A Randomized, Double-blind, Placebo-controlled Clinical Study to Evaluate Mavacamten in Adults with Cardiomyopathy

Phase 1

Conditions: Symptomatic Nonobstructive Hypertrophic Cardiomyopathy
MedDRA version: 20.0Level: PTClassification code 10049813Term: Non-obstructive cardiomyopathySystem Organ Class: 10007541 - Cardiac disorders
MedDRA version: 20.0Level: PTClassification code 10020871Term: Hypertrophic cardiomyopathySystem Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Registration Number: EUCTR2021-005329-26-DE

Lead Sponsor: Myokardia, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 420

Inclusion Criteria

1. Participants must be 18 years old or local age of majority at the time of signing the informed consent
2. Female participants must adhere to highly effective contraceptive methods or have documented proof that they are not of childbearing potential
3. No additional contraceptive measures are required to be used for male participants
4. Diagnosis of HCM consistent with current American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guidelines.
5. Peak LVOT pressure gradient < 30 mmHg at rest and < 50 mmHg with provocation (Valsalva maneuver and stress echocardiography)
6. CPET: Documented oxygen saturation at rest >90% at Screening. Able to perform an upright cardiopulmonary stress test (CPET) and has a respiratory exchange ratio (RER) = 1.0 at Screening per central reading. If the RER is between 0.91 and 1.0, the participant may be enrolled if the central CPET laboratory determines that peak exercise has been achieved. Participants with subpeak performance may not be enrolled as described in the CPET Laboratory Manual.
7. New York Heart Association (NYHA) Class II or III
8. NT-proBNP=200 pg/mL or BNP=70 pg/mL
9. LVEF =60 % as determined by the echocardiography central laboratory

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 400
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

Exclusion Criteria

Medical Conditions
- Known infiltrative or storage disorder causing cardiac hypertrophy that mimics nHCM such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy
- History of unexplained syncope within 6 months prior to screening
- History of sustained ventricular tachyarrhythmia (> 30 seconds) within 6 months prior to Screening
- Paroxysmal or persistent (non-permanent) AF detected at the time of screening. Permanent AF is allowed if the participant is anticoagulated and the investigator considers the heart rate adequately controlled
- CV diseases or treatments that in the opinion of the investigator increase the unpredictability of or change the participants’ clinical course.
- Acute heart failure from 4 weeks prior to screening up to randomization
- Coronary artery disease requiring intervention, including myocardial infarction (increase in cardiac enzymes in combination with symptoms of ischemia or new ischemic ECG changes), coronary artery bypass graft surgery, or other major CV surgery, stroke, or transient ischemic attack in the past 90 days
- Women who are breastfeeding or pregnant.

Prior/Concomitant Therapy
- Any adjustments of beta-blockers, verapamil, or diltiazem within 2 weeks prior to Screening and up to the day of randomization
- Concomitant use of strong inhibitors of cytochrome P450 (CYP) 2C19
Note: Use should be discontinued for a minimum of 5 elimination half-lives prior to first dose of study intervention.

Other Exclusion Criteria
- Any other serious condition that in the opinion of the investigator could prevent participation in the study and follow-up, including active
infection with COVID-19 from 4 weeks prior to screening up to randomization
- Completed a study with an investigational device < 30 days prior to screening or an investigational drug < 5 half-lives prior to screening
- Participants who have completed a study with mavacamten or aficamten
-Enrolled in another study and receiving any investigational treatment (device or drug) other than the study intervention given in this study.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the efficacy of a 48-week course of<br>mavacamten compared to placebo on patient reported health status<br><br>To assess the efficacy of a 48-week course of<br>mavacamten compared to placebo on exercise<br>capacity;Secondary Objective: Evaluate the effects of mavacamten on exercise capacity as measured by VE/VCO2 slope<br><br>Evaluate the effects of mavacamten on NYHA classification<br><br>Evaluate the effects of mavacamten on the composite of NYHA and pVO2<br><br>Evaluate the effects of mavacamten on cardiac biomarkers<br><br>Evaluate the effects of mavacamten on patient reported shortness of breath<br><br>Evaluate the effects of mavacamten on composite of cardiovascular events<br>;Primary end point(s): 1. Change from baseline in KCCQ CSS <br>2. Change from baseline in pVO2 <br> <br>;Timepoint(s) of evaluation of this end point: 1. Week 48<br>2. Week 48

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Change from baseline in VE/VCO2 slope <br>2. Proportion of participants with at least 1 class of NYHA improvement from baseline <br>3. Change from baseline in NT-pro BNP <br>4. Change from baseline in cTn-T <br>5. Change from baseline in HCMSQ-SoB domain <br>6. Time to First MACE-Plus events defined as any CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, or hospitalization for arrhythmias or appropriate ICD therapy<br>;Timepoint(s) of evaluation of this end point: 1. Week 48<br>2. Week 48<br>3. Week 48<br>4. Week 48<br>5. Week 48<br>6. Week 48<br>7. From the study drug initiation to occurrence of the first MACE-Plus or when the last subject reaches Week 48

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