patients), trough concentration (Ctrough), apparent first-order terminal 
elimination rate constant (λz)(on Day 1 in Part 1 and Day 9 in Part 2 only), and mean 
residence time (MRT). PK parameters at steady-state will be compared to those observed 
after the first dose in this study, and the accumulation ratios determined (with the 
appropriate confidence intervals) based on Cmax and AUC0-t after a single dose and at 
steady-state as well as λz. Additionally, the apparent terminal-phase elimination half-life 
(t1/2z) will be calculated after each dosing day in Part 1 and on Day 7 in appropriate 
patients. 
 
 
Pharmacodynamic Analyses: 
The PD Analysis population will include patients who have any interpretable TTE data. 
TTE data for LVSV (derived from LVOT-VTI), LVEF, LVFS, and SET will be analyzed 
using descriptive statistics. Observations by timepoint and change from Baseline (predose 
in that dosing period) for each timepoint will be summarized by treatment arms. Change 
from Baseline will be analyzed with attention to relationship to time postdose, dose level, 
and comparison with placebo. For SAD Cohorts, placebo-adjusted change from Baseline 
will be calculated for each subject at each postbaseline timepoint and then summarized at 
each dose level. In addition, for SAD and MAD Cohorts, least square means of 
placebo-adjusted change from Baseline for the key PD parameters (LVSV [derived from 
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LVOT-VTI], LVEF, LVFS, SET) at each postbaseline time point at each dose level may 
be estimated using mixed model.  
Pharmacokinetic/Pharmacodynamic Analyses: 
Correlations of LVSV (derived from LVOT-VTI), LVEF, LVFS, SET, and/or vital signs 
with MYK-491 dose and/or plasma concentration may be assessed.
 
 
 
Sample Size Considerations: 
No formal statistical hypothesis testing will be performed. In Part 1, enrollment of 4-
8 patients per cohort is planned and in Part 2, 8 patients per cohort with the potential to 
expand to 24 patients, with up to an additional 2 replacements per cohort, in order to meet 
study objectives. Based on the study design, the sample size is considered appropriate to 
explore tolerability and safety parameters, PK profile, and PD effects of MYK-491. 
Compliance Statement: 
This study will be conducted in accordance with the International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines; US Title 21 Code of 
Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312; European Union (EU) GCP and 
Good Manufacturing Practices (GMP); and the principles enunciated in the Declaration of 
Helsinki and all human clinical research regulations where the study is to be conducted. 
 
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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ..............................................................................................1 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................14 
LIST OF TABLES ...................................................................................................................18 
LIST OF FIGURES .................................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................19 
1 
INTRODUCTION .................................................................................................22 
1.1 
Background ......................................................................................................23 
1.1.1 
In Vitro Studies ....................................................................................23 
1.1.3 
Drug Metabolism .................................................................................24 
1.1.5 
MYK-491 .............................................................................................25 
1.2 
Clinical Studies ................................................................................................25 
1.3 
Known and Potential Risks and Benefits .........................................................26 
2 
RATIONALE FOR THE STUDY AND FOR DOSE AND DOSING 
SCHEDULE ...........................................................................................................28 
2.1 
Rationale for the Study ....................................................................................28 
2.2 
Rationale for Dose and Dosing Schedule ........................................................28 
2.2.1 
Part 1 (SAD) Cohort 1 Dose Levels ....................................................28 
2.2.1.1 
Low-Dose Level Cohort 1 ..........................................................28 
2.2.1.2 
Second Dose Level Cohort 1 ......................................................28 
2.2.1.3 
Third Dose Level Cohort 1 .........................................................29 
2.2.2 
Part 1 (SAD) Cohort 2 Dose Levels ....................................................29 
2.2.3 
Part 2 (MAD) Cohort A Dose ..............................................................29 
2.2.4 
Part 2 (MAD) Cohorts B and C Doses .................................................30 
2.3 
Rationale for Exceeding NOAEL ....................................................................30 
3 
STUDY OBJECTIVES ..........................................................................................32 
3.1 
Primary Objective ............................................................................................32 
3.2 
Secondary Objectives .......................................................................................32 
 
4 
OVERALL STUDY DESIGN AND PLAN ..........................................................33 
4.1 
Study Design ....................................................................................................33 
4.1.1 
Part 1 Study Design .............................................................................33 
4.1.2 
Part 2 Study Design .............................................................................34 
4.2 
Stopping Criteria ..............................................................................................37 
4.2.1 
Stopping Criteria for an Individual Participant in Part 1 (SAD) .........37 
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4.2.2 
Criteria for Unscheduled SRC Review of the Study in Part 1 
(SAD) ...................................................................................................38 
4.2.3 
Dose-Modification Criteria for an Individual Participant in Part 2 
(MAD)..................................................................................................39 
4.2.4 
Stopping Criteria for an Individual Participant in Part 2 (MAD) ........39 
4.2.5 
Criteria for Unscheduled SRC Review of the Study in Part 2 
(MAD)..................................................................................................40 
4.3 
Study Duration .................................................................................................40 
4.4 
Safety Review Committee ...............................................................................41 
4.4.1 
Safety Review Committee Meetings ...................................................41 
4.4.2 
Composition of Safety Review Committee .........................................41 
4.5 
Independent Safety Adjudication .....................................................................42 
5 
SELECTION AND WITHDRAWAL OF STUDY POPULATION .....................43 
5.1 
Inclusion Criteria .............................................................................................43 
5.2 
Exclusion Criteria ............................................................................................44 
5.3 
Withdrawal and Replacement of Patients ........................................................46 
5.3.1 
Withdrawal from the Study ..................................................................46 
5.3.2 
Follow-up Procedures After Withdrawal .............................................47 
5.3.3 
Replacement of Patients .......................................................................47 
6 
RANDOMIZATION AND BLINDING PROCEDURES.....................................48 
6.1 
Randomization .................................................................................................48 
6.2 
Blinding............................................................................................................48 
7 
STUDY TREATMENT .........................................................................................50 
7.1 
Investigational Medicinal Product ...................................................................50 
7.1.1 
Supply of Investigational Medical Product ..........................................50 
7.1.2 
Storage and Handling Procedures ........................................................50 
7.1.3 
Packaging and Labeling .......................................................................50 
7.2 
Study Medication, Administration, and Schedule ...........................................51 
7.2.1 
Administration Relative to Meals ........................................................51 
7.3 
Treatment Compliance .....................................................................................52 
7.4 
Guidelines for the Management of an Exaggerated Pharmacological Effect ..52 
7.5 
Overdose ..........................................................................................................52 
7.6 
Concomitant Therapy.......................................................................................53 
8 
RISKS AND PRECAUTIONS ..............................................................................54 
8.1 
General .............................................................................................................54 
8.2 
Pregnancy .........................................................................................................54 
8.2.1 
Avoidance of Pregnancy ......................................................................54 
8.2.2 
Restrictions for Male Patients ..............................................................54 
8.2.3 
Acceptable Forms of Contraception ....................................................55 
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8.2.4 
Reporting and Follow up of Pregnancies .............................................55 
9 
STUDY ASSESSMENTS AND PROCEDURES .................................................56 
9.1 
Efficacy Assessments .......................................................................................56 
9.2 
Pharmacodynamic Assessments ......................................................................56 
9.2.1 
Transthoracic Echocardiography .........................................................56 
9.3 
Pharmacokinetic, Pharmacogenetic, and Biomarker Assessments ..................57 
9.3.1 
Pharmacokinetic Assessments .............................................................57 
 
9.4 
Safety Assessments ..........................................................................................57 
9.4.1 
Medical History ...................................................................................58 
9.4.2 
Vital Signs ............................................................................................58 
9.4.3 
Physical Examination...........................................................................58 
9.4.4 
Systolic Ejection Time .........................................................................58 
9.4.5 
Electrocardiograms (12-Lead ECG) ....................................................59 
9.4.6 
Electrocardiogram Telemetry ..............................................................59 
9.4.7 
Holter Electrocardiogram.....................................................................60 
9.4.8 
ICD Download (For Patients with ICD) ..............................................60 
9.4.9 
Troponin Levels ...................................................................................60 
9.4.10 
Adverse Events ....................................................................................61 
9.4.11 
Safety Laboratory Tests (Other Than Troponin) .................................61 
9.5 
Missed Evaluations ..........................................................................................61 
9.6 
Patient Restrictions During the Study ..............................................................61 
10 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS ................................................................................................................63 
10.1 
Definitions........................................................................................................63 
10.1.1 
Adverse Event ......................................................................................63 
10.1.2 
Serious Adverse Event .........................................................................64 
10.2 
Events NOT Meeting the Definition of an Adverse Event ..............................64 
10.3 
Adverse Event Reporting and Descriptions .....................................................64 
10.3.1 
Reporting Period and Follow Up .........................................................64 
10.3.1.1 
Recording and Assessing Adverse Events ..................................65 
10.3.1.2 
Description ..................................................................................65 
10.3.1.3 
Relationship to Study Treatment ................................................65 
10.3.1.4 
Severity .......................................................................................66 
10.3.1.5 
Pregnancy ....................................................................................66 
11 
STATISTICAL METHODS ..................................................................................67 
11.1 
Determination of Sample Size .........................................................................67 
11.2 
Study Endpoints ...............................................................................................67 
11.2.1 
Primary Endpoint .................................................................................67 
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11.2.2 
Secondary Endpoints ...........................................................................68 
11.3 
Statistical Analysis ...........................................................................................69 
11.3.1 
Analysis Populations ............................................................................69 
11.3.2 
General Considerations ........................................................................70 
11.3.3 
Patient Disposition ...............................................................................70 
11.3.4 
Demographics and Baseline Characteristics ........................................70 
11.3.5 
Pharmacokinetic Analyses ...................................................................70 
11.3.6 
Pharmacodynamic Analyses ................................................................70 
11.3.7 
Safety Analyses ....................................................................................71 
11.3.7.1 
Systolic Ejection Time ................................................................71 
11.3.7.2 
Adverse Events ...........................................................................71 
11.3.7.3 
12-lead Electrocardiogram ..........................................................71 
11.3.7.4 
Holter Electrocardiograms ..........................................................72 
11.3.7.5 
Other Safety Analyses .................................................................73 
12 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS ........................74 
12.1 
Compliance Statement .....................................................................................74 
12.2 
Informed Consent.............................................................................................74 
12.3 
Ethics Committee .............................................................................................74 
13 
ADMINISTRATIVE PROCEDURES ..................................................................76 
13.1 
Sponsor’s Responsibilities ...............................................................................76 
13.1.1 
Patient Confidentiality .........................................................................76 
13.1.2 
Study Supplies .....................................................................................77 
13.1.3 
Investigator Training ............................................................................77 
13.1.4 
Ongoing Communication of Safety Information During the Study .....77 
13.1.5 
Study Monitoring .................................................................................77 
13.1.6 
Study Auditing and Inspecting.............................................................78 
13.2 
Investigator’s Responsibilities .........................................................................78 
13.2.1 
Screening Log ......................................................................................78 
13.2.2 
MYK-491 and Matching Placebo Accountability ...............................78 
13.2.3 
Reporting and Recording of Study Data ..............................................78 
13.2.4 
Source Data and Source Documents ....................................................79 
13.2.5 
Patient Identification Information ........................................................79 
13.2.6 
Records Retention ................................................................................79 
13.2.7 
Protocol Deviations ..............................................................................80 
13.2.8 
Blood Sample Collection/Storage ........................................................80 
13.3 
Clinical Trial Insurance ....................................................................................80 
13.4 
Protocol Amendments and Study Administrative Letters ...............................80 
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14 
DATA QUALITY ASSURANCE .........................................................................82 
15 
ADMINISTRATIVE CONSIDERATIONS ..........................................................83 
15.1 
Use of Computerized Systems .........................................................................83 
15.2 
Study Records ..................................................................................................83 
16 
PUBLICATION .....................................................................................................85 
17 
REFERENCE LIST ...............................................................................................86 
APPENDIX 1 
PART 1 SCHEDULE OF STUDY PROCEDURES – SINGLE, 
ASCENDING DOSES .........................................................................87 
APPENDIX 2 
PART 2 SCHEDULE OF STUDY PROCEDURES - MULTIPLE, 
ASCENDING DOSES .........................................................................96 
APPENDIX 4 
LABORATORY ASSESSMENTS ...................................................107 
APPENDIX 5 
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING 
AND ADDITIONAL ASSESSMENTS REPORTING .....................108 
APPENDIX 6 
INVESTIGATOR’S SIGNATURE ...................................................110 
LIST OF TABLES 
Table 1 
Schedules of Assessments ..........................................................................56 
Table 2 
Part 1 (SAD): Screening, Dosing Periods, and Follow up – High-Level ..87 
Table 3 
Part 1 (SAD): Dosing Periods and Follow up – Detailed ..........................90 
Table 4 
Part 1 (SAD): Split Dose Screening, Dosing Periods, and Follow up – 
Detailed ......................................................................................................93 
Table 5 
Part 2 (MAD): Screening, Dosing Periods, and Follow up – High-
Level ..........................................................................................................96 
Table 6 
Part 2 (MAD): Dosing Periods and Follow up – Detailed for Days 3 
and 9 .........................................................................................................101 
Table 9 
Safety Laboratory Parameters ..................................................................107 
 
LIST OF FIGURES 
Figure 1 
Study Schema.............................................................................................36 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
λz 
apparent first-order terminal elimination rate constant  
ACE 
angiotensin converting enzyme 
ADP 
adenosine diphosphate 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ARB 
angiotensin receptor blocker 
ARNI 
angiotensin receptor neprilysin inhibitor 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
 
 
CK-MB 
creatine kinase-MB 
Cmax 
maximum observed plasma concentration 
CRT 
cardiac resynchronization therapy 
CV 
cardiovascular 
 
 
 
 
DB 
double-blind 
 
 
DILI 
drug-induced liver injury 
EC 
ethics committee; refers to an IRB or IEC or equivalent 
ECG 
electrocardiography, electrocardiogram 
eCRF 
electronic case report form 
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EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
 
  
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HFrEF 
heart failure with reduced ejection fraction 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
LVEF 
left ventricular ejection fraction 
LVFS 
left ventricular fractional shortening 
LVOT-VTI 
left ventricular outflow tract-velocity time integral 
LVSV 
left ventricular stroke volume 
MAD 
multiple-ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
mean residence time 
NOAEL 
no observable adverse effect level 
QTc 
heart rate-corrected QT interval 
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QTcF 
QT interval, corrected using Fridericia’s formula 
PD 
pharmacodynamic(s) 
 
 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SET 
systolic ejection time 
sMDRD 
simplified Modification of Diet in Renal Disease 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
apparent first-order terminal elimination half-life 
t1/2z 
the apparent terminal-phase elimination half-life 
TBL 
total bilirubin 
Tmax 
time of maximum observed plasma drug concentration 
TTE 
transthoracic echocardiography, transthoracic 
echocardiogram 
ULN 
upper limit of normal 
US 
United States 
 
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1 
INTRODUCTION 
This is the first administration of MYK-491 to patients with heart failure. Heart failure 
affects about 6.5 million people in the United States (US) and its prevalence is increasing due 
to the aging of the population. Despite therapeutic advances made over the past 10 to 
20 years, it remains a major source of morbidity and mortality, comparable to cancer, with 
more than 50% of heart failure patients dying within 5 years. Heart failure is the leading 
cause of hospitalization in Medicare patients in the US and represents a major financial 
burden to society (Braunwald 2013; Yancy et al, 2013; Benjamin et al, 2017). New, 
innovative therapies are therefore desperately needed for this condition. 
 
 
 
 
 
 
 
 
 
 
 
 
Contemporary medical therapy for HFrEF centers on counteracting the effects of 
neurohormonal activation with β-adrenergic blockers, diuretics, and modulators of the 
renin-angiotensin-aldosterone-system. Although these drugs attenuate some of the 
maladaptive consequences and improve clinical outcomes, none address the underlying 
causal pathways of myocardial dysfunction. 
Several inotropic agents are used in clinical practice to augment cardiac contractility by 
increasing intracellular calcium or cyclic adenosine monophosphate, mechanisms that 
increase myocardial oxygen demand. Their use is limited to short-term therapy in patients 
with refractory or end-stage heart failure because chronic studies with these drugs have 
demonstrated increased mortality due to arrhythmias and ischemia. However, these drugs do 
improve hemodynamics and symptoms. 
An alternative approach to improving hemodynamics is to target the contractile apparatus 
directly. Omecamtiv mecarbil is a small-molecule myosin ATPase allosteric activator 
currently in clinical development for patients with chronic heart failure. It enhances cardiac 
contractility by increasing the number of actin/myosin crossbridges, effectively increasing 
calcium sensitivity at the level of the sarcomere. Clinically, this mechanism is reflected in a 
prolongation of the systolic ejection time (SET). Initial studies in patients with chronic heart 
failure treated with omecamtiv mecarbil suggest that modulation of the sarcomere by myosin 
activation increases stroke volume and promotes beneficial cardiac reverse remodeling. In 
the Phase 2 COSMIC Trial conducted in HFrEF patients, omecamtiv was associated with 
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increased stroke volume and beneficial cardiac reverse remodeling. Although high exposures 
have been associated with myocardial ischemia in a few subjects (Teerlink et al, 2011), in the 
vast majority of patients, the treatment was well-tolerated. A low-level increase in troponin 
was commonly observed without associated clinical ischemia or ECG changes 
(Teerlink et al, 2016). A large randomized cardiovascular (CV) Outcome Phase 3 trial, 
GALACTIC-HF, is currently ongoing in HFrEF patients (ClinicalTrials.gov Identifier: 
NCT02929329). 
MyoKardia undertook detailed biochemical and biophysical studies to understand the 
mechanistic contributors to increased SET by myosin activators. The focus was on 2 steps 
within the actin/myosin chemomechanical cycle: phosphate release (a measure of crossbridge 
formation) and adenosine diphosphate (ADP) release (a measure of crossbridge detachment). 
It was hypothesized that enhanced crossbridge formation increases contractility, whereas 
impaired detachment contributes to further prolongation of ejection time to achieve a given 
degree of contraction. Based on this premise, MyoKardia identified MYK-491, a myosin 
modulator that increases crossbridge formation (measured as phosphate release) without 
inhibition of crossbridge detachment (measured as ADP release). 
 
 
 
 
 
 
 
MyoKardia considers that nonclinical data and preliminary data from healthy volunteers 
support the safe initiation of clinical pharmacology studies of MYK-491 in patients with 
heart failure. 
 
1.1 
Background 
1.1.1 
In Vitro Studies 
MYK-491 reversibly binds to myosin, increasing the number of myosin/actin crossbridges 
available to participate in the strongly bound state of the chemomechanical cycle, thereby 
increasing contraction. MYK-491 does not affect any of the other states of the cycle, nor 
does it affect calcium homeostasis. 
MYK-491 is biochemically specific for striated muscle myosin and selective for the 
slow-twitch isoform found in the heart. Studies in skinned fibers confirm activity in 
slow-twitch fibers (skeletal or cardiac) with minimal effect on fast-twitch skeletal fibers. 
Studies in adult rat cardiac ventricular myocytes demonstrated exposure-dependent increase 
in contraction and confirm that MYK-491 does not modulate calcium homeostasis. Studies in 
skinned cardiac myofibers have demonstrated exposure-dependent increased sensitivity to 
calcium. 
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1.1.3 
Drug Metabolism 
Pharmacokinetics of MYK-491 were determined following single oral and intravenous (IV) 
doses of MYK-491 to FVB mouse, Sprague-Dawley rat, cynomolgus monkey, beagle dog, 
and farm pig (IV only). 
 
 
 
 
 
No unanticipated accumulation in plasma or tissues has been observed in nonclinical studies 
performed to date. Metabolic profiles were generated using rat, monkey, dog, and human 
liver microsomes and hepatocytes. All of the identified metabolites formed from incubations 
with human hepatocytes were also formed in incubations with either rat or dog hepatocytes. 
These results thereby validated the use of rat and dog for toxicology studies. 
 
 
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1.1.5 
MYK-491 
Please refer to the Investigator’s Brochure (IB) for more detailed information on MYK-491. 
1.2 
Clinical Studies 
A single-ascending dose, double-blind (DB), placebo-controlled tolerance, PK, and PD study 
in healthy volunteers has been completed (MYK-491-001). A total of 64 subjects were 
enrolled across 8 cohorts, each consisting of 8 healthy volunteers (6 receiving MYK-491 and 
2 receiving placebo). 
 
No additional Dose-Escalation Cohort(s) are planned. 
In general, MYK-491 has been well-tolerated at all doses.
 
 
 
 
 
 
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1.3 
Known and Potential Risks and Benefits 
There is no expectation of clinical benefit for the patients who volunteer to participate in this 
study. The risks of administering MYK-491 to humans are unknown, but based on 
nonclinical observations and the administration to healthy volunteers, MyoKardia considers 
that it can safely be administered if patients are carefully observed. Safety testing in other 
mammalian species demonstrates that dose-limiting toxicity is related only to on-target 
exaggerated pharmacology with development of myocardial ischemia and heart failure at 
high doses and after prolonged exposures. No off-target adverse effects were observed in the 
toxicology studies. The initial doses of MYK-491 given in this study have already been 
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administered as a single dose to healthy volunteers in a previous study (MYK-491-001) and 
shown to be well-tolerated (see above Section 1.2). 
In Part 1 (single-ascending dose), patients will be admitted to the clinical research facility for 
dosing and will remain confined for a total of 3 days and 3 nights for each of 3 or 4 dosing 
periods or longer if the Safety Review Committee (SRC) believes it is important to assure the 
safety of the patients or to obtain robust PK and/or PD data. In no case will the patients 
remain confined for more than 5 days after the administration of the last dose of MYK-491.  
In Part 2 (multiple-ascending doses), patients will be confined to the clinical research facility 
for the duration of the dosing and 2 days after dosing unless they have an ICD. Patients with 
the ICD will be observed frequently either in the research facility or by a home health nurse 
for all of the dosing, and the collection of the study parameters (plasma samples, safety labs, 
vital signs, and TTEs). Thus, all patients will be under close supervision, and the clinic staff 
will be responsible for the ongoing safety and well-being of the patients while they are 
confined for during the dosing periods. If a home health nurse is utilized, the nurse and site 
will be in daily communication to ensure safety. The initial dose for the MAD Cohort is 
predicted to reach exposures that have previously been observed in patients in Part 1. 
 
 
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2 
RATIONALE FOR THE STUDY AND FOR DOSE AND DOSING 
SCHEDULE 
2.1 
Rationale for the Study 
MYK-491 was well-tolerated in healthy volunteers after the administration of single doses 
(see Section 1.2) and has been studied extensively preclinically across a variety of 
pharmacological activity and nonclinical safety evaluation platforms. The purpose of this 
study is to determine the safety, tolerability, PK profile, and PD activity of MYK-491 in 
patients with HFrEF. In animal studies, paced dogs with heart failure were found to be more 
sensitive to the positive inotropic effects of MYK-491 compared to healthy dogs. Patients 
suffering from HFrEF have reduced cardiac output and reduced organ perfusion. It is 
therefore important to understand any potential differences in the safety, tolerability, PK, and 
PD inotropic effects of MYK-491 in patients with HFrEF compared to healthy volunteers. 
This study will allow for the initial assessment of the therapeutic dose/concentration range of 
MYK-491 and guide the choice of doses to be studied in subsequent trials in HFrEF patients. 
Randomization and blinding are employed to minimize bias in ascertainment of potential 
causality with respect to overall tolerability and adverse clinical and laboratory events. A 
placebo control is used to provide a degree of assay sensitivity with respect to these 
parameters. 
2.2 
Rationale for Dose and Dosing Schedule 
2.2.1 
Part 1 (SAD) Cohort 1 Dose Levels 
2.2.1.1 
Low-Dose Level Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
the 175 mg dose has been selected as the initial dose level in 
Cohort 1. 
2.2.1.2 
Second Dose Level Cohort 1 
The second dose that will be studied in Cohort 1 is 350 mg.
 
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2.2.1.3 
Third Dose Level Cohort 1 
A third active dose may be administered to some patients in Cohort 1. The third active dose 
will be determined for individual patients by the SRC after reviewing data for the first and 
second doses. The third dose may be different for each subject based on individual PK (or 
dose/exposure) 
 
 
 
 
 
 
 
 
 
. 
2.2.2 
Part 1 (SAD) Cohort 2 Dose Levels 
The selection of the 3 doses for Cohort 2 will be determined based on SRC review of data 
from Cohort 1 together with other available data on MYK-491. 
 
 
 
 
 
 
 
 
 
 Cohort 2 could also include less than 3 doses. 
The SRC may determine that some or all of the doses in Cohort 2 may be given in 2 aliquots 
as a split dose, in order to achieve higher exposure. The SRC will determine the timing of the 
administration of the second half of the dose relative to the first. 
2.2.3 
Part 2 (MAD) Cohort A Dose 
The dose level chosen for Cohort A in Part 2 of the study is 75 mg given twice daily. 
 
 
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2.2.4 
Part 2 (MAD) Cohorts B and C Doses 
 
 
The actual medium and high doses will be determined 
and confirmed by the Safety Review Committee (SRC) after data from prior cohorts are 
reviewed.
 
  
2.3 
Rationale for Exceeding NOAEL 
It should be noted that achieving plasma concentrations in humans exceeding the NOAEL 
maximum observed plasma concentration (Cmax) values 
 
 is likely to be necessary in order to adequately evaluate the safety and 
tolerability of pharmacologically active single doses of MYK-491 in humans (healthy 
subjects and heart failure patients), in light of the following considerations: 
• MYK-491 is expected to have a PD effect in humans because the primary pharmacology 
studies establishing the biochemical mechanism of action confirmed its activity using 
recombinant human myosin (IB, Sections 4.1.2 and 4.2.1). However, differences in free 
fraction/protein binding and in potency on cardiac tissue may account for observed 
interspecies differences. 
• 
• 
• In the definitive toxicology studies (IB, Sections 1.6 and 4.4), all toxicities above the 
NOAEL were consistent with on-target exaggerated pharmacological effects of 
MYK-491. No evidence of off-target toxicity was observed.  
• The PK profile observed in humans is generally in line with the one predicted from 
nonclinical PK and toxicokinetic data, which provide confidence in the exposures with 
further dose escalation. 
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• Both studies (491-001 and 491-003) were/will be conducted under the surveillance of 
Study Safety Review Committees (1 each for 491-001 and 491-003 studies). 
• In addition, Study 491-003 includes adequate safeguards to maximize patient safety. 
These include but not are limited to: close patient monitoring with serial assessments of 
vital signs, AEs, safety labs (including troponin), serial ECGs, continuous real-time 
telemetry and/or Holter, and PK data. Also, Study 491-003 includes clear stopping 
criteria for both individual patients and for the overall study based on observed 
safety/tolerability, AEs, and predefined levels of on-target TTE PD activity. 
 
All the above features provide a strong rationale to identify, in a safe manner and with 
appropriate safeguards, a clear pharmacologically active dose for MYK-491, a new and 
innovative oral positive inotropic agent for heart failure patients.  
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to establish preliminary safety and tolerability of single- 
and multiple-ascending oral doses of MYK-491 in ambulatory patients with stable HFrEF. 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To establish preliminary human PK of MYK-491 after single- and multiple-ascending 
oral doses of MYK-491 in patients with HFrEF 
• To determine changes in left ventricular stroke volume [LVSV] derived from left 
ventricular outflow tract-velocity time integral [LVOT-VTI]), left ventricular ejection 
fraction (LVEF) and change in left ventricular fractional shortening [LVFS] with 
MYK-491 after ascending single and multiple doses compared with Baseline and placebo 
as measured by transthoracic echocardiography (TTE) 
• To determine changes in SET with MYK-491 after ascending single and multiple doses 
compared with Baseline and placebo as measured by TTE 
• To determine changes in PD dose/concentration effects (change in LVSV [derived from 
LVOT-VTI], LVEF, LVFS) with MYK-491 compared with Baseline and placebo after 
ascending single and multiple doses, as measured by TTE 
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4 
OVERALL STUDY DESIGN AND PLAN 
4.1 
Study Design 
This is a two-part study. Part 1 will evaluate single-ascending doses of MYK-491 (SAD 
Cohorts) and Part 2 will evaluate multiple-ascending doses of MYK-491(MAD Cohorts). 
Note: Part 2 (MAD portion) of the study is planned to start before Cohort 2 of Part 1 (SAD 
Cohort) is complete. If a patient at a site qualifies for enrollment in either Part 1 (SAD) or 
Part 2 (MAD), Part 2 will generally take priority; however, a patient may enroll in both, ie 
Part 1 (SAD) followed by Part 2 (MAD) or Part 2 (MAD) followed by Part 1 (SAD). In such 
cases, sites should consult with the monitoring team to discuss details. 
4.1.1 
Part 1 Study Design 
Part 1 is a randomized, crossover, DB, placebo-controlled, two-cohort, sequential ascending 
(oral) single-dose study in ambulatory patients with heart failure. All patients will receive 
placebo and 2 or 3 active doses of MYK-491. Each patient will undergo sequential, single-
dose treatment events separated by no fewer than 5 days and no more than 14 days. Patients 
in Cohort 1 may also return for a fourth dosing period (open label) after the SRC reviews 
available data and recommends the dose. Patients enrolled prior to the implementation of 
Amendment 1 may be offered the opportunity to return for the open-label period. Patients 
who return for this additional period must sign the amended informed consent form (ICF). 
Patients in Cohort 2 may participate in 2 to 4 dosing periods, based on SRC decision. Patients 
will be randomized to 1 of the different dosing sequences outlined in Figure 1. Multiple 
patients can be dosed at the same time or during the same week depending on administrative 
issues, ie, capacity and scheduling.  
For each dosing period, patients will be admitted to the clinical site on Day -1. Patients will 
be assessed for absence of exclusion criteria (eg, new lab abnormalities and/or conditions that 
indicate the patient is clinically unstable). They will receive MYK-491 or placebo in the 
morning of Day 1 followed by serial PK and PD assessments, as well as serial safety 
assessments. Patients will be discharged on Day 3 (ie, ~48 hours following Day 1 dosing). 
An additional outpatient plasma PK sample will be taken on the morning of Day 4 at 
72 hours postdose. 
Before administering a dose, the investigator or the subinvestigator will review all available 
safety data, including vital signs, safety laboratory values including locally assayed troponin 
concentrations, TTEs, ECGs, and ECG telemetry. Dosing with DB treatment will take place 
at the same time each of the dosing days. Background concomitant medications, including 
diuretic if applicable, should also be administered at same time each of the dosing days. Prior 
to dosing, any patient with a predose resting HR ≥ 95 bpm will be considered ineligible and 
not treated. HR is the mean of 3 measurements. 
A full PK profile and multiple TTEs and ECGs will be obtained at Baseline and after each 
dose. Patients will return for a final safety Follow-up visit 7 days (± 1 day) following the last 
dose. 
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During the study, the patients should continue to ingest their medications for the treatment of 
their congestive heart failure and other medical conditions at the same doses and as close to 
the same times as usual. 
4.1.2 
Part 2 Study Design 
This is a randomized, parallel-group, DB, placebo-controlled, adaptive design, sequential 
ascending (oral) multiple-dose study in stable patients with heart failure. Three MAD 
Cohorts (A, B, C) are initially planned (with additional optional cohorts) with 8 patients each 
(2 placebo, 6 active). An SRC will review results from each cohort and will determine the 
dose and confirm initial sample size for the subsequent cohort. Additionally, the first 3 
patients in each cohort must have LVEF ≥ 25%; the SRC will review preliminary safety data 
from these patients and decide whether to open cohort enrollment to patients with LVEF 
< 25%. 
After Screening and qualification, patients will be confined to a clinical testing facility from 
Day 1 (Check-in) to Day 11. This includes an initial 2-day placebo dosing period (Days 1 
and 2), followed by a 7-day randomized treatment period (Days 3 through 9) and 48 hours of 
monitoring following the last dose of study drug (Days 10 and 11). An additional outpatient 
plasma PK sample will be taken on the morning of the day following discharge at 72 hours 
after the last dose (Day 12). 
Note: Confinement is not required for patients with an ICD: Patients with an ICD may 
reside for some or all of the period from Day 1 to 12 in close proximity to the Clinical 
Testing Unit, eg, at a hotel, provided they can return for all study drug dosing and all study 
assessments, including but not limited to all serial PK and TTEs. Alternatively, patients may 
be visited by a home health nurse for study drug administration and for any assessments that 
can be performed away from the clinical site. 
Each patient will initially receive placebo BID for 2 days (Days 1 and 2) in single-blinded 
manner (“run-in” during acclimatization to confinement in the Clinical Testing Unit) prior to 
receiving the randomized DB study drug treatment on Day 3. All patients will then receive 
either placebo or active MYK-491 for 7 days (Days 3 through 9). More than one patient can 
be dosed in a cohort at the same time or during the same week depending on administrative 
issues, i.e., capacity and scheduling. 
Patients will be dosed twice daily (every 12 hours). Doses may occur ± 2 hours from 
scheduled dosing times as long as doses are separated by at least 10 hours and by no more 
than 14 hours. The exception to the twice daily dosing is on Day 9 (last dose of randomized 
DB study drug treatment). On Day 9, a single morning dose will be administered followed by 
72 hours of PK and PD assessments.  
Before each dosing event, all available safety data from the previous days will be reviewed 
(for non-confined patients, if a home health nurse is utilized, the nurse and site will be in 
daily communication to ensure safety). Dosing of DB treatment will take place at 
approximately the same time each day.  
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A full PK profile and multiple TTEs and ECGs will be obtained on Days 3 and 9 
(corresponding to first and last day of DB treatment respectively) before and after the 
morning dose. 
Patients will return for a Follow-up visit 7 days following the last dose of study drug. In case 
of premature permanent treatment discontinuation, end-of-treatment visit (same assessments 
as Day 9) will be performed as close as possible to last DB dose (ie, as best as possible on 
day of last dose or next day). This visit should include (but is not limited to) the following 
assessments: TTE, PK, 12-lead ECG, safety labs, troponin and adverse events. 
Note: Screening may continue during planned and unplanned SRC meetings. The protocol-
specified Screening window may be extended to account for delays due to SRC meetings. 
Recommendations by the SRC will include, but not be limited to: (a) evaluation of dose-
modification and dose-stopping criteria; (b) doses to be given in specified cohorts; (c) size of 
specified cohorts; and (d) modification of the number and timing of PK and PD assessments 
(see Section 4.4.1). 
 
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Figure 1 
Study Schema 
 
BID, twice daily; MAD, multiple-ascending doses; PLBO, placebo; QD, once daily; R, randomization; SAD, single-ascending doses; SRC, Safety Review 
Committee; TBD, to be determined (Period D is optional, based on SRC evaluation). 
NOTE: Additional Cohorts D and E, and possible additional cohorts, may be enrolled, eg to explore QD dosing or an alternative BID regimen. 
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4.2 
Stopping Criteria 
For Part 1, as each patient will receive several, ascending single doses, there are stopping 
criteria for which further dosing of an individual patient must be suspended, and also 
stopping criteria for the study to be considered by SRC. 
For Part 2, as each patient will receive 9 days of study drug treatment (including 2 days of 
single-blind placebo and 7 days of DB active or placebo), there are dose-modification criteria 
and stopping criteria for individual patients, as well as stopping criteria for the study to be 
considered by SRC. 
4.2.1 
Stopping Criteria for an Individual Participant in Part 1 (SAD) 
If the following events occur, as determined by investigator assessment, dosing of a patient 
must be suspended, AE/SAE forms completed as applicable, and the event reviewed by the 
SRC. The SRC may decide to perform selected unblinding pertaining to one or several 
periods for a given patient or recommend that further dosing of the patient be suspended. The 
following is a list of possible criteria for suspension of dosing of an individual and review of 
the data by the SRC: 
• A patient has drug-related cardiac ischemia, as determined by investigator (Note: The 
whole context [ie, clinical symptoms, ECG, and cardiac biomarkers such as troponin, 
CK-MB, cardiac imaging, and coronary angiograms, if applicable] should be taken into 
account by the investigator in making that determination since patients enrolled in the 
study are likely to have an abnormal ECG and/or elevated and/or fluctuating troponin at 
Baseline in relation to their heart failure condition. This information will also be 
submitted for subsequent central adjudication.  
• A patient has an increase in the maximal SET > 75 ms on 2 sequential TTE recordings 
based on site evaluations. 
• A patient has clinically significant and drug-related changes in his/her vital signs that are 
persistent over a period of time such as a new arrhythmia, systolic BP < 90 or 
> 170 mm Hg, or HR < 40 or > 100 bpm. The diagnosis and clinical significance of a 
new arrhythmia will be adjudicated by the SRC as it relates to this stopping criterion, 
including core lab assessments as appropriate. 
• A patient experiences a drug-related SAE (including, but not limited to, serious 
unexpected suspected adverse reactions [SUSARs] or coronary ischemic events). 
• A patient has a QTc interval > 500 ms (Fridericia’s correction, average of triplicate 
ECGs) not attributable to pacing or prolonged QRS duration. 
• Any patient fulfills the criteria for potential drug-induced liver injury (Hy’s Law). These 
include: 
- 
Aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase 
[AST]) are > 3 times ULN with an associated elevation of total bilirubin (TBL) 
> 2 times ULN without evidence of hemolysis, or 
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- 
ALT or AST activity that is > 5 times ULN, or 
- 
TBL > 3 times ULN. 
• A patient has 2 successive echocardiograms that show a > 50% relative increase from 
Baseline in at least 2 contractility indices (LVSV [derived from LVOT-VTI], LVEF, or 
LVFS). 
4.2.2 
Criteria for Unscheduled SRC Review of the Study in Part 1 (SAD) 
If any of the following events occur at any time during the study, an ad hoc SRC review will 
be performed. Dosing may be paused for SRC review; eg, in case of drug-related SAEs, 
SUSAR, or coronary ischemic events (see Section 4.2.1). Based on the review of the data, the 
SRC may decide to unblind selected patients, terminate the study, continue dosing the 
patients using a modified dose-escalation scheme, or continue the dosing of the patients.  
• The dosing of 2 patients who received MYK-491 is suspended because they reached the 
individual stopping criteria. The SRC will adjudicate stopping criteria. 
• During the planned review by the SRC after the initial 4 patients in Cohort 1, evidence of 
PD activity will be considered to have been observed and dose escalation will be 
terminated if there is a Baseline-corrected, group mean relative increase of > 40% in 
2 successive timepoints in 2 contractility indices (LVSV [derived from LVOT-VTI], 
LVEF, LVFS) in patients receiving MYK-491. Placebo-adjusted evaluation may be 
considered. The study may continue with the enrollment of Cohort 2, but the daily doses 
to be administered will not be greater than the daily dose that demonstrated the PD 
activity that terminated dose escalation. 
• Any patient receiving MYK-491 experiences a drug-related SAE (including, but not 
limited to, a SUSAR or coronary ischemic event) that has not also occurred in a patient 
receiving placebo. 
• Two or more patients receiving MYK-491 have QTc prolongation defined as > 500 ms 
(Fridericia’s correction, average of triplicate ECGs) not attributable to pacing or 
prolonged QRS duration. 
• Any patient receiving MYK-491 fulfills the definition for Hy’s law:  
• Aminotransferases (ALT or AST) are > 3 times ULN with an associated elevation of 
TBL > 2 times ULN without evidence of hemolysis, or 
• ALT or AST activity that is > 5 times ULN, or 
• TBL > 3 times ULN. 
Note: Screening may continue during an unscheduled SRC meeting, and if dosing is paused, 
Screening windows may be extended until dosing resumes. 
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4.2.3 
Dose-Modification Criteria for an Individual Participant in Part 2 (MAD) 
If the following events occur, as determined by investigator assessment, dosing of a patient 
should be modified by skipping one dose of study drug and resuming dosing at a lower dose 
(25% to 50% lower). The lower dose to be administered for a given cohort will be 
determined by SRC and communicated along with starting dose. 
 
  
• An increase in the maximal SET > 75 ms on 2 sequential TTE recordings based on site 
evaluations 
• A patient has 2 successive echocardiograms that show a > 50% relative increase from 
Baseline in at least 2 contractility indices (LVSV [derived from LVOT-VTI], LVEF, or 
LVFS). 
Note: Day 3, predose echo in the morning should be used as Baseline for local site 
evaluation. 
In addition, in case of an AE, DB treatment may be temporarily suspended, as determined by 
the investigator. In such cases, the Sponsor medical monitor should be contacted without 
delay. 
4.2.4 
Stopping Criteria for an Individual Participant in Part 2 (MAD) 
If the following events occur, as determined by investigator assessment, dosing of a patient 
must be terminated, AE/SAE forms completed as applicable, and Sponsor should be 
informed without delay: 
• Drug-related coronary ischemia, as determined by investigator  
Note: Whole context ie, clinical symptoms, ECG, cardiac biomarkers such as troponin, 
CK-MB, cardiac imaging, and coronary angiograms, if applicable, should be taken into 
account by the investigator in making that determination since patients enrolled in the 
study are likely to have elevated and/or fluctuating troponin and/or abnormal ECGs at 
Baseline in relation to their heart failure condition. This information will also be 
submitted for subsequent central adjudication. 
• The patient has clinically significant and drug-related changes in his/her vital signs that 
are persistent over a period of time such as a new arrhythmia, systolic BP < 90 or 
> 170 mm Hg, or HR < 40 or > 100 bpm. The diagnosis and clinical significance of a 
new arrhythmia will be adjudicated by the SRC as it relates to this stopping criterion. 
• A patient experiences a drug-related SAE (including, but not limited to, SUSARs or 
coronary ischemic events). 
• A patient has a QTcF interval > 500 ms (Fridericia’s correction, average of triplicate 
ECGs) not attributable to pacing or prolonged QRS duration. 
• Any patient fulfills the criteria for potential drug-induced liver injury (Hy’s Law). These 
include: 
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- 
Aminotransferases (ALT or AST) are > 3 times ULN with an associated elevation of 
TBL > 2 times ULN without evidence of hemolysis, or 
- 
ALT or AST activity that is > 5 times ULN, or 
- 
TBL > 3 times ULN. 
4.2.5 
Criteria for Unscheduled SRC Review of the Study in Part 2 (MAD) 
If any of the following events occur at any time during the study, an ad hoc SRC review will 
be performed. Dosing may be paused until SRC review; eg, in case of drug-related SAEs, 
SUSAR, or coronary ischemic events. Based on the review of the data, the SRC may decide 
to unblind selected patients, terminate the study, continue dosing the patients using a 
modified dose-escalation scheme or continue the dosing of the patients.  
• Two patients in a cohort receiving MYK-491 reached individual dose-modification 
and/or stopping criteria. The SRC will adjudicate stopping criteria. 
• Any patient receiving MYK-491 experiences a drug-related SAE (including, but not 
limited to, a SUSAR or coronary ischemic event) that has not also occurred in a patient 
receiving placebo. 
• Any patient receiving MYK-491 fulfills the definition for Hy’s law  
• Aminotransferases (ALT or AST) are > 3 times ULN with an associated elevation of 
TBL > 2 times ULN without evidence of hemolysis, or 
• ALT or AST activity that is > 5 times ULN, or 
• TBL > 3 times ULN. 
Note: Screening and dosing may be paused or may continue during an unscheduled SRC 
meeting. 
4.3 
Study Duration 
The overall expected study duration is approximately 24 months. 
In Part 1 (SAD), each patient is expected to be in the study no more than 77 days: up to 
28 days for Screening plus up to 42 days for dosing including 7 days for follow up after the 
last dose (or longer if clinically indicated). Patients returning for an additional dosing period 
in Cohort 1 may have prolonged participation. Patients will be resident at the clinical site for 
each dosing period, each consisting of check-in on Day -1, dosing the following morning 
(Day 1) followed by ~24 hours of serial PD and ~48 hours of serial PK assessments, 
followed by discharge the following morning (Day 3). An additional outpatient plasma PK 
sample will be taken on the morning of Day 4 at 72 hours postdose. 
In Part 2 (MAD), patients are expected to be in the study no more than 56 days: up to 28 days 
for Screening plus up to 28 days for (a) scheduling, (b) 11 days of dosing and associated 
assessments, and (c) 7 days of follow up after the last dose (or longer if clinically indicated). 
Patients who are in Screening while dosing is on hold due to SRC meeting may have 
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participation extended to allow dosing to be scheduled after SRC has convened. While 
waiting for a cohort to open to patients with LVEF < 25%, these patients may be in 
Screening up to 12 weeks (if the patient remains stable) while the SRC convenes. 
Total time in the study may be longer for patients who participate in both Part 1 (SAD) and 
Part 2 (MAD). 
4.4 
Safety Review Committee 
4.4.1 
Safety Review Committee Meetings 
In Part 1 (SAD), the SRC will meet to review the data after each patient in Cohort 1 has 
completed the first 3 dosing periods (175 mg, 350 mg, and placebo). The SRC will determine 
if the subject will receive a third active dose level (open-label Period D) and what the dose 
should be. The SRC will also meet at the conclusion of Cohort 1 and after all of the patients 
have completed the study. The SRC will review all relevant data to select the dosing levels 
for Cohort 2. During Cohort 2 dosing, the SRC will meet to review the data after every 2 to 
4 patients have completed all dosing periods. The SRC may recommend dose modification 
for the remainder of the cohort. 
In Part 2 (MAD), the SRC will review data after at least 4 to 8 patients from a cohort have 
been dosed. The SRC will then confirm the sample size, dose, and regimen (BID or QD) for 
next MAD Cohort, or may decide to expand current MAD Cohort. Additionally, the SRC 
will review preliminary safety data after the first 3 patients in each cohort, with LVEF 
≥ 25%, to decide whether to open cohort enrollment to patients with LVEF < 25%. 
A Notification Letter with the rationale for the choice of doses selected by the SRC will be 
sent to the investigator, who will inform the appropriate Institutional Review Boards (IRBs) 
as necessary. 
Refer to Section 4.2.2 and Section 4.2.5 for criteria leading to ad hoc SRC meetings. 
SRC data review will be based on unblinded data summary (see Section 6.2). 
4.4.2 
Composition of Safety Review Committee 
The SRC will be composed of at least 5 members including 2 Sponsor representatives and 
3 independent cardiologists. The Sponsor’s medical monitor will act as chair of the 
committee. Sponsor representatives (including the Sponsor’s medical monitor) will not be 
voting members. The 3 independent cardiologists will be the only voting members. Three 
members including the Sponsor’s medical monitor and 2 independent cardiologists need to 
be present for a quorum, with at least 2 independent cardiologists available for voting. In 
case of a tie, all 3 independent cardiologists should vote. Other individuals may attend the 
meeting to share data, but they will not be voting members. All dosing recommendations for 
individual patients in Period D in SAD Cohort 1 will be discussed with the investigators 
whose patient it is. 
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Following review of the existing study data, the SRC may consider recommending changes 
to the protocol intended to enhance patient safety, data integrity, data robustness, or 
efficiency of study conduct. As part of the review process, the SRC may need to review the 
unblinded data. SRC members should consider the possible scenarios and the nature of the 
decision on study continuation or dose level and what they would consider the appropriate 
next step (eg, repeat the dose level, continue the dose escalation with reduced dose-escalation 
steps, or terminate the study). 
• All substantial changes to the study protocol will be captured in the meeting minutes, and 
a protocol amendment will be instituted if needed. 
• Nonsubstantial changes to the study approved by the SRC may be implemented 
immediately without a protocol amendment, and the IRB/Ethics Committee (EC) (as 
defined in Section 12.3) will be immediately notified in writing of the change. Examples 
of these changes are: reducing the dose of the study medication, expanding enrollment, or 
adjusting timepoints for procedures. Additional blood samples for PK may be obtained 
but no more than 2 additional timepoints for each dosing period (a maximum increase of 
36 mL of blood in total) will be requested. An increase in the number of TTEs, ECGs, or 
vital sign determinations that may be obtained will also be considered a nonsubstantial 
change, as these are noninvasive procedures, but no more than 2 additional TTEs will be 
obtained per dosing period. 
 
For Part 2 (MAD), the SRC will review data after at least 4 to 8 patients from a cohort have 
been dosed. The SRC will then confirm the sample size, dose, and regimen (BID or QD) for 
next MAD Cohort, or may decide to expand current MAD Cohort. 
All decisions of the SRC will be documented and provided as appropriate to parties involved 
with the study. 
4.5 
Independent Safety Adjudication 
Suspected cardiac ischemia (new chest pain or angina equivalent, or new ECG changes 
suggestive of ischemia), new or worsening ventricular arrhythmia, and troponin elevations 
will be reviewed centrally by an independent safety Adjudication Committee. Adjudication 
package will include relevant associated clinical data and source documents including but not 
limited to ECGs.  
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5 
SELECTION AND WITHDRAWAL OF STUDY POPULATION 
In Part 1 (SAD), enrollment of at least 4, and no more than 8, patients is planned for 
Cohort 1, with 1 patient randomized to each sequence of dose escalation and placebo 
administration (see Figure 1). For Cohort 2, at least 4, and no more than 8, patients will be 
enrolled and 2 patients will be randomized to each sequence of dose escalation. 
There will be an option for the SRC to expand Cohort 1 or Cohort 2 to meet study objectives. 
Decision to expand the number of patients or not will be made by the SRC. Two additional 
patients may be enrolled as replacements for drop-outs in each cohort, so the maximum 
number of patients that may be enrolled will be approximately 32. 
In Part 2 (MAD), enrollment of a total of a minimum of 24 patients is planned, with 
8 patients enrolled the low-dose group (Cohort A), 8 patients enrolled in the medium-dose 
group (Cohort B) and 8 patients enrolled in the high-dose group (Cohort C). In addition, the 
planned size of Cohorts D and E, and possible additional cohorts, will be 8 patients each. The 
final total sample size for Part 2 will not exceed 96 patients if the SRC decides to expand one 
or more cohorts up to 24 patients. In addition, up to 2 additional patients may be enrolled per 
cohort as replacements for drop-outs or patients non-evaluable for PK-PD at steady-state. 
Cohorts in Part 2 will be randomized 3:1 (active drug: placebo). Additional patients may be 
enrolled in each cohort as replacements for drop-outs. 
Note: Part 2 (MAD portion) of the study is planned to start before Cohort 2 of Part 1 (SAD 
Cohort) is complete. If a patient at a site qualifies for enrollment in either Part 1 (SAD) or 
Part 2 (MAD), Part 2 will generally take priority. However, a patient may also enroll in both; 
ie, Part 1 (SAD) followed by Part 2 (MAD) or Part 2 (MAD) followed by Part 1 (SAD). If a 
patient will cross over, sites should consult with the monitoring team to discuss prior to 
randomization. 
5.1 
Inclusion Criteria 
This study is to be performed in patients with HFrEF due to any etiology. Each patient must 
meet the following criteria to be included in this study: 
1. Able to understand and comply with the study procedures, understand the risks involved 
in the study, and provide written informed consent according to federal, local, and 
institutional guidelines before the first study-specific procedure 
2. Men or women 18 to 80 years of age at the Screening visit 
3. Body mass index (BMI) 18 to 40 kg/m2, inclusive, at the Screening visit and all required 
assessments can be reliably performed. 
4. Sinus rhythm or stable atrial pacing with mean resting HR 50-95 beats per minute (bpm), 
inclusive (Patient will be ineligible to dose if, on Day 1, the predose HR measurement is 
≥ 95 bpm. Heart rate is the mean of 3 measurements taken 1 minute apart. A single 
measurement would not make a patient ineligible.) 
5. Has stable, chronic HFrEF of moderate severity as defined by all of the following: 
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• For the first 3 patients in each MAD Cohort testing a new (higher) daily dose: 
documented LVEF 25% to 35% during Screening (as confirmed by ECHO Central 
Lab) 
• For other patients in the MAD Cohorts (and all patients in SAD Cohorts): 
documented LVEF 15% to 35% during Screening (as confirmed by ECHO Central 
Lab) 
• LVEF must be confirmed with second screening ECHO to be 
performed at least 7 days after initial screening ECHO.  Results of 
both must meet inclusion criteria and must be received from core lab 
prior to dosing.  In the event of extended screening windows due to 
SRC reviews, effort should be made to ensure second ECHO is near 
planned time of randomization. 
• Chronic medication for the treatment of heart failure consistent with current 
guidelines that has been given at stable doses for ≥ 2 weeks with no plan to modify 
during the study. This includes treatment with at least one of the following unless not 
tolerated or contraindicated: beta-blocker, angiotensin converting enzyme (ACE) 
inhibitor/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor 
(ARNI). 
6. Female patients must not be pregnant or lactating. Male patients (including men who 
have had vasectomies), as there may be a risk of drug being secreted in the ejaculate, 
should use barrier methods for the duration of the study and for 3 months after the last 
dose of study medication. All patients, if sexually active, must be using one of the 
following highly-effective birth control methods from the Screening visit through 
3 months after the last dose of investigational medicinal product (IMP): 
• Hormonal contraception associated with inhibition of ovulation, intrauterine device 
(IUD), or intrauterine hormone-release system (IUS) plus barrier (eg, male using 
condom or female using diaphragm or cervical cap) 
• Vasectomy plus barrier  
• Female is surgically sterile for 6 months or postmenopausal for 1 year. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, 
and/or documented bilateral tubal occlusion at least 6 months prior to Screening. 
Females are considered postmenopausal if they have had amenorrhea for at least 
1 year or more following cessation of all exogenous hormonal treatments, and 
follicle-stimulating hormone (FSH) levels are in the postmenopausal range. 
• Male patients with postmenopausal partners 
5.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
1. Inadequate echocardiographic acoustic windows 
2. Any of the following ECG abnormalities: (a) QTcF > 480 ms (Fridericia’s correction, not 
attributable to pacing or prolonged QRS duration, average of triplicate Screening ECGs) 
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or (b) second-degree atrioventricular block type II or higher in a patient who has no 
pacemaker 
3. Hypersensitivity to MYK-491 or any of the components of the MYK-491 formulation 
4. Active infection as indicated clinically as determined by the investigator 
5. History of malignancy of any type within 5 years prior to Screening, with the exception 
of the following surgically excised cancers occurring more than 2 years prior to 
Screening: in situ cervical cancer, nonmelanomatous skin cancers, ductal carcinoma in 
situ, and nonmetastatic prostate cancer 
6. Positive serologic test at Screening for infection with human immunodeficiency virus 
(HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) 
7. Hepatic impairment (defined as alanine aminotransferase (ALT)/ aspartate 
aminotransferase (AST) > 3 times ULN and/or total bilirubin (TBL) > 2 times ULN) 
8. Severe renal insufficiency (defined as current estimated glomerular filtration rate [eGFR] 
< 30 mL/min/1.73 m2 by simplified Modification of Diet in Renal Disease equation 
[sMDRD]) 
9. Serum potassium < 3.5 or > 5.5 mEq/L 
10. Any persistent out-of-range safety laboratory parameters (chemistry, hematology, 
urinalysis), considered by the investigator and medical monitor to be clinically significant 
11. History or evidence of any other clinically significant disorder, condition, or disease 
(including substance abuse) that, in the opinion of the investigator or MyoKardia 
physician, would pose a risk to patient safety or interfere with the study evaluation, 
procedures, or completion, or lead to premature withdrawal from the study 
12. Participated in a clinical trial in which the patient received any investigational drug (or is 
currently using an investigational device) within 30 days prior to Screening, or at least 
5 times the respective elimination half-life (whichever is longer) 
13. Previous participation in a clinical trial with MYK-491, with the exception that patients 
that participated or were screen failures in one part of this trial may participate in the 
other part, ie patients may enroll in Part 1 (SAD) followed by Part 2 (MAD) or Part 2 
(MAD) followed by Part 1 (SAD), with the following caveats: 
• If the patient has an ongoing AE, has had an SAE, or has met any stopping 
criteria, the investigator should contact the Sponsor prior to enrolling the patient 
in a subsequent cohort. 
• Patients must have at least 1 week washout after the end of MAD dosing prior to 
SAD dosing, or at the end of SAD dosing prior to MAD dosing. 
• Patients do not need to rescreen if MAD screening occurred within 12 weeks of 
the first SAD dosing, or if SAD screening occurred within 12 weeks of the first 
MAD dosing. Investigators should verify that patients are clinically stable and no 
exclusions have occurred during the interim; if > 12 weeks have elapsed or there 
is clinical instability, then patients should be rescreened. 
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14. Unable to comply with the study restrictions/requirements, including, in particular, the 
number of required overnight stays at the clinical site 
15. Is employed by, or is a first-degree relative of someone employed by, MyoKardia or 
Sanofi, the investigator, or his/her staff or family 
16. At Screening, symptomatic hypotension, or systolic BP > 170 mmHg or < 90 mmHg, or 
diastolic BP > 95 mmHg, or HR < 50 bpm. HR and BP will be the mean of 
3 measurements taken at least 1 minute apart. 
17. Current angina pectoris 
18. Recent (< 90 days) acute coronary syndrome 
19. Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery 
bypass graft [CABG]) within the prior 3 months 
20. Recent (< 90 days) hospitalization for heart failure, use of chronic IV inotropic therapy or 
other cardiovascular event (e.g., cerebrovascular accident) 
21. Uncorrected severe valvular disease 
22. Elevated Troponin I (> 0.15 ng/mL) at Screening, based on Central Laboratory 
assessments. Note: Central Laboratory Troponin I assay ULN is 0.03 ng/mL 
23. Presence of disqualifying cardiac rhythms that would preclude study ECG or 
echocardiographic assessments, including: (a) Current atrial fibrillation, (b) recent 
(< 2 weeks) persistent atrial fibrillation, or (c) frequent premature ventricular 
contractions. Note: Patients with active cardiac resynchronization therapy (CRT) or pace-
maker (PM) are eligible if initiated at least 2 months prior with no plan to change CRT or 
PM settings during the study. 
24. A life expectancy of < 6 months 
5.3 
Withdrawal and Replacement of Patients 
The investigator will make every reasonable attempt to retain patients so that they complete 
the study. Two additional patients may be enrolled in each cohort as replacements for 
drop-outs as long as the patients did not permanently discontinue treatment because of drug-
related AEs, or for patients non-evaluable for PK-PD at steady state. 
5.3.1 
Withdrawal from the Study 
Patients may withdraw from further participation in the study at any time and for any reason. 
The degree to which a patient withdraws can vary, and efforts will be made to collect 
important safety data if feasible and the patient agrees. 
Patients can: 
• Withdraw from treatment and agree to participate in the Early Termination (Safety 
Follow-up) visit 
• Withdraw from treatment and all follow up 
 
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The investigator or MyoKardia may withdraw a patient from treatment in the study for any of 
the following (or other) reasons: 
• AE 
• Noncompliance with study procedures/restrictions 
• Study termination by MyoKardia 
 
In all cases, the reason(s) for study withdrawal will be recorded in the source document and 
on the appropriate electronic case report form (eCRF). 
5.3.2 
Follow-up Procedures After Withdrawal 
The investigator will make every effort to complete the protocol-specified follow-up 
procedures as specified in Appendix 1 and Appendix 2, including the follow up of any 
unresolved AEs until the AE is resolved or stabilized. 
If patient discontinues DB treatment prematurely, every effort should be made to have an 
end-of-treatment visit conducted as soon as possible (ie, as best as possible same day or next 
day) after the last dose of DB treatment, and perform PK, safety labs, and TTE assessments. 
5.3.3 
Replacement of Patients 
Patients who do not receive MYK-491 or placebo will be replaced. Patients who 
withdraw/are withdrawn permanently due to a drug-related AE may not be replaced. Patients 
who drop out of the study after receiving study medication for reasons other than 
drug-related AEs or patients who are not evaluable for PK-PD at steady state may be 
replaced at the discretion of MyoKardia in consultation with the investigator, but no more 
than 2 patients per cohort may be replaced. 
All data from patients who receive IMP will be documented and maintained in the clinical 
trial database. 
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6 
RANDOMIZATION AND BLINDING PROCEDURES 
6.1 
Randomization 
In Part 1 (SAD), eligible patients will be randomized to 1 of 3 (Cohort 1) or 4 (Cohort 2) 
different treatment sequences (Figure 1). 
In Part 2 (MAD), eligible patients will be randomized in a 3:1 ratio to receive active drug or 
placebo, respectively (Note: All patients will receive placebo on Days 1 and 2). 
After reconfirming eligibility, each patient will be randomized within 24 hours of the planned 
first dose of study medication. If a randomized patient withdraws/is withdrawn from the 
study, the randomization code cannot be reused. The randomization list will provide 
replacement randomization codes. 
Patients who fail to meet all inclusion criteria or meet any exclusion criterion will not, under 
any circumstances, be enrolled into the study. There can be no exceptions to this rule. 
Patients who do not meet the inclusion criteria or meet any exclusion criterion at initial 
Screening but, in the opinion of the investigator may be eligible for the study upon 
rescreening, may be rescreened for eligibility. 
If a patient who does not meet the selection criteria is enrolled in error and this is identified 
before dosing, the patient should be withdrawn from the study. If a patient is withdrawn prior 
to dosing, they will be replaced. 
If a patient who does not meet the selection criteria is dosed before the error is identified, the 
PI will inform the medical monitor of the error, and a joint decision will be made as to 
whether the patient should continue in the study or be replaced. 
6.2 
Blinding 
All staff at the clinical center, with the exception of the study pharmacist and other pharmacy 
staff who ensure accurate study medication preparation and dispensation for each patient, 
will be blinded to the assigned treatment. Any unblinded clinical staff involved in the 
preparation of the IMP cannot serve in other roles for the study. The randomization list 
should be kept in a secure location at the site until the database is locked. 
In addition, each patient, clinical site monitor, central cardiac core laboratory staff, safety 
laboratory staff, and CROs responsible for clinical monitoring will also be blinded to the 
assigned treatment. An unblinded monitor will be assigned to review IMP accountability 
records throughout the study. Designated MyoKardia pharmacovigilance members will be 
unblinded for SUSAR reporting purposes. Designated MyoKardia biostatisticians, statistical 
programmers, pharmacologists, and a Quality representative are unblinded. The 
biostatisticians and statistical programmers will create the randomization list and statistical 
analysis to support SRC meetings, and the unblinded Quality representative will 
communicate with the unblinded pharmacist at the site. These unblinded personnel will take 
appropriate precautions to ensure no other personnel are unblinded. The SRC may review 
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unblinded data prior to database lock. Each cohort may be locked and unblinded 
independently upon its completion. 
If an emergency unblinding is required, the investigator will have immediate access to 
individual sealed patient codes. In addition, if required, the site pharmacist or his/her delegate 
who will have dispensed the medication can release the code to the investigator and other 
medical personnel as appropriate. In the event of a medical emergency when management of 
a patient’s condition requires knowledge of the study medication, the treatment received may 
be revealed by personnel authorized by the PI. When possible, such emergencies are to be 
discussed with MyoKardia prior to disclosure of the treatment allocation. If the treatment 
assignment is revealed, the following must be recorded in the subject’s source documents: 
the reason(s) and justification(s) for breaking a code, the date and time when the code was 
broken, the identity of the person responsible and other unblinded personnel. Information that 
would lead to further unblinding in the eCRF or source documents should not be recorded. 
The bioanalyst assaying the PK samples will be unblinded so only the appropriate samples 
will be analyzed. On days in which the patients received placebo, only 1 sample obtained at 
about the time of the predicted maximum plasma concentration will be assayed to ensure that 
the patient received placebo. 
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7 
STUDY TREATMENT 
IMP is defined as MYK-491 or placebo. In Part 1 (SAD), study patients will receive separate 
ascending doses of MYK-491 (2 to 3 doses) and a single dose of matching placebo. 
In Part 2 (MAD), study patients will receive single-blind placebo BID for Days 1 and 2 and 
will then receive DB treatment (either placebo or MYK-491) for 7 days (Days 3 through 9). 
In Cohorts A, B, and C, on Day 9 patients will receive a single dose of placebo or MYK-491 
in the morning for serial PK/PD assessments, while on Days 3 through 8 patients in these 
cohorts will receive placebo or MYK-491 BID.  
In optional Cohorts D and E, and possible additional cohorts, patients may receive placebo or 
MYK-491 QD or BID dosing as determined by SRC. 
7.1 
Investigational Medicinal Product 
MYK-491 drug substance is a 
 synthetic molecule with a molecular 
weight of 435.4 g/mol. 
 
 
MYK-491 will be provided as a tablet. Placebo will be provided as matching tablet. 
7.1.1 
Supply of Investigational Medical Product 
The clinical trial material for the MYK-491-003 study will be manufactured, packaged, 
labeled, and distributed by 
. MyoKardia will provide 25 mg tablets, 100 mg tablets, 
and matching placebo tablets for this study. The tablets will be blistered and then carded, 
Each blister card will contain either only 25 mg, only 100 mg, or only placebo. There will be 
no mixed strength blister cards. Each blister card will be labeled as required by local 
regulations and will be “open” in labeling, ie, the label will identify the contents of the blister 
card. The blister cards will be packaged into “Kit Boxes.” Each kit box will be labeled as 
required by local regulations and will be “open” in labeling, ie, the label will identify the 
contents of the kit box. 
The pharmacist, who is unblinded in this protocol for purposes of dose preparation, will 
prepare blinded doses, which he/she will provide to the clinician, who will administer it to 
the patient. Both the clinician and the patient will not know what dose it contains. 
7.1.2 
Storage and Handling Procedures 
MYK-491 must be stored in accordance with the labeled storage conditions in the packaging 
supplied by MyoKardia. IMP at the investigational site will be stored in a secure area with 
access limited to authorized study personnel. 
7.1.3 
Packaging and Labeling 
MYK-491 and the matching placebo tablets will be shipped in appropriately labeled 
containers. Blinding will occur at the site by the unit’s pharmacists or qualified delegated 
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staff. All study medication will be labeled according to applicable local regulatory 
guidelines. 
7.2 
Study Medication, Administration, and Schedule 
Study medication will consist of MYK-491 25 mg tablets, 100 mg tablets, or matching 
placebo tablets. 
MYK-491 tablets and matching placebo tablets will be manufactured according to current 
Good Manufacturing Practice (cGMP) regulations.  
In Part 1 (SAD), MYK-491 or placebo will be administered after an overnight fast (at least 
6 hours), while in Part 2 (MAD) MYK-491 will be administered after a 2 hour fast. The dose 
should be ingested with a minimum of 240 mL of water, but more water may be ingested as 
needed. The entire dose should be administered over a period of up to 15 minutes. The time 
of dose used to determine future assessments will be the time the last tablet is taken. 
In Part 1 (SAD), if the SRC specifies that the total dose should be split for selected periods, 
all dosing should be completed before approximately 12 noon so that the expected peak drug 
effect occurs before bedtime and when there is adequate staffing present. The exact timing 
may be determined by the site based on scheduling needs. For example, the first half of the 
dose may be given between 6 and 8 AM and the second half given between 10 AM and 
12 noon. Appendix 1 provides a schedule of assessments to be followed in the event of a split 
dose. Four hours is the expected interval for split dose but timing may be modified based on 
emerging PK data.  
In the initial cohorts for Part 2 (MAD), a BID regimen will be used (see Section 4.1.2). 
Patients with ICD who are not confined in the Clinical Testing Unit should return to the 
Clinical Testing Unit for dosing with IMP. Alternatively, patients may be visited by a home 
health nurse for study drug administration and for any assessments that can be performed 
away from the clinical site. Only a single dose may be dispensed at one time to the home 
health nurse in this manner. 
7.2.1 
Administration Relative to Meals 
In Part 1 (SAD), patients will fast overnight (approximately 6 hours) through 4 hours 
postdose. With the exception of the water consumed with the dose, water may be ingested 
until approximately 1 hour prior to dosing and approximately 1 hour after dosing. If doses are 
split, subjects should fast 6 hours prior to the first half-dose. A light, low-fat snack may be 
consumed 2 hours after the first half-dose and a fast continued through 2 hours after the 
second half-dose. 
In Part 2 (MAD), patients will fast for 2 hours before and 2 hours after dosing. For example, 
if morning dosing will occur at 8 AM, patients can have a snack at 6 AM and a full breakfast 
at 10 AM. If afternoon dosing will occur at 8 PM, patients can have dinner at 6 PM and a 
snack at 10 PM. These times may be adjusted based on local scheduling preferences, but 
doses should be separated by at least 10.5 hours. The fasting requirement may be eliminated 
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or modified during the conduct of this study if the results of a planned food effect study 
become available. 
Patients with ICD who are not confined in the Clinical Testing Unit should be educated 
with respect to meal and fasting requirements for the study. In particular, it is important also 
to remind patients who will not be taking their meal in the Clinical Testing Unit to maintain a 
stable diet throughout the study, to continue to remain adherent to their usual diet 
recommended for their heart failure condition (low to moderate salt diet) and to take their 
meals at about the same time every day from Day 1 until Day 11. 
7.3 
Treatment Compliance 
MYK-491 or placebo will be administered by a qualified member of the clinical staff. Study 
staff will verify that each patient ingests the entire dose of the study medication with at least 
240 mL of water. Clinical site staff will be responsible for accurately completing the 
patient’s study medication records. 
Patients with ICD who are not confined in the Clinical Testing Unit should return to the 
Clinical Testing Unit for dosing or be administered the study drug by a home health nurse.  
7.4 
Guidelines for the Management of an Exaggerated Pharmacological 
Effect 
Based on the nonclinical pharmacological characteristics, exaggerated effects of MYK-491 
may lead to myocardial ischemia. The duration of effect would follow the PK profile of 
MYK-491
 
 
. The clinical signs and symptoms, which may include chest pain, lightheadedness, 
diaphoresis, and ECG changes should start to abate over a short period of time. Any patient 
with signs and/or symptoms that may be secondary to cardiac ischemia should be 
immediately evaluated by the physician for the possibility of cardiac ischemia and additional 
ECGs and serial troponins obtained as part of the evaluation as appropriate. If evidence of 
cardiac ischemia is present, then the patient should receive standard therapy for ischemia as 
appropriate, including supplemental oxygen and nitrates. 
 
 
 
 
 
7.5 
Overdose 
There is no antidote for MYK-491. Patients who receive a greater dose than planned should 
be supported as appropriate. If there is an exaggerated pharmacologic effect, the patients 
should be supported as described in Section 7.4. 
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If a subject should experience an overdose, the investigator will report the overdose within 
24 hours, even if there are no signs or symptoms associated with the overdose in the subject. 
Follow up on the subject’s condition will be conducted. 
7.6 
Concomitant Therapy 
During the study, the patients should continue to ingest their medications for the treatment of 
their congestive heart failure and other medical conditions at the same doses and as close to 
the same times as usual, in order to maintain as best as possible similar preload and afterload 
conditions throughout the study in order to minimize confounding factors for the assessment 
of the effects of MYK-491. In particular, if patient is treated with diuretics, time of 
administration of diuretic relative to DB treatment should be kept similar throughout the 
study. Times of administration of diuretics, if applicable, will be collected in the eCRF. If 
patient is not confined, instruct patient to maintain timing of daily administration of 
medications constant, including diuretic if applicable. Patients should record the time of 
administration of diuretics. 
All prescription and over-the-counter medications must be reviewed by the investigator. 
Questions concerning enrollment or medications should be discussed with the medical 
monitor. 
 
 
 
 
 
 
 
If the patient has an AE requiring treatment (including the ingestion of acetaminophen or 
ibuprofen), the medication should be recorded in the appropriate section of the eCRF; 
including time of the administration (start/stop), date, dose, and indication. 
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8 
RISKS AND PRECAUTIONS 
8.1 
General 
The risks of administering MYK-491 to patients with heart failure are unknown, but single 
doses administered to healthy volunteers were well-tolerated (Section 1.2). Safety testing in 
other mammalian species demonstrates that dose-limiting toxicity is related to an 
exaggerated pharmacological effect, and not to off-target adverse effects. 
Dose/exposure/effect relationships based on data from the single-dose study in healthy 
volunteers have been taken into consideration in the selection of the initial and subsequent 
dose levels. In addition, stopping criteria, to ensure that MYK-491 will be administered 
safely, are part of this study. 
8.2 
Pregnancy 
8.2.1 
Avoidance of Pregnancy 
Women of childbearing potential will be allowed to participate if they are not currently 
pregnant and/or breastfeeding and agree to not become pregnant for up to 3 months after the 
last dose of study medication. Women 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, bilateral salpingectomy, and bilateral tubal occlusion 
or ligation at least 6 months prior. Women are considered postmenopausal if they have had 
amenorrhea for at least 1 year following cessation of all exogenous hormonal treatments and 
FSH levels are in the postmenopausal range. Pregnancy tests (urine or blood determined by 
local requirements [eg, only serum is acceptable in the UK]) should be performed on all 
females. 
8.2.2 
Restrictions for Male Patients 
There is no information about effects that MYK-491 could have on the development of the 
fetus in humans. Therefore, it is important that the partners of male patients do not become 
pregnant during the study and for a total period of 3 months after the male patient has taken 
the last dose of study medication. As a precaution, all male patients should avoid fathering a 
child by using appropriate methods of birth control, as listed in Section 8.2.3, for the duration 
of the study and for 3 months after the last dose of study medication. This is to ensure that 
the fetus is not potentially exposed to the study medication in the ejaculate.  
In addition, male patients with partners should use condoms for the duration of the study and 
for 3 months after the last dose of study medication, even if the partner is not pregnant or 
capable of becoming pregnant, in order to prevent passing MYK-491 to the partner in the 
ejaculate.  
Male patients should be advised not to donate sperm for 3 months after the last dose of study 
medication. 
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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 medication, patients should practice true abstinence or 
use effective means of contraception as follows: 
• Hormonal contraception associated with inhibition of ovulation, IUD, or intrauterine 
hormone-release system (IUS) plus barrier (eg, male using condom or female using 
diaphragm or cervical cap) 
• Vasectomy plus barrier  
• Female is surgically sterile for 6 months or postmenopausal for 1 year. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, 
and/or documented bilateral tubal occlusion at least 6 months prior to Screening. Females 
are considered postmenopausal if they have had amenorrhea for at least 1 year or more 
following cessation of all exogenous hormonal treatments, and FSH levels are in the 
postmenopausal range. 
• Male partners of postmenopausal females 
 
8.2.4 
Reporting and Follow up of Pregnancies 
All pregnancies in female patients and female partners of male patients receiving at least 
1 dose of study medication will be reported if they occur anytime from first dose to 3 months 
after the last dose of study medication. The investigator is responsible for informing 
MyoKardia of the pregnancy. The patient 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. 
Procedures to be performed during the study are detailed in Appendix 1 and Appendix 2 of 
this document. Refer to the appropriate schedule(s) of assessments, as indicated in Table 1. 
Table 1 
Schedules of Assessments 
Study Part 
Table 
Part 1 (SAD): Screening, Dosing Periods, and Follow up – High-Level 
Table 2 
Part 1 (SAD): Dosing Periods and Follow up – Detailed 
Table 3 
Part 1 (SAD): Split Dose Screening, Dosing Periods, and Follow up – Detailed 
Table 4 
Part 2 (MAD): Screening, Dosing Periods, and Follow up – High-Level 
Table 5 
Part 2 (MAD): Dosing Periods and Follow up – Detailed for Days 3 and 9 
Table 6 
MAD, multiple-ascending dose; SAD, single-ascending dose 
 
The timelines in Appendix 1 and Appendix 2 should be followed by patients enrolled in 
Cohort 1 and Cohort A, respectively. Subsequently, the SRC will review all available data. 
The committee may modify the timing of the assessments or increase or decrease the number 
of assessments, based on the accumulating data. 
Screening values and assessments will be made by the Central Laboratory/reader; in Part 1 
(SAD), Day -1 assessments will be split with one sample assayed locally for review by the 
investigator and one sample assayed centrally. 
When several assessments are to be conducted at the same timepoint, the preferred order of 
assessments is ECG, vital signs, PK, and then TTE. The order of assessments may vary 
slightly at specific timepoints (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 patients to be in a semirecumbent or supine position, 
assessments should be conducted with the patient in the same position at all timepoints. 
9.1 
Efficacy Assessments 
There are no efficacy assessments in this study. 
9.2 
Pharmacodynamic Assessments 
9.2.1 
Transthoracic Echocardiography 
TTE evaluations of LVSV (derived from LVOT-VTI), LVEF, LVFS, SET, and other 
parameters will be PD assessments at the timepoints indicated in Appendix 1 and Appendix 2 
(with a window of ± 1 hour). The patients should be at bed rest for 10 minutes before the 
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TTEs are obtained. The actual timing of TTE should be modified and/or additional TTEs 
obtained at other timepoints based on the review of data from prior treatment periods by the 
SRC. In Part 2 (MAD), TTEs are usually obtained before the morning dose and/or at 7 hours 
postdose (ie, close to the anticipated peak effect based on the PK profile from the healthy 
volunteer studies). Up to an additional 2 observations may be requested per treatment period 
by the SRC after review of the data from previous treatment periods. 
Echocardiograms will be evaluated locally for changes that might affect dosing decisions for 
subsequent doses in one patient or others in the cohort, but the official reading will be done 
centrally by experts in a core laboratory in a blinded manner with results provided to the 
SRC. 
The sonographers to be used in the study will complete echo protocol training and submit an 
example of a study to the core laboratory for evaluation. The core TTE lab will certify that 
the sonographer is able to perform the TTEs at a level satisfactory for obtaining the required 
protocol data. All echocardiography data will be sent to a central imaging laboratory. 
9.3 
Pharmacokinetic
 Assessments 
9.3.1 
Pharmacokinetic Assessments 
Blood samples will be collected for PK assessments as indicated in Appendix 1 and 
Appendix 2. It is important that PK sampling occurs as close as possible to the scheduled 
time. Unscheduled or additional PK samples may be collected if appropriate in the opinion of 
the investigator and/or Sponsor. Timing of the samples may be modified and an additional 
2 samples per treatment period requested by the SRC following review of the data from 
previous time periods. 
  If an 
unscheduled echocardiogram is requested by the investigator, serum PK should also be 
collected at this timepoint. 
9.4 
Safety Assessments 
Safety will be assessed throughout the study as indicated in Appendix 1 and Appendix 2. 
Safety assessments include medical history, physical examinations, SET as determined by 
TTE, 12-lead ECGs, ECG telemetry (in confined patients), Holter ECG (in Part 2), vital 
signs, observed and patient-reported AEs, serum troponin concentrations, and safety 
laboratory tests.
 
 
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The actual timing of the assessment of ECGs, TTEs, and vital signs may be modified or up to 
an additional 2 sets of observations or samples per treatment period may be requested by the 
SRC after review of the data from previous treatment periods. 
Any abnormal findings judged by the investigator to be clinically important will be recorded 
as an AE. 
9.4.1 
Medical History 
A complete medical history will be recorded at the Screening visit, which will include 
evaluation (past or present) of the cardiovascular and heart failure medical history as well as 
the following: general, head and neck, eyes, ears, nose, throat, chest/respiratory, 
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). The 
medical history will be updated at admission if needed. 
9.4.2 
Vital Signs  
Vital signs are to be assessed throughout the study as indicated in Appendix 1 and 
Appendix 2. The actual timing of the vital sign measurements may be modified and/or 
additional sets per treatment period may be requested by the SRC. Clinically significant 
abnormal values will be flagged. On days with multiple vital sign assessments, temperature 
needs to be assessed once, unless clinically indicated. 
9.4.3 
Physical Examination 
Height (cm) will be measured at Screening and body weight (kg) will be measured at 
Screening and admission (first dosing period only in Part 1 [SAD]) BMI (kg/m2) will be 
calculated. Patients will be required to remove their shoes and wear indoor clothing as 
specified by the clinical site. 
At Screening and admission, a complete physical examination will be conducted including a 
neurological examination (gross motor and deep tendon reflexes), 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 
timepoints, an abbreviated physical examination (pulmonary, cardiac, abdominal, and other 
systems related to symptoms) will be conducted. 
9.4.4 
Systolic Ejection Time 
See Section 9.2 for a description of assessment of SET using TTE. 
 
 
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9.4.5 
Electrocardiograms (12-Lead ECG) 
The 12-lead ECG should be obtained as indicated in Appendix 1 and Appendix 2. The actual 
timing of the ECGs may be modified and/or up to an additional 2 ECGs per treatment period 
may be requested by the SRC after review of the data from previous patients or treatment 
periods. In addition, the investigator may add extra 12-lead ECG assessments if there are any 
abnormal findings or if the investigator considers it is required for any other safety reason. If 
the patient has a new troponin abnormality (see Section 9.4.9) or any signs or symptoms 
suggestive of possible cardiac ischemia, additional ECGs should be obtained. These 
assessments should be recorded as unscheduled assessments. All ECG data will be sent to a 
central cardiac laboratory. 
The investigator will judge the overall interpretation as (a) normal, (b) abnormal without 
clinical significance, or (c) abnormal with clinical significance. If clinically significant, the 
abnormality will be recorded. In addition, before each treatment period, the investigator or 
subinvestigator should review the available ECGs from the previous treatment periods 
looking for signs of ischemia. If there are signs of ischemia, continued dosing should be 
withheld until there is full understanding of the possible ischemic changes. Only the overall 
evaluation (normal/abnormal) will be recorded in the eCRF. The investigator will review the 
ECG and correlate abnormal findings with any other clinical findings, patient’s medical 
history, and laboratory data to determine the clinical importance of the finding. 
The 12-lead ECG abnormalities suggestive of ischemia (eg, new or worsened ST depression 
or new T-wave inversions), as determined by investigator, will be reviewed centrally by an 
Adjudication Committee. 
9.4.6 
Electrocardiogram Telemetry 
Real-time telemetry ECG (at least 3-lead) will be displayed starting at least 1 hour predose 
and continuing through 48 hours postdose (in Part 2 [MAD], postfinal dose on Day 9). The 
investigator or designee will monitor the continuous ECG telemetry data and correlate the 
finding(s) with any other clinical findings, study participant’s medical history, study 
participant’s clinical status, and laboratory data to determine the clinical importance of the 
finding. Clinically significant findings that are new or worsened (compared to baseline), as 
determined by investigator, will be reported in CRF as AEs (see Section 10). 
If the investigator notes an event as clinically significant, the relevant strip should be printed 
and sent to the central ECG cardiac laboratory. The investigator should modify/stop dosing 
based on local assessment if indicated but the final read will be made centrally. A copy of the 
event and subsequent central cardiac ECG laboratory analysis should be kept in the subject’s 
source documentation. 
New or worsening ventricular arrhythmia observed on ECG telemetry or on a 12-lead ECG, 
as determined by investigator, will be reviewed centrally by an Adjudication Committee. 
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Worsened ventricular arrhythmia would include but is not limited to increase over baseline in 
the frequency or complexity of premature ventricular contractions (PVCs). 
9.4.7 
Holter Electrocardiogram 
In Part 2 (MAD), Holter ECG recordings (or equivalent technology) will be acquired as 
indicated in Appendix 2. During the 48-hour Holter ECG, site staff should periodically verify 
that Holter device is adequately functioning ie, that continuous recording is occurring as 
intended. If alternative comparable technology is identified by the Sponsor, the device used 
and the length of recording may be modified. 
9.4.8 
ICD Download (For Patients with ICD) 
An ICD download should be performed at the end of the study (Day 16 ± 1 week) unless the 
site encounters significant technical difficulties and is required in case of shock(s) delivered 
by the ICD during the study. 
9.4.9 
Troponin Levels  
Troponin samples will be collected at timepoints as indicated in Appendix 1 and Appendix 2. 
Samples for troponin should be split with one sample assayed locally in order to be locally 
reviewed by the investigator. The local troponin evaluated can be either Troponin I or 
Troponin T, based on local site access to assays. The other sample will be analyzed at a 
Central Laboratory. The Central Laboratory will analyze Troponin I and Troponin T. 
Results of troponin assays from the local lab should guide patient evaluation. Results of 
troponin assays from Central Lab will be used for further research purposes by the Sponsor, 
and will not be communicated back to the Investigator (with the exception of Central Lab 
Troponin I values which will be communicated to determine patient eligibility). 
Abnormal and/or rising troponin values (as per investigator’s judgment and taking into 
account potential baseline troponin elevation frequently observed in heart failure) should lead 
to patient being clinically evaluated for possible myocardial ischemia. Also, if the patient has 
any signs or symptoms suggestive of possible cardiac ischemia, additional serial troponin 
(and other safety labs, including creatine kinase-MB [CK-MB] samples) should be obtained 
and continued dosing should be withheld until there is full understanding of the possible 
ischemic event. The investigator will evaluate the entire clinical context (eg, signs, 
symptoms, new ECG changes, new troponin, and CK-MB abnormalities) and correlate with 
any other relevant clinical findings, patient’s medical history, and laboratory data to 
determine the clinical significance of the findings. 
Troponin results performed on Day 2 of Part 1 (SAD) and Day 10 of Part 2 (MAD) at local 
lab should be reviewed prior to patient being discharged the next day. 
All elevated levels of troponin above the upper limit of normal from either the local or 
Central Lab, regardless of baseline levels, will be centrally reviewed by an independent 
adjudicator (Section 4.5). 
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If the investigator assessment is that an AE has occurred, the event should also be reported as 
an AE according to Section 10.  
9.4.10 
Adverse Events 
Please see Section 10 for information on evaluating, recording, and reporting AEs. 
9.4.11 
Safety Laboratory Tests (Other Than Troponin) 
Samples will be drawn for safety laboratory tests at the timepoints indicated in Appendix 1 
and Appendix 2. At Screening, assessments will be made by the Central Laboratory. Safety 
laboratory samples should be split for one sample to be analyzed locally and one sample 
processed centrally. Local lab results should be reviewed, and eligibility confirmed, prior to 
dosing. If the investigator has any questions regarding eligibility, the Sponsor should be 
contacted. 
9.5 
Missed Evaluations 
Evaluations should occur within the assessment window specified by the protocol. If an 
evaluation is missed, it should be performed as close as possible to the original time. 
9.6 
Patient Restrictions During the Study 
The following restrictions apply for the specified times during the study period. If a patient 
does not comply with these restrictions or they may be excluded or withdrawn from the 
study. 
• Throughout the study, starting at Screening, patients should maintain stable medications, 
activity levels, fluid intake, and meals. 
• During the confinement period at the clinical site, meals will be served at scheduled 
times. If patient is not confined, instruct patients to have meals at consistent times. 
• From 72 hours prior to the first dose through the final Follow-up visit, patients should 
not engage in unaccustomed intensive exercise. 
• From the time of Screening through the Follow-up visit, every effort should be taken 
to maintain concomitant medications at stable doses. To minimize variability in 
cardiac loading conditions for cardiac echo assessments, medications (including 
diuretics) should be taken at the same time every day and timing of diuretics if 
applicable will be recorded. Patients not confined should be advised to take all 
medications, including diuretics if applicable, at the same time every day. 
• In Part 1 (SAD), the patients will fast overnight (at least 6 hours) prior to the morning 
dosing. In Part 2 (MAD), the patients will fast 2 hours prior and 2 hours after dosing. 
With the exception of the water consumed with the dose, patients may ingest water up to 
1 hour before and 1 hour after ingestion of the dose. Fasting and fluid restriction periods 
can be made shorter or eliminated at the discretion of the SRC. 
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• Starting at Screening, patients will be required to abstain from blood or plasma donation 
until 3 months after the final study visit. 
• From Screening through the final Follow-up visit, patients 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. 
• Patients with ICD who are not confined in the Clinical Testing Unit should be 
educated about all above requirements, including but not limited to: fasting instructions 
and following their physician-recommended diet (ie, low to moderate salt diet, taking 
their medications, and meals at consistent times every day). Patients should be advised to 
avoid alcohol or excessive caffeine consumption. 
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10 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS 
10.1 
Definitions 
10.1.1 
Adverse Event 
An AE is any untoward medical occurrence, or the deterioration of a preexisting medical 
condition (other than the condition that is being treated by the study) associated with the use 
of a study medication in humans, whether or not it is considered related to the study 
medication. An AE (also referred to as an adverse experience) can, therefore, be any 
unfavorable and unintended sign (eg, tachycardia, enlarged liver, clinically important 
abnormal laboratory result or diagnostic procedure), patient-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 patient 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 patient 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 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 
• Any clinically important test abnormality that suggests a disease and/or organ toxicity 
that has worsened or is new (eg, > 3 times 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 patient to have study medication discontinued or 
interrupted or in the clinical judgment of the investigator 
• Any test abnormality that requires the patient 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. 
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10.1.2 
Serious Adverse Event 
An SAE is an AE that fulfills 1 or more of the following criteria in the opinion of the 
investigator or MyoKardia: 
• Results in death 
• Is immediately life-threatening (places the patient at immediate risk of death from the 
event as it occurred) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it may require medical or surgical intervention to prevent 1 of the outcomes 
listed above 
 
10.2 
Events NOT Meeting the Definition of an Adverse Event 
If an event is not an AE then it cannot be an SAE, even if the event outcome meets the 
definition for seriousness defined by the criteria in Section 10.1.2. Instances where an event 
is not an AE include 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
hospital admission/extension for convenience) 
• 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 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) that 
are present or detected at the start of the study that do not worsen 
 
10.3 
Adverse Event Reporting and Descriptions 
10.3.1 
Reporting Period and Follow Up 
All AEs will be reported from the time the patient provides informed consent through the last 
visit or 30-day period after last dose of study medication, whichever is longer. SAEs 
occurring after providing informed consent but before the first dose of study medication will 
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be reported as SAEs only if they are considered related to protocol or study procedure. 
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. Overdose should be reported using the same method as SAE 
reporting. 
Any AEs that are unresolved at the patient’s last visit in the study are to be followed by the 
investigator until resolved or stabilized and are considered irreversible, or the patient has 
died. 
MyoKardia retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study if judged necessary. 
All SAEs 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. Deaths and SAEs occurring beyond this timepoint and 
considered related to study medication or study procedure must also be reported.  
10.3.1.1 
Recording and Assessing Adverse Events 
10.3.1.2 
Description 
All AEs spontaneously reported by the patient 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. 
10.3.1.3 
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 IMP/study 
medication?” 
The following factors can be used in consideration of causality assessment: 
• Dechallenge/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 
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• Confounding risk factors 
• Amount and duration of study drug exposure 
• Concomitant medications 
 
10.3.1.4 
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) 
• 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 stated above.  
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. 
All SAEs regardless of causality will be reported by the investigator or designee to 
MyoKardia or its designee per the reporting period defined in Section 10.3.1 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. Deaths and SAEs 
occurring beyond this timepoint and considered related to study medication or study 
procedure must also be reported.  
10.3.1.5 
Pregnancy 
Pregnancy, or if a partner of a male patient becomes pregnant during the study or for a period 
of 3 months after the male patient has taken the last dose of study medication, must be 
reported within the same timelines of an SAE. Pregnancies will be followed until final 
outcome and live births will be followed for 6 months after birth. SAE reporting instructions 
are provided in the Investigator Site File. 
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11 
STATISTICAL METHODS 
11.1 
Determination of Sample Size 
Part 1 is a single-ascending (oral) dose study and Part 2 is a multiple-ascending (oral) dose 
study to evaluate safety and tolerability of MYK-491. No formal statistical hypothesis testing 
will be performed. 
In Part 1 (SAD), enrollment of at least 4 patients is planned for Cohort 1, with 1 patient 
randomized to each sequence of dose escalation and placebo administration. For Cohort 2, 4 
to 8 patients will be enrolled and randomized to each sequence of dose escalation. There will 
be an option for the SRC to expand Cohort 1 or Cohort 2 to meet study objectives. Decision 
to expand or not the number of patients will be made by the SRC. Two additional patients 
may be enrolled as replacements for drop-outs in each cohort, so the maximum number of 
patients that may be enrolled will be approximately 32. 
In Part 2 (MAD), enrollment of a total of a minimum of 24 patients is planned, with 
8 patients enrolled the low-dose group (Cohort A), 8 patients enrolled in the medium-dose 
group (Cohort B) and 8 patients enrolled in the high-dose group (Cohort C). In addition, the 
planned size of additional optional Cohorts will be 8 patients each. The final total sample size 
for Part 2 will not exceed 96 patients if the SRC decides to expand one or more cohorts up to 
24 patients. In addition, up to 2 additional patients may be enrolled per cohort as 
replacements for drop-outs or for patients non-evaluable for PK-PD at steady state. 
Based on the study design, the sample is considered appropriate to explore tolerability and 
safety parameters, PK profile, and pharmacodynamic effects of MYK-491 in patients with 
heart failure. 
11.2 
Study Endpoints 
11.2.1 
Primary Endpoint 
Primary safety measures will include the following: 
• Treatment-emergent AEs and SAEs 
• ECG recordings (Central Laboratory manual over-read), interpretation, and intervals 
• Vital signs 
• Serum Troponin I concentrations 
• Laboratory abnormalities 
• Physical examination abnormalities 
 
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11.2.2 
Secondary Endpoints 
The following are secondary endpoints: 
• The human PK profile of MYK-491. The analysis includes at a minimum the following 
PK parameters. Additional PK parameters may be determined as appropriate. 
- 
Cmax for each dose level 
- 
Tmax for each dose level 
- 
AUC for each dose level dose 
- 
Apparent first-order terminal elimination half-life (t1/2) 
- 
Mean residence time (MRT) for each dose level 
- 
Accumulation ratios determined (with the appropriate confidence intervals) for Cmax 
and AUC0-t (Part 2 only) 
• SET as determined using TTE. The main parameters are the change from Baseline at 
each timepoint by treatment levels and the maximum change from Baseline. 
• The following as assessed by TTE: 
- 
Change from Baseline in LVSV (derived from LVOT-VTI) 
- 
Change from Baseline in LVEF 
- 
Change from Baseline in LVFS 
- 
Change from Baseline in SET 
 
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11.3 
Statistical Analysis 
Before database lock, a statistical analysis plan (SAP) for clinical data and an analysis plan 
for PK will be prepared that will contain full details of all planned analyses. The analyses 
presented here represent an outline of the intended methodology. 
11.3.1 
Analysis Populations  
Three analysis populations are defined in this study, the Safety population, the PK Analysis 
population, and the PD Analysis population. 
The Safety population is defined as patients who are randomized and receive any amount of 
study medication (MYK-491 or placebo), including patients who prematurely withdraw from 
the study. Except as noted, all safety analyses, including demographic and Baseline 
characteristics, will be performed based on the Safety population.  
The PK Analysis population is defined as patients who are randomized and receive any 
amount of MYK-491, have detectable plasma concentration data, and have no major or 
critical protocol deviations related to IMP (eg, incomplete ingestion of the drug, vomiting up 
to 8 hours after drug administration). During the placebo dosing period, a single plasma 
sample will be evaluated near the predicted Tmax of MYK-491 to confirm lack of circulating 
MYK-491 and will not be included in the PK Analysis population. 
The PD Analysis population is defined as patients who are randomized and receive any 
amount of study medication (MYK-491 or placebo), have any interpretable PD data, and 
have no critical or major protocol deviations related to IMP (eg, incomplete ingestion of the 
drug, vomiting up to 8 hours after drug administration). The PD analyses will be performed 
based on the PD Analysis population.  
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The PK/PD analysis will be performed based on MYK-491-treated patients that are in both 
the PK Analysis population and the PD Analysis population and/or Safety population 
depending on which parameters are to be included in the PK/PD analysis. 
11.3.2 
General Considerations 
Clinical data will be summarized by treatment group. Descriptive summary statistics for 
continuous variables will include the number of patients, mean, standard deviation (SD), 
median, minimum, and maximum. Categorical variables will be summarized using counts 
and percentages.  
11.3.3 
Patient Disposition 
The number and percentage of patients who complete or discontinue the study, as well as 
reasons for early discontinuation, will be presented. 
11.3.4 
Demographics and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized descriptively. 
11.3.5 
Pharmacokinetic Analyses 
Plasma 
 concentration data for MYK-491 will be summarized using descriptive 
statistics, including mean or geometric mean as appropriate, SD, median, minimum, and 
maximum values and CV%. PK parameters will include (but are not limited to) Cmax, Tmax, 
AUC, apparent first-order terminal elimination rate constant (λz), and MRT. In addition, the 
accumulation ratios will be calculated with Cmax and AUC0-t (t = dose interval or τ) after dose 
on Day 9 (at steady-state) and Day 3 (1st dose). Additionally, the apparent terminal-phase 
elimination half-life (t1/2z) will be calculated. 
 
 
 
 
11.3.6 
Pharmacodynamic Analyses 
TTE data for LVEF, SET, LVFS, LVSV will be analyzed using descriptive statistics. No 
inferential analysis will be performed. Observations by timepoint and change from Baseline 
(either absolute or percent relative change) at each timepoint will be summarized by 
treatment period (Part 1) and treatment group (Part 2). Change from Baseline will be 
analyzed with attention to the relationship to time postdose, dose level, and comparison with 
placebo. For SAD Cohorts, placebo-adjusted change from Baseline will be calculated for 
each subject at each postbaseline timepoint and then summarized at each dose level. In 
addition, for SAD and MAD Cohorts, least square means of placebo-adjusted change from 
Baseline for the key PD parameters (LVEF, LVFS, LVSV, SET) at each postbaseline time 
point at each dose level may be estimated using mixed model. 
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The relationship between the TTE endpoints and MYK-491 plasma concentration will be 
assessed using linear or nonlinear correlations. 
 
 
11.3.7 
Safety Analyses 
All safety analyses except SET as determined by TTE will be performed on the Safety 
Analysis population. Analyses of SET as determined by TTE will be performed on the PD 
Analysis population. 
11.3.7.1 
Systolic Ejection Time 
SET as determined by TTE will be assessed using summary statistics. Observations and 
change from Baseline will be summarized by treatment at each timepoint and the maximum 
change from Baseline will be determined for each patient. 
 
 
 
 
11.3.7.2 
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 on or after the first dose of study 
medication, or with an onset before the first dose of study medication that increase in severity 
on or after the first dose of study medication, will also be monitored. Treatment-emergent 
AEs will be summarized for the Safety Analysis population by MedDRA system organ class 
and preferred term, and by severity and relationship to treatment. Severe and life-threatening 
AEs, SAEs, AEs leading to study withdrawal, if any, will be presented in data listings. 
11.3.7.3 
12-lead Electrocardiogram 
The RR, PR, QRS, and QT intervals will be measured. HR will be calculated as 
60/(RR times 1000) (with RR expressed in ms) and rounded to the nearest integer. 
QTc will be calculated using the manually over-read QT values per the standard procedures 
of the central ECG laboratory. Each individual ECG QT value will be corrected for HR. 
The measured QT data will be corrected for HR using the Fridericia method (QTcF) as per 
the following formulae/method (with QT, RR and QTc expressed in ms): 
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QTcF =
QT
RR
1000
0.33 
11.3.7.3.1 
ECG Numeric Variables 
HR, PR, QRS, and QTcF will be summarized using descriptive statistics. The change from 
Baseline of these ECG parameters at each timepoint will be listed for each patient. For each 
timepoint of measurement, the changes from Baseline will be summarized. The relationship 
between HR/ECG intervals and time will be plotted. 
Separate analyses will be performed in patients who are not paced and have no prolonged 
QRS at Baseline. 
11.3.7.3.2 
Categorical Analysis 
The incidence count and percentage of patients with any postdose QTcF values of > 450 ms, 
> 480 ms, and > 500 ms will be tabulated for all patients. Patients with QTc values > 500 ms 
will be listed with corresponding Baseline values, ∆QTcF, and Baseline and treatment HR. 
The incidence count and percentage of patients with ∆QTcF increase of > 30 ms and > 60 ms 
will be tabulated. 
A separate QTcF analysis will be performed in patients who are not paced and have no 
prolonged QRS at Baseline.  
11.3.7.3.3 
Morphology Findings 
New ECG morphologies for each patient not present on any ECG at Baseline for that patient 
will be summarized for all observation timepoints combined.  
The number and percentage of patients 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. 
11.3.7.3.4 
Concentration-QTc Analyses 
A concentration-QTc regression analysis, based on data collected from the ECG recordings 
after study drug administration and drug plasma concentration values for each patient at each 
matching timepoint, may be performed. 
11.3.7.4 
Holter Electrocardiograms 
The interpretation and analysis of the Holter ECG data will be performed by the central ECG 
laboratory. Data from the 12-lead Holter recorder digital flashcard will be transmitted to the 
central ECG laboratory using a digital uploading system. The recordings will be reviewed for 
the presence of any clinically significant arrhythmias. The actual time of dosing will be 
communicated to the central ECG laboratory by the clinical site.  
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Analysis of blinded Holter recordings will be performed to assess the nature, frequency, and 
severity of any ventricular arrhythmias. Parameters evaluated will include but not be limited 
to total number of premature ventricular complexes (PVCs) during the recording period, 
average number of PVCs per hour, maximum number of PVCs per hour, total number of 
PVC pairs, total number of PVC triplets, total number of ventricular tachycardia (VT) runs 
(4 or more PVCs in a row), longest VT run, maximum HR during a VT run, minimum HR 
during a VT run, PVCs per 1000. Additional ECG abnormalities will be noted, including 
supraventricular arrhythmias and instances of heart block.  
11.3.7.5 
Other Safety Analyses 
Safety laboratory data including hematology, chemistry, ECG telemetry, and vital signs will 
be evaluated by timepoint for the Safety Analysis population using descriptive statistics. 
Changes from Baseline at each postbaseline timepoint will also be assessed. Listings of 
patients with laboratory and/or vital sign values that are observed to be out of the reference 
range will be produced. Abnormal physical examination results will be listed. Concomitant 
medications will be summarized. 
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12 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
12.1 
Compliance Statement 
This study will be conducted in accordance with the International Council for Harmonisation 
(ICH) Good Clinical Practice (GCP) guidelines; US Title 21 Code of Federal Regulations 
(CFR) Parts 11, 50, 54, 56, and 312; European Union (EU) GCP; cGMP; the principles 
enunciated in the Declaration of Helsinki; and all human clinical research regulations in the 
countries where the study is to be conducted. 
12.2 
Informed Consent 
The ICFs used for the study must comply with the Declaration of Helsinki, US 21 CFR 
Part 50, ICH GCP guidelines, and any other local regulations. The investigator, or a person 
delegated by the investigator, must explain the medical aspects of the study including the 
nature of the study and the treatment, orally and in writing, in such a manner that the 
potential patient is aware of potential benefits and risks. Potential patients must be informed 
that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. Patients must give informed consent in writing. 
Prior to participation in any study-related procedures, patients must sign and date an 
EC-approved written ICF in a language the patient 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 patient 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 patient. Before informed consent is 
obtained, the investigator should provide the potential patient 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 patient. The 
written ICF should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. All patients will receive a copy of his/her signed 
and dated ICF. 
12.3 
Ethics Committee 
The term EC used in this document refers to an 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 
• Patient recruitment procedures/documents (eg, advertisements) 
• Written information to be provided to patients 
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• IB and available safety information (Note: ECs do not approve IBs but are responsible for 
acknowledging receipt) 
• Information about payments and compensation available to patients 
 
The EC approval must be in writing, clearly identifying the study (by protocol date and/or 
version), the documents reviewed (including informed consent), and the 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 
• Any new information that may affect adversely the safety of the patients 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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13 
ADMINISTRATIVE PROCEDURES 
13.1 
Sponsor’s Responsibilities 
MyoKardia reserves the right to terminate the study at any time for any reason or for no 
reason. MyoKardia and the investigators will assure that adequate consideration is given to 
the protection of the patients’ 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 include: 
• Request by Health Authority to terminate the study 
• Unsatisfactory patient enrollment with regard to quality or quantity 
• Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on patients, maintain adequate study records or inaccurate, 
incomplete, or late data recording on a recurrent basis 
• The incident or severity of AEs in this or other studies indicating potential health hazard 
caused by the study treatment 
 
13.1.1 
Patient 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 patient. 
MyoKardia, whose responsibilities require access to personal data, agrees to keep the identity 
of patients confidential. This confidentiality will be maintained throughout the complete data 
processing. 
Patients 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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13.1.2 
Study Supplies 
MyoKardia will supply or ensure the coordination of sufficient quantities of the following 
materials to each clinical site: 
• MYK-491 tablets and the corresponding placebo 
• IB for MYK-491 
• ECG equipment 
• 
 
 
13.1.3 
Investigator Training 
A site-specific study initiation meeting and/or an Investigator Meeting will be held to ensure 
the center staff understands the protocol, study requirements, and data capture processes. 
This training will take place before the first patient is enrolled. The clinical site will be 
provided with information regarding GCP and regulations specific to the conduct of the 
clinical studies. The clinical site will be responsible for ensuring that new team members are 
adequately trained and the training is documented. 
13.1.4 
Ongoing Communication of Safety Information During the Study 
MyoKardia will provide the investigator with documentation of SAEs from the study and 
other studies with MYK-491 that are unexpected (refer to Section 10.3), as appropriate. The 
investigator must forward this documentation to the EC as described in Section 10.3. 
MyoKardia will also notify the investigator 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 patients, affect the conduct of the study, or alter the EC’s 
opinion about the continuation of the study. 
13.1.5 
Study Monitoring 
MyoKardia will monitor this clinical study through remote data checks and monitoring visits 
to check the adequacy of clinical site staff and facilities, and to ensure adherence to the 
protocol, study procedures, and applicable regulations. The clinical site monitor will also 
assess proper eCRF completion and source document retention. The investigator 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 will permit 
study-related monitoring, audits, EC review, and regulatory inspection(s), providing direct 
access to source data/documents and study-related facilities (e.g., pharmacy, diagnostic 
laboratories). 
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13.1.6 
Study Auditing and Inspecting 
MyoKardia may audit the study conduct, compliance with the protocol, and accuracy of the 
data. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, and inspections 
by MyoKardia, EC, government regulatory authority(ies), and MyoKardia’s quality 
assurance personnel or its designees by providing direct access to source data/documents 
after appropriate notification from MyoKardia. 
13.2 
Investigator’s Responsibilities 
13.2.1 
Screening Log 
The investigator must keep a record that lists all patients who signed an informed consent 
and the reason for noninclusion if the potential patient does not ultimately enroll and receive 
IMP. 
13.2.2 
MYK-491 and Matching Placebo Accountability 
The investigator must ensure that the study medications at the investigational site are 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 return of all study medication to be able to reconcile 
the study medication records (ie, accountability or dispensing logs) at the end of the study. 
The study medication records must be readily available for inspection by the (unblinded) site 
monitor and/or auditor. In general, no study medication can be returned to 
MyoKardia/clinical site or disposed of at the clinical site until the clinical site monitor has 
verified the accuracy of the study medication records at the clinical site and indicated 
whether the medication should be destroyed at the clinical site or returned to 
MyoKardia/designee. 
13.2.3 
Reporting and Recording of Study Data 
Data will be captured and compiled using procedures developed by MyoKardia or designee. 
All requested study data must be clearly recorded on the eCRF and other forms as required. 
Whenever possible, the reason for missing data in the source document must be recorded. 
Only individuals who are identified on the study personnel responsibility/signature log and 
who have received appropriate training on the electronic data capture (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 change, will be documented. 
Patient 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 accidental or premature destruction of 
documents. Data collected on the eCRF must match the source documents. 
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An eCRF must be completed for each patient who receives at least 1 dose of IMP. All entries 
into the eCRF are ultimately the responsibility of the investigator. The investigator is 
responsible for ensuring accurate, authentic, and complete records for each patient. 
An electronic copy of the eCRF casebooks will be sent to the clinical site for retention with 
other study documents after full completion of the study. 
13.2.4 
Source Data and Source Documents 
The nature and location of all source documents will be identified to ensure that all sources 
of original data required to complete the eCRF are known to MyoKardia 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 patient: 
• Patient identification and contact information (name, date of birth, sex, address, phone) 
• Documentation verifying patient 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 must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. 
The investigator will provide certified copies of the patient’s medical records in the event 
that the clinical site’s policy does not permit direct access to the electronic medical records. 
13.2.5 
Patient Identification Information 
To permit easy identification of the individual patient during and after the study, the 
investigator is responsible for keeping an updated log that contains the patient identification 
information. This document will be reviewed by the clinical site monitor for completeness. 
However, to ensure the patient’s confidentiality, the document will be maintained at the 
clinical site and no copy will be made. 
13.2.6 
Records Retention 
MyoKardia will inform the investigator in writing when it is acceptable to dispose of any 
study records. To enable evaluation and/or audits from regulatory authorities or MyoKardia, 
the investigator agrees to keep records, including the identity of all patients (eg, patient 
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identification code list and all source documents), all original signed ICFs, copies of all 
eCRFs, original laboratory reports, detailed records of study medication disposition, and all 
essential documents for the conduct of a clinical study. To comply with international 
regulations, the records should be retained by the investigator for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the IMP. However, the 
investigator may need to retain these documents for a longer period if required by the local 
regulatory requirements or by an agreement with MyoKardia. 
13.2.7 
Protocol Deviations 
Unless there is a safety concern, there should be no deviations or violations of 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 
patients without prior EC approval. If required, 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 a protocol deviation results in inadequate patient data, 
MyoKardia may determine that the patient should be replaced. The medical monitor will 
notify the study monitor of the decision. 
13.2.8 
Blood Sample Collection/Storage 
Blood samples that are collected as part of routine medical care or as part of protocol 
procedures may be stored and analyzed for PK or PD analyses. 
 
13.3 
Clinical Trial Insurance 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating 
clinical sites upon request. 
13.4 
Protocol Amendments and Study Administrative Letters 
Study procedures will not be changed without the mutual agreement of the investigator and 
MyoKardia. 
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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/typographical errors/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 will be communicated to or approved by the 
EC. 
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14 
DATA QUALITY ASSURANCE 
Quality assurance and quality control systems will be implemented and maintained with 
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 Good Clinical Practice: Consolidated Guidance, and 
the applicable regulatory requirements. 
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15 
ADMINISTRATIVE CONSIDERATIONS 
15.1 
Use of Computerized Systems 
This study will require the use of the following electronic data collection methods: 
• EDC system to capture protocol-required patient data: the clinical site will enter data 
from source documents onto eCRFs for each study timepoint 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 echocardiographic data 
from digital equipment used by clinical site personnel to collect patient data. 
 
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 EU and the data collected will be 
archived (at minimum) for the period specified by applicable regulatory requirements. 
15.2 
Study Records 
The investigator and affiliated institution shall maintain the study documents and records as 
specified in “Essential Documents for the Conduct of a Clinical Trial” (ICH E6, Good 
Clinical Practice, Section 8), and as required by the applicable regulatory requirement(s). 
This includes, but is not limited to, the protocol, eCRFs, AE reports, patient 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. 
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The eCRF must be completed at the time of, or shortly after the patient’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 patient’s eCRF will be maintained by the investigator. 
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16 
PUBLICATION 
The data and results of the study will be owned solely by MyoKardia and shall be 
confidential information of MyoKardia, subject 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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17 
REFERENCE LIST 
Benjamin E, Blaha M, Chiuve S, Cushman M, Das S, Deo R, et al. Heart disease and stroke 
statistics – 2017 update: A report from the American Heart Association. Circulation. 
2017;135(10):e146-603. 
Braunwald E. Heart failure. JACC Heart Fail. 2013;1(1):1-20. 
 
 
 
 
Teerlink J, Clarke C, Saikali K, Lee J, Chen M, Escandon R, et al. Dose-dependent 
augmentation of cardiac systolic function with the selective cardiac myosin activator, 
omecamtiv mecarbil: a first-in-man study. Lancet. 2011;378(9792):667-75. 
Teerlink J, Felker G, McMurray J, Solomon S, Adams K Jr, Cleland J, et al. Chronic Oral 
Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a 
phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 
2016;388(10062):2895-2903. 
Yancy C, Jessup M, Bozkurt B, Butler J, Casey D, Drazner M, et al. 2013 ACCF/AHA 
guideline for the management of heart failure: a report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J 
Am Coll Cardiol. 2013;62(16):e147-239. 
 
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APPENDIX 1 
PART 1 SCHEDULE OF STUDY PROCEDURES – SINGLE, ASCENDING DOSES 
Table 2 
Part 1 (SAD): Screening, Dosing Periods, and Follow up – High-Level 
 
 
Dosing Periods 
 
Period 
Screen 
A 
B 
C 
Da 
Follow-
upb 
Day 
-28 to 
-2 
-1 
1 
2 
3 
4 
-1 
1 
2 
3 
4 
-1 
1 
2 
3 
4 
-1 
1 
2 
3 
4 
7 ± 1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the unitc 
 
AD 
X 
X 
D/C 
 
AD 
X 
X 
D/C 
 
AD 
X 
X 
D/C 
 
AD 
X 
X 
D/C 
 
 
IMP Administration 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Medical historyd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
Body height 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Vital signsf 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
12-lead ECGsg 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
AEs/SAEsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TTEi 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
ECG telemetryk 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
Serologyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testm 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
FSH leveln 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyo 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Chemistryo 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Urinalysiso 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Troponinp 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
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MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 88 
Confidential 
 
 
Dosing Periods 
 
Period 
Screen 
A 
B 
C 
Da 
Follow-
upb 
Day 
-28 to 
-2 
-1 
1 
2 
3 
4 
-1 
1 
2 
3 
4 
-1 
1 
2 
3 
4 
-1 
1 
2 
3 
4 
7 ± 1 
Plasma for PKr 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
AD, admission; AE, adverse event; BP, blood pressure; bpm, beats per minute; 
 eCRF, electronic case report form; 
D/C, discharge; ECG, electrocardiogram; FSH, follicle-stimulating hormone; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency 
virus; HR, heart rate; ICF, informed consent form; IMP, investigational medicinal product; PK, pharmacokinetic; SAD, single-ascending dose; SAE, serious 
adverse event; SRC, Safety Review Committee; TTE, transthoracic echocardiography. 
a 
Dosing Period D is optional, based on SRC evaluation. 
b 
Follow-up visits should take place after Period C. If the patient is scheduled for Period D, a second Follow-up visit will be performed. Follow-up 
assessments should be performed if a patient withdraws. A TTE should be obtained at follow up if the patient’s last locally reviewed TTE has not returned to 
Baseline. 
c 
The patient will be discharged from the site on the morning of Day 3 of each dosing period after all procedures have been completed and the investigator 
deems it safe.  
d 
A complete medical history 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. Update medical history at Day -1, if needed. 
e 
At Screening and Day -1, a complete physical examination will be conducted including a neurological examination (gross motor and deep tendon reflexes), 
height and weight, and assessment of the following: general appearance, skin, head and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, 
cardiovascular, neurological, and respiratory systems. All other timepoints can be abbreviated physical examination (pulmonary, cardiac, abdominal, and 
other systems related to any symptoms). 
f 
Vital signs include temperature, HR, and BP after resting for at least 5 minutes. HR and BP taken predose, 6 hours, and 24 hours postdose will be obtained 
with the patient in the supine position 1 time after standing for 2 minutes and 1 time after standing for 5 minutes. All other HR and BP measurements should 
be the mean of 3 measurements taken in supine position, and BP should be taken via an automated recorder. Throughout Day 1, assessment of vital signs 
may be initiated up to 5 minutes before the assigned timepoint. On Day 1, patient will be ineligible to dose if HR ≥ 95 bpm at predose. 
g 
Triplicate 12-lead ECG evaluations taken within a 20-minute window will be performed in the supine position after 10 minutes of rest. The predose ECG on 
Day 1 should be performed within 2 hours of dosing. The timing of the 12-lead ECGs in this table applies to patients enrolled in Cohort 1. The actual timing 
of the ECGs may be modified and/or up to an additional 2 ECGs may be requested by the SRC after review of the data from previous cohorts. The 
Approved
1.0
v


MYK-491 
MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 89 
Confidential 
investigator may add extra 12-lead ECG safety assessments if there are any abnormal findings or if the investigator considers it required for any other safety 
reason. If the patient has any signs or symptoms suggestive of possible cardiac ischemia, additional ECGs should be obtained. These assessments should be 
recorded as unscheduled assessments. 
h 
Changes in a Baseline condition after the ICF is signed but before IMP is administered are recorded on the medical history eCRF unless the change is 
considered an AE related to a study procedure. All changes that occur after administration of the study medication are recorded as AEs. 
i 
A full TTE must be performed at Screening. Two TTEs will be performed during screening, no fewer than 7 days apart. Eligibility must be confirmed by 
core laboratory for both TTEs. Effort should be made for the second TTE to be performed as close to time of dosing as is feasible, taking into account core 
laboratory processing time and patient availability. After the Screening assessment, abbreviated TTEs will be performed. It is important that the TTEs are 
completed as close as possible to the scheduled time. TTEs will be evaluated locally for changes that might affect dosing decisions for others in the cohort, 
but the official reading will be done centrally by experts in a core laboratory in a blinded manner with results provided to the SRC. The SRC may modify the 
timing of the TTEs after the initial cohort so that for each subsequent cohort a TTE is obtained at the time of the predicted peak pharmacological effect. This 
will be based on the PK and TTE profiles from the previous cohorts. If appropriate, the SRC can request up to 2 additional TTEs be obtained. 
 
 
k 
ECG telemetry will be initiated at least 1 hour predose and continued through at least 48 hours. Additional monitoring may be needed based on data and/or 
patient’s tolerance to the treatment. 
l 
Blood sample for HIV, HCV, and HBV will be collected at Screening. 
m 
Pregnancy tests, urine or blood based on the policy of the local institution or regulating Health Authority (eg, requirement for serum-based testing in the 
UK), should be performed on all females at Screening, Day-1, and Follow-up. 
n 
FSH tests will be included for potentially postmenopausal women. 
o 
Samples for safety laboratory tests will be taken at Screening, Day -1, 24 hours postdose, and Follow up. Screening values and assessments will be made by 
the Central Laboratory; Day -1 assessments will be split with one sample assayed locally for review by the investigator and one sample assayed centrally. 
Safety laboratory tests may be added at the discretion of the investigator. 
p 
Samples for troponin should be split with 1 sample assayed locally in order to be locally reviewed by the investigator. The other sample will be assayed in 
Central Lab. Troponin testing performed at the Central Laboratory will be used for research purposes and will not be communicated to the study site except 
for Troponin I at Screening. If the patient has any signs or symptoms suggestive of possible cardiac ischemia, additional serial troponin samples should be 
obtained as appropriate to evaluate the possibility of ischemia. Lab results should be reviewed prior to patient discharge. 
 
 
  
r 
It is important that PK sampling occurs as close as possible to the scheduled time. Unscheduled or additional PK samples may be collected if appropriate in 
the opinion of the investigator and/or Sponsor. 
 
 
 
 
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MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 90 
Confidential 
Table 3 
Part 1 (SAD): Dosing Periods and Follow up – Detailed 
 
 
Detailed Treatment and Observation for Each of 4 Dosing Periods A, B, C, and D 
 
Day 
-1 
1 
2 
3 
4 
Hour 
 
Predosea 
0 
1 
2 
3 
4 
5 
6 
8 
9 
12 
18 
24 
36 
48 
72 
Confinement in the 
unitb 
AD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D/C 
 
IMP Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
12-lead ECGsf 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
 
 
AEs/SAEsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TTEh 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
ECG telemetryj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Chemistryl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysisl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Troponinm 
X 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
X- 
 
 
Plasma for PKo 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
AD, admission; AE, adverse event; BP, blood pressure; CK-MB, creatine kinase-MB; eCRF, electronic case report form; D/C, discharge; 
ECG, electrocardiogram; HR, heart rate; ICF, informed consent form; IMP, investigational medicinal product; PK, pharmacokinetic; SAE, serious adverse event; 
SRC, Safety Review Committee; TTE, transthoracic echocardiography. 
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MYK-491 
MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 91 
Confidential 
a 
All predose assessments should be performed within 2 hours of administering the oral dose of MYK-491 or placebo, with the following exceptions: predose 
or trough PK blood samples should be taken within 1 hour predose, and ECG telemetry monitoring should be initiated at least 1 hour prior to dosing. 
b 
The patient will be discharged from clinical research unit on Day 3 after all procedures have been completed and the investigator deems it safe.  
c 
Update medical history at Day -1, if needed. 
d 
At Screening and Day -1, a complete physical examination will be conducted including a neurological examination (gross motor and deep tendon reflexes), 
height and weight, and assessment of the following: general appearance, skin, head and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, 
cardiovascular, neurological, and respiratory systems. At 6 hours postdose and at the Follow-up visit, an abbreviated physical examination (pulmonary, 
cardiac, abdominal, and other systems related to any symptoms) will be conducted. 
e 
Vital signs will be taken at Screening, at Day -1, predose, and at 3, 6, 12, and 24 hours postdose, and at the Follow-up visit. Vital signs include temperature, 
HR, and BP after resting for at least 5 minutes. HR and BP taken predose, 6 hours, and 24 hours postdose will be obtained with the patient in the supine 
position, 1 time after standing for 2 minutes and 1 time after standing for 5 minutes. All other HR and BP measurements should be the mean of 3 
measurements taken in supine position, and BP should be taken via an automated recorder. On Day1, patient will be ineligible to dose if HR ≥ 95 bpm at 
predose. 
f 
Triplicate 12-lead ECG evaluations taken within a 20-minute window will be performed in the supine position after 10 minutes of rest at Screening, Day -1, 
predose, and at 3, 5, 9, 12, 24, and 36 hours postdose. The predose ECG on Day 1 should be performed within 2 hours of dosing. The timing of the 12-lead 
ECGs in this table applies to patients enrolled in Cohort 1. The actual timing of the ECGs may be modified and/or up to an additional 2 ECGs may be 
requested by the SRC after review of the data from previous cohorts. The investigator may add extra 12-lead ECG safety assessments if there are any 
abnormal findings or if the investigator considers it required for any other safety reason. If the patient has any signs or symptoms suggestive of possible 
cardiac ischemia, additional ECGs should be obtained. These assessments should be recorded as unscheduled assessments. 
g 
Changes in a Baseline condition after the ICF is signed but before IMP is administered are recorded on the medical history eCRF unless the change is 
considered an AE related to a study procedure. All changes that occur after administration of the study medication are recorded as AEs. 
h 
A full TTE must be performed at Screening. After the Screening assessment, abbreviated TTEs will be performed predose, and at 3, 6, 9, and 24 hours 
postdose. It is important that the TTEs are completed as close as possible to the scheduled time. TTEs will be evaluated locally for changes that might affect 
dosing decision for others in the cohort, but the official reading will be done centrally by experts in a core laboratory in a blinded manner with results 
provided to the SRC. The SRC may modify the timing of the TTEs after the initial cohort so that for each subsequent cohort a TTE is obtained at the time of 
the predicted peak pharmacological effect. This will be based on the PK and TTE profiles from the previous cohorts. If appropriate, the SRC can request up 
to 2 additional TTEs be obtained. 
 
 
j 
ECG telemetry will be initiated at least 1 hour predose and continued through at least 48 hours. Additional monitoring may be needed based on data and/or 
patient’s tolerance to the treatment. 
k 
Pregnancy tests, urine or blood based on the policy of the local institution or regulating Health Authority (eg, requirement for serum-based testing in the 
UK), should be performed on all females. 
l 
Samples for safety laboratory tests will be taken at Screening, Day -1, 24 hours postdose, and Follow up. Screening values and assessments will be made by 
the Central Laboratory; Day -1 assessments will be split with one sample assayed locally for review by the investigator and one sample assayed centrally. 
Safety laboratory tests may be added at the discretion of the investigator. 
Approved
1.0
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MYK-491 
MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 92 
Confidential 
m 
Troponin samples will be collected at Screening, Day -1, and at 3, 5, 9, 12, 24, and 36 hours postdose. Samples for troponin should be split with one sample 
assayed locally in order to be locally reviewed by the investigator. The other sample will be analyzed at a Central Laboratory. Troponin testing performed at 
the Central Laboratory will be used for research purposes and will not be communicated to the study site except for Troponin I at Screening. Results of 
troponin from local lab should guide patient evaluation. Abnormal and/or rising troponin values (as per investigator’s judgment and taking into account 
potential Baseline troponin elevation) should lead to patient being clinically evaluated for possible myocardial ischemia. Also, if the patient has any signs or 
symptoms suggestive of possible cardiac ischemia, additional serial troponin (and other safety labs, including CK-MB samples) should be obtained. Last 
troponin result performed at local lab (36h postdose) should be reviewed prior to patient discharge. 
 
 
  
o 
Plasma PK samples will be obtained within 1 hour predose and at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose during confinement, as well as an 
additional outpatient sample taken during an ambulatory visit 72 hours postdose. It is important that PK sampling occurs as close as possible to the 
scheduled time. Unscheduled or additional PK samples may be collected if appropriate in the opinion of the investigator and/or Sponsor. 
 
 
 
 
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1.0
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MYK-491 
MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 93 
Confidential 
Table 4 
Part 1 (SAD): Split Dose Screening, Dosing Periods, and Follow up – Detailed 
This Table should be followed for any dosing period when a single dose is split. 
 
 
Detailed Treatment and Observation for Each of 4 Dosing Periods A, B, C, and D 
 
Day 
-1 
1 
2 
3 
4 
Hour 
 
Predosea 
0 
1 
2 
3 
4 
5 
6 
8 
9 
10 
12 
18 
24 
36 
48 
72 
Confinement in the 
unitb 
AD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D/C 
 
IMP Administration 
 
 
X 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Medical historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
12-lead ECGsg 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
AEs/SAEsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TTEi 
 
X 
 
- 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
ECG telemetryk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologym 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Chemistrym 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysism 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Troponinn 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Plasma for PKp 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AD, admission; AE, adverse event; BP, blood pressure; CK-MB, creatine kinase-MB; eCRF, electronic case report form; D/C, discharge; 
ECG, electrocardiogram; HR, heart rate; ICF, informed consent form; IMP, investigational medicinal product; PK, pharmacokinetic; SAE, serious adverse event; 
SRC, Safety Review Committee; TTE, transthoracic echocardiography. 
Approved
1.0
v


MYK-491 
MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 94 
Confidential 
a 
All predose assessments should be performed within 2 hours of administering the oral dose of MYK-491 or placebo, with the following exceptions: predose 
or trough PK blood samples should be taken within 1 hour predose, and ECG telemetry monitoring should be initiated at least 1 hour prior to dosing. 
b 
The patient will be discharged from clinical research unit on Day 3 after all procedures have been completed and the investigator deems it safe. 
c 
Four hours is the expected interval for split dosing, but timing may be modified based on emerging PK data. 
d 
Update medical history at Day -1, if needed. 
e 
At Screening and Day -1, a complete physical examination will be conducted including a neurological examination (gross motor and deep tendon reflexes), 
height and weight, and assessment of the following: general appearance, skin, head and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, 
cardiovascular, neurological, and respiratory systems. At 6 hours postdose and at the Follow-up visit, an abbreviated physical examination (pulmonary, 
cardiac, abdominal, and other systems related to any symptoms) will be conducted. 
f 
Vital signs will be taken at Screening, at Day -1, predose, and at 3, 6, 9, 12, and 24 hours postdose, and at the Follow-up visit. Vital signs include 
temperature, HR, and BP after resting for at least 5 minutes. HR and BP taken predose, 6 hours, and 24 hours postdose will be obtained with the patient in 
the supine position, 1 time after standing for 2 minutes and 1 time after standing for 5 minutes. All other HR and BP measurements should be the mean of 3 
measurements taken in supine position, and BP should be taken via an automated recorder. On Day1, patient will be ineligible to dose if HR ≥ 95 bpm at 
predose. 
g 
Triplicate 12-lead ECG evaluations taken within a 20-minute window will be performed in the supine position after 10 minutes of rest at Screening, Day -1, 
predose, and at 3, 5, 9, 12, 24, and 36 hours postdose. The predose ECG on Day 1 should be performed within 2 hours of dosing. The timing of the 12-lead 
ECGs in this table applies to patients enrolled in Cohort 1. The actual timing of the ECGs may be modified and/or up to an additional 2 ECGs may be 
requested by the SRC after review of the data from previous cohorts. The investigator may add extra 12-lead ECG safety assessments if there are any 
abnormal findings or if the investigator considers it required for any other safety reason. If the patient has any signs or symptoms suggestive of possible 
cardiac ischemia, additional ECGs should be obtained. These assessments should be recorded as unscheduled assessments. 
h 
Changes in a Baseline condition after the ICF is signed but before IMP is administered are recorded on the medical history eCRF unless the change is 
considered an AE related to a study procedure. All changes that occur after administration of the study medication are recorded as AEs. 
i 
A full TTE must be performed at Screening. After the Screening assessment, abbreviated TTEs will be performed predose, and at 3, 6, 9, and 24 hours 
postdose. It is important that the TTEs are completed as close as possible to the scheduled time. TTEs will be evaluated locally for changes that might affect 
dosing decision for others in the cohort, but the official reading will be done centrally by experts in a core laboratory in a blinded manner with results 
provided to the SRC. The SRC may modify the timing of the TTEs after the initial cohort so that for each subsequent cohort a TTE is obtained at the time of 
the predicted peak pharmacological effect. This will be based on the PK and TTE profiles from the previous cohorts. If appropriate, the SRC can request up 
to 2 additional TTEs be obtained. 
 
 
k 
ECG telemetry will be initiated at least 1 hour predose and continued through at least 48 hours. Additional monitoring may be needed based on data and/or 
patient’s tolerance to the treatment. 
l 
Pregnancy tests, urine or blood based on the policy of the local institution or regulating Health Authority (eg, requirement for serum-based testing in the 
UK), should be performed on all females. 
m 
Samples for safety laboratory tests will be taken at Screening, Day -1, 24 hours postdose, and Follow up. Screening values and assessments will be made by 
the Central Laboratory; Day -1 assessments will be split with one sample assayed locally for review by the investigator and one sample assayed centrally. 
Safety laboratory tests may be added at the discretion of the investigator. 
Approved
1.0
v


MYK-491 
MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 95 
Confidential 
n 
Troponin samples will be collected at Screening, Day -1, and at 3, 5, 9, 12, 24, and 36 hours postdose. Samples for troponin should be split with one sample 
assayed locally in order to be locally reviewed by the investigator. The other sample will be analyzed at a Central Laboratory. Troponin testing performed at 
the Central Laboratory will be used for research purposes and will not be communicated to the study site except for Troponin I at Screening. Results of 
troponin from local lab should guide patient evaluation. Abnormal and/or rising troponin values (as per investigator’s judgment and taking into account 
potential Baseline troponin elevation) should lead to patient being clinically evaluated for possible myocardial ischemia. Also, if the patient has any signs or 
symptoms suggestive of possible cardiac ischemia, additional serial troponin (and other safety labs, including CK-MB samples) should be obtained. Last 
troponin result performed at local lab (36h postdose) should be reviewed prior to patient discharge. 
 
  
p 
Plasma PK samples will be obtained within 1 hour predose and at 1, 2, 3, 4 (before second dose of IMP), 5, 6, 8, 9, 10, 12, 18, 24, 36, and 48 hours postdose 
during confinement, as well as an additional outpatient sample taken during an ambulatory visit 72 hours postdose. It is important that PK sampling occurs 
as close as possible to the scheduled time. Unscheduled or additional PK samples may be collected if appropriate in the opinion of the investigator and/or 
Sponsor.  
 
 
 
 
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1.0
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MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 96 
Confidential 
APPENDIX 2 
PART 2 SCHEDULE OF STUDY PROCEDURES - MULTIPLE, ASCENDING DOSES 
Table 5 
Part 2 (MAD): Screening, Dosing Periods, and Follow up – High-Level 
 
 
High-level Treatment and Observation  
Day 
-28 
to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16± 1 
Period 
Screena 
Baseline  
Single-blind  
Placebo BID 
Double-blind Treatment BID 
Follow Up 
CONFINED: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the 
unitb with telemetry 
 
Admission 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
NON-CONFINEDb: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic visit 
mandatoryc 
X 
AM, 3PM AM, 
7h 
X 
(all day) 
7h 
 
 
AM 
 
X 
(all day) 
AM 
AM 
X 
X 
Clinic visit (optional) 
or HHN visitd  
 
PM 
PM 
 
AM, 
PM 
AM, PM 
AM, 
PM  
PM  
AM, 
PM  
 
 
 
 
 
All Dosing and Assessments below apply to both CONFINED or NON-CONFINED Patients  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Single-blind placebo 
administration 
 
X 
Q12h 
X 
Q12h 
 
 
 
 
 
 
 
 
 
 
 
Randomized DB IMP 
administratione 
 
 
 
X 
Q12h 
X 
Q12h 
X 
Q12h 
X 
Q12h 
X 
Q12h 
X 
Q12h 
X 
Once 
(AM) 
 
 
 
 
Assessment of dose-
modification/stopping 
criteriaf 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
X 
X 
 
X 
 
 
 
X±1d 
 
X 
X 
X 
 
X 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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MyoKardia, Inc. 
MYK-491 Protocol: MYK-491-003, Amendment 4, 19 March 2019 
Page 97 
Confidential 
 
 
High-level Treatment and Observation  
Day 
-28 
to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16± 1 
Period 
Screena 
Baseline  
Single-blind  
Placebo BID 
Double-blind Treatment BID 
Follow Up 
AEs/SAEsi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
therapy (incl. stable 
HF background 
treatment)j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTEk 
X 
X 
3pm 
X 
0, 7h 
X 
0, 7h 
X 
7h 
 
 
X 
0h 
 
X 
0, 7hr 
X 
24h 
X 
48h 
 
 
ECG telemetryl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Holter ECGm 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGsn 
X 
 
X 
0h 
X 
0, 7h 
X 
7h 
 
 
X±1d 
 
X 
0h 
X 
24h 
X 
48h 
 
X 
ICD downloado 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(± 1w) 
Serologyp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FSH levelr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologys 
X 
 
X 
 
X  
7h 
 
 
X±1d 
 
X 
 
X 
 
X 
Chemistrys 
X 
 
X 
 
X  
7h 
 
 
X±1d 
 
X 
 
X 
 
X 
Urinalysiss 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Troponint 
X 
 
X 
0h 
X 
0,7h 
X 
7h 
 
 
X±1d 
 
X 
0h 
X 
24h 
X 
48h 
 
X 
NT-proBNP 
X 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
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High-level Treatment and Observation  
Day 
-28 
to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16± 1 
Period 
Screena 
Baseline  
Single-blind  
Placebo BID 
Double-blind Treatment BID 
Follow Up 
PK (plasma)w 
 
 
 
X 
Mult 
X 
0, 7h 
 
 
X 
0h  
 
X 
Mult 
X 
24h 
X 
48h 
X 
72h 
 
AE, adverse event; BP, blood pressure; bpm, beats per minute; CK-MB, creatine kinase-MB; DB, double-blind, 
 
ECG, electrocardiogram; eCRF, electronic case report form; HF, heart failure; HHN, home health nurse; HR, heart rate; ICD, implantable cardioverter 
defibrillator; ICF, informed consent form; IMP, investigational medicinal product; PK, pharmacokinetic; Pk/Tr, peak/trough; Q12h, every 12 hours; SAE, serious 
adverse event; SRC, Safety Review Committee; TTE, transthoracic echocardiography. 
a 
Patients with LVEF < 25% may be screened for up to 12 weeks to accommodate SRC review of first 3 patients of each cohort.  Patients must remain 
clinically stable to meet eligibility. 
b 
If a patient has an ICD, confinement is not required. The patient may elect to stay in close proximity to the investigational site (eg, at a nearby hotel), but 
must return to the clinic for all IMP administrations and assessments. Alternatively, patients may be visited by a home health nurse for IMP administrations 
and assessments not requiring central equipment.. For all patients, ECGs, TTEs, and PK blood draws will be performed at the study site. If a patient is not 
confined, it is expected that the home health nurse will be in daily contact with the study site. All patients will be discharged from clinical research unit on 
Day 11 after all procedures have been completed and the investigator deems it safe. 
c 
For Day 3 and Day 9, a clinic visit from morning AM (pre-dose) until evening PM dose (12h later) is required. Refer to Table 6 for a detailed schedule  
d 
Randomization will occur on Day 3 following local labs on Day 2. For patients who are not confined, some IMP administrations and assessments could be 
completed by a HHN.  Days 1, 2, 4, 7 could have a HHN visit for the PM dose.  Days 5, 6, 8 could utilize a HHN for both doses.  Day 3 will require an 
in-clinic visit for both doses. Day 9 visit will be in-clinic and no evening dose and, therefore, no HHN visit.  Days 10-12 assessments will be done on site. 
e 
For Cohorts D and E, and any additional cohorts, all IMP administration may be QD or BID for each dosing day, as determined by the SRC. 
f 
Further detail regarding dose-modification and stopping criteria are described in Section 4.2. 
g 
At Screening, a complete physical examination will be conducted including a neurological examination (gross motor and deep tendon reflexes), height and 
weight, and assessment of the following: general appearance, skin, head and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, cardiovascular, 
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neurological, and respiratory systems. At all other time points an abbreviated physical examination (pulmonary, cardiac, abdominal, and other systems 
related to any symptoms) will be conducted. Physical exams should be conducted prior to the morning dose on dosing days. 
h 
Vital signs will be taken at Screening, every day prior to the morning dose, and at the Follow-up visit. See detailed level of assessments for Day 3 and 9 in 
Table 6 for additional times vital signs are taken. Vital signs include temperature, HR, and BP after resting for at least 5 minutes. On Day 2 and once on 
Day 9 (see Table 6 for Day 9 instructions), vitals should include HR and BP taken in the supine position, one standing for 2 minutes, and one time standing 
for 5 minutes. All other HR and BP measurements should be the mean of 3 measurements taken in supine position, and BP should be taken via an automated 
recorder during confinement or during a clinic visit, and, if available, during home health nurse visits. On Day 1, patient will be ineligible to dose if HR 
≥ 95 bpm at predose, if the average of 3 readings is higher than 95 bpm. 
i 
Changes in a Baseline condition after the ICF is signed but before IMP is administered are recorded on the medical history eCRF unless the change is 
considered an AE related to a study procedure. All changes that occur after administration of the study medication are recorded as AEs. 
j 
Every effort should be made to maintain stable background HF treatment and to administer such treatments (including diuretic as applicable) at the same 
time every day throughout the duration of the study.  
k 
Two TTEs will be performed during screening, no fewer than 7 days apart.  Eligibility must be confirmed by core laboratory for both TTEs.  Effort should 
be made for the second TTE to be performed as close to time of dosing as is feasible, taking into account core laboratory processing time and patient 
availability.  A full TTE should be performed at all time points indicated (with morning ‘0h’ TTE on Day 3, Day 7 and Day 9 to be performed pre-dose). It is 
important that the TTEs are completed as close as possible to the scheduled time (±1 hour). TTEs will be evaluated locally for changes that might affect 
stopping criteria and/or dose modification, but the official reading for final results will be done centrally by experts in a core laboratory in a blinded manner. 
For all patients, TTEs will be performed at the study site. 
l 
ECG telemetry will be initiated at least 1 hour prior to first dose (single-blind) on Day 1 and continued through Day 11 (ie, until about 48 hours post final 
double-blind dose on Day 9). Additional monitoring may be needed based on data and/or patient’s tolerance to the treatment.  Note: ECG telemetry is not 
required for patients who are not confined. 
m 
Continuous Holter monitoring will be acquired in 2 timepoints, first from Day 1 until Day 3 morning (before first dose of DB treatment, 48 hours total) and 
from Day 7 until Day 9 . Holter may be set up any time on Day 7 and should be removed 48 hours later on Day 9. Holter may be set up by a trained home 
health nurse or at the study site. All patients, whether confined or not confined, must have Holter monitoring during the required times.  
n 
Triplicate 12-lead ECG evaluations will be performed in the supine position after 10 minutes of rest at Screening and at Follow-up visit. See detailed 
schedule for Days 3 and 9. On Day 2, ECGs should be taken prior to the morning dose. On Day 4 ECG should be taken 7 hours post morning dose. On 
Day 7 (±1 day) ECGs should be taken prior to morning dose. On Day 10, ECG is 24 hours post final dose and on Day 11 ECG is post 48 hours final dose. 
All predose ECGs should be taken within 2 hours of dose, and all other ECGs should be taken plus or minus 2 hours of time point indicated. The investigator 
may add extra 12-lead ECG safety assessments if there are any abnormal findings or if the investigator considers it required for any other safety reason. If 
the patient has any signs or symptoms suggestive of possible cardiac ischemia, additional ECGs should be obtained. These assessments should be recorded 
as unscheduled assessments. For all patients, ECGs will be performed at the study site.  
o 
ICD download to be performed unless site encounters significant technical difficulties and is required in case of shock(s) delivered by the ICD during the 
study.  
p 
Blood sample for HIV, HCV, and HBV will be collected at Screening. 
q 
Pregnancy tests, urine or blood based on the policy of the local institution or regulating Health Authority (eg, requirement for serum-based testing in the 
UK), should be performed on all females. 
r 
FSH tests will be included for potentially postmenopausal women. 
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s 
Safety laboratory tests should be split and one sample evaluated by local lab and the other sent to Central Lab. Samples will be taken on days indicated prior 
to morning dose (except on Day 4, where labs will be taken at 7 hours post-dose). Day 2 local lab results must be evaluated prior to dosing on Day 3. If 
needed to accommodate local laboratory time tables, Day 2 samples may be taken on Day 1. Safety laboratory tests may be added at the discretion of the 
investigator. NOTE: Day 7 safety laboratory assessments can be performed ±1 day if the assessments would fall on a weekend. 
t 
Troponin samples will be collected as indicated. The 0 hour assessment samples should be taken prior to dosing. On Day 10, samples should be taken 24 
hours post last dose. On Day 11, samples should be taken 48 hours post last dose. Samples for troponin should be split, with one sample assayed locally in 
order to be locally reviewed by the investigator. Troponin I or Troponin T is acceptable for local troponin, based on availability of assay at site. The other 
sample will be analyzed at a Central Laboratory. Results of troponin from local lab should guide patient evaluation. Abnormal and/or rising troponin values 
(as per investigator judgment and taking into account potential Baseline troponin elevation) should lead to patient being clinically evaluated for possible 
myocardial ischemia. Also, if the patient has any signs or symptoms suggestive of possible cardiac ischemia, additional serial troponin (and other safety labs, 
including CK-MB samples) should be obtained. NOTE: Day 7 troponin samples can be taken ±1 day if the assessments would fall on a weekend. Troponin 
testing performed at the Central Laboratory will be used for research purposes and will not be communicated to the study site except for Troponin I at 
Screening. 
 
 
 
 
 
 
 
 
w 
Refer to Table 6 for Day 3 and Day 9 timepoints. On Day 10, samples should be taken 24 hours post final dose. On Day 11 samples should be taken 48 hours 
post final dose and Day 12 at 72 hours post final dose. It is important that PK sampling occurs as close as possible to the scheduled time. Unscheduled or 
additional PK samples may be collected if appropriate in the opinion of the investigator and/or Sponsor. For all patients, PK blood draws will be performed 
at the study site. 
 
 
 
 
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Table 6 
Part 2 (MAD): Dosing Periods and Follow up – Detailed for Days 3 and 9 
 
 
Detailed Treatment and Observation for Randomized Study Drug on Days of First and Last Double-
blind Dose (All-Day In Clinic Days 3 and 9) 
 
 
Study Hour 
Hour 
Predosea 
0 
1 
2 
3 
4 
5 
6 
7 
9 
12 
Vital signsb 
X 
 
 
 
 
 
 
 
X 
 
 
12-lead ECGsc 
X 
 
 
 
 
 
 
 
X 
(Day 3 only) 
 
 
Troponind 
X 
 
 
 
 
 
 
 
X 
(Day 3 only)  
 
 
PK (plasma)e 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TTEg 
X 
 
 
 
 
 
 
 
X 
 
 
AE, adverse event; BP, blood pressure; CRF, case report form; ECG, electrocardiogram; HR, heart rate; ICD, implantable cardioverter defibrillator; 
IMP, investigational medicinal product; PK, pharmacokinetic; SAE, serious adverse event; SRC, Safety Review Committee; TTE, transthoracic 
echocardiography. 
a 
All predose assessments should be performed within 2 hours of administering the oral dose of MYK-491 or placebo, with the following exceptions: predose 
or trough PK blood samples should be taken within 1 hour predose, and ECG telemetry monitoring should be initiated at least 1 hour prior to the first dose. 
b 
Vital signs include temperature, HR, and BP after resting for at least 5 minutes. On Day 9, in the morning (predose), HR and BP should be taken once in the 
supine position, once after 2 minutes standing, once after 5 minutes standing. All other HR and BP measurements should be the mean of 3 measurements 
taken in supine position, and BP should be taken via an automated recorder. 
c 
Triplicate 12-lead ECG evaluations will be performed in the supine position after 10 minutes of rest at Screening, predose, and at 7 hours postdose. The 
predose ECG on Day 1 should be performed within 2 hours of dosing. The investigator may add extra 12-lead ECG safety assessments if there are any 
abnormal findings or if the investigator considers it required for any other safety reason. If the patient has any signs or symptoms suggestive of possible 
cardiac ischemia, additional ECGs should be obtained. These assessments should be recorded as unscheduled assessments. For all patients, ECGs will be 
performed at the study site. 
d 
Samples for troponin should be split with one sample assayed locally in order to be locally reviewed by the investigator. The other sample will be analyzed 
at a Central Laboratory. Results of troponin from local lab should guide patient evaluation. Abnormal and/or rising troponin values (as per investigator’s 
judgment and taking into account potential Baseline troponin elevation) should lead to patient being clinically evaluated for possible myocardial ischemia. 
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Also, if the patient has any signs or symptoms suggestive of possible cardiac ischemia, additional serial troponin (and other safety labs, including CK-MB 
samples) should be obtained.  Troponin testing performed at the Central Laboratory will be used for research purposes and will not be communicated to the 
study site except for Troponin I at Screening. 
e 
Plasma PK samples will be obtained at time points indicated. The 12-hour time point should be collected prior to evening dose on Day 3. It is important that 
PK sampling occurs as close as possible to the scheduled time. Unscheduled or additional PK samples may be collected if appropriate in the opinion of the 
investigator and/or Sponsor. For all patients, PK blood draws will be performed at the study site. 
 
 
g 
It is important that the TTEs are completed as close as possible to the scheduled time (±1 hour). TTEs will be evaluated locally for changes that might affect 
dosing decision for others in the cohort, but the official reading will be done centrally by experts in a core laboratory in a blinded manner with results 
provided to the SRC. For all patients, TTEs will be performed at the study site. 
 
 
 
 
 
 
 
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APPENDIX 4 
LABORATORY ASSESSMENTS 
The following safety laboratory parameters will be measured. 
Table 9 
Safety Laboratory Parameters 
Hematology 
Serum Chemistry 
Urinalysisa 
• CBC, including differential 
count 
• Sodium 
• Specific gravity 
• Platelet count 
• Potassium 
• pH 
 
• Chloride 
• Protein 
 
• Bicarbonate 
• Glucose 
 
• Calcium 
• Leukocyte esterase 
 
• Magnesium 
• Blood 
 
• Urea 
 
 
• Creatinine 
 
 
• ALP 
 
 
• ALT 
 
 
• AST 
 
 
• Total bilirubin 
 
 
• Glucose 
 
 
• CPK 
 
ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; CBC, complete 
blood count; CPK, creatine phosphokinase. 
 
Urine microscopy will be performed if there is a significant abnormality in the dipstick. 
Troponin I, Troponin T,
 will also be assessed (Appendix 1 and 
Appendix 2). 
The following nonsafety laboratory parameters will be measured in this study:  
• Serology (HIV, hepatitis panel) 
• FSH 
• Pregnancy, assessed in urine or blood based on the policy of the local institution or 
regulating Health Authority (eg, requirement for serum-based testing in the UK) 
 
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APPENDIX 5 
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING 
AND ADDITIONAL ASSESSMENTS REPORTING 
To facilitate appropriate monitoring for signals of drug-induced liver toxicity (DILI), cases of 
concurrent AST/ALT and TBL elevation according to the criteria specified in Section 4.2 
(3 times ULN for AST/ALT and 2 times ULN for TBL in patients 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 an SAE within 24 hours of discovery or 
notification of the event (ie, before additional etiologic investigations have been 
concluded). 
• The appropriate eCRFs (eg, Adverse Event eCRFs) that capture information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities are to be completed 
and sent to MyoKardia. 
 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Section 10.1.2. 
Additional Clinical Assessments and Observation 
All patients in whom investigational product(s) or protocol-required therapies is/are withheld 
(either permanently or conditionally) due to potential DILI or who experience AST/ALT 
elevations > 3 times ULN are to undergo a period of close observation until abnormalities 
return to normal or to the patient’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, TBL); in 
cases of TBL ≥ 2 times ULN or AST/ALT much greater than 3 × ULN, retesting is to be 
performed within 24 hours. 
- 
Patients 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 patient is 
asymptomatic. 
• Obtain prothrombin time/international normalized ratio, fractionated bilirubin, and any 
other potentially relevant laboratory evaluations of liver function or disease. 
• Obtain complete blood count with differential to assess for eosinophilia. 
• Obtain appropriate blood sampling for PK analysis if this has not already been collected. 
• Obtain a more detailed history of the following: 
- 
Prior and/or concurrent diseases or illness 
- 
Exposure to environmental and/or industrial chemical agents 
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- 
Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-type 
reactions, fatigue, nausea, vomiting, and fever 
- 
Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
- 
Concomitant medications (including nonprescription medicines and herbal and 
dietary supplements) 
• Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A, B, C, 
D, E, Epstein-Barr virus, herpes simplex virus, etc.); evaluate for other potential causes of 
DILI, including but not limited to: nonalcoholic steatohepatitis, hypoxic/ischemic 
hepatopathy, and biliary tract disease. 
• Obtain gastroenterology or hepatology consult. 
• Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider 
these tests in cases of concurrent transaminase and TBL elevation as specified in 
Section 4.2. 
• Follow the patient 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 6 
INVESTIGATOR’S SIGNATURE 
MYK-491-003 (HF-SAD/MAD), Edition 5, Release date: 19 March 2019 
I have read and understand the contents of the clinical protocol, MYK-491-003, a 
Randomized, Double-blind, Placebo-controlled, Two-Part, Adaptive Design Study of Safety, 
Tolerability, Preliminary Pharmacokinetics, and Pharmacodynamics of Single and Multiple 
Ascending Oral Doses of MYK-491 in Patients with Stable Heart Failure with Reduced 
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 
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 reviewed and documented approval from the EC, except 
to eliminate an immediate hazard to the study participants, or when change(s) involves 
only logistical or administrative aspects of the clinical study 
• To permit direct monitoring and auditing by MyoKardia or MyoKardia’s representatives 
and inspection by the appropriate regulatory authority(ies) 
• That I am thoroughly familiar with the appropriate use of the Investigational Medicinal 
Product (IMP) and other study medication(s) (if applicable), as described in this protocol, 
and any other information provided by MyoKardia or designee, including, but not limited 
to the current Investigator’s Brochure (IB) or equivalent document and marketed 
prescription information (if applicable) 
• To provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically, and safely 
• To ensure that all persons assisting in this study are adequately informed about the 
protocol, IMP/study medication(s) and their clinical study-related duties and functions 
 
 
Signed: ____________________________________ 
Date: ___________________ 
(sign name with credentials) 
Printed Name: ______________________________ 
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