Heart muscle disease inherited hart disease
Conditions
Interventions
Participants will receive mavacamten immediate release capsules 5 mg or
matching placebo QD for the first 8 weeks of the dosing period with trough PK
samples drawn at Week 4, Week 6, and Week 8. If
Sponsors
MyoKardia, Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1.Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent according to federal, local, and institutional guidelines before the first study specific procedure 2.Is at least 18 years old at Screening 3.Body weight is greater than 45 kg at Screening 4.Has adequate acoustic windows to enable accurate TTEs 5.Diagnosed with oHCM consistent with current AACF/AMA and ESC, ie, satisfy both criteria below (criteria to be documented by the echocardiography core laboratory): A.Has unexplained left ventricular (LV) hypertrophy with nondilated ventricular chambers in the absence of other cardiac (eg, hypertension, aortic stenosis) or systemic disease and with maximal LV wall thickness *15 mm (or *13 mm with positive family history of hypertrophic cardiomyopathy [HCM]), as determined by core lab interpretation and B.Has LVOT peak gradient *50 mmHg during Screening as assessed by echocardiography at rest, after Valsalva maneuver, or postexercise (confirmed by echocardiography core laboratory interpretation) 6.Has documented left ventricular ejection fraction (LVEF) *55% by echocardiography core laboratory read of Screening TTE at rest 7. Has LVOT gradient with Valsalva maneuver at screening TTE of *30mmHg, determined by echocardiography core laboratory. 8.Has New York Heart Association (NYHA) functional Class II or III symptoms at Screening 9.Has documented oxygen saturation at rest *90% at Screening 10.Is able to perform an upright 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 only if it is determined by the central CPET laboratory that peak exercise has been achieved in the subject (the only permitted reasons for subpeak performance are [1] a decrease in systolic blood pressure or [2] severe angina as described in the CPET Laboratory Manual) 11.Female participants must not be pregnant or lactating and, 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). Combined (estrogen-and progestogen-containing) hormonal contraception associated with inhibition of ovulation or progestogen-only hormonal contraception associated with inhibition of ovulation by oral, implantable, or injectable route of administration. - intrauterine device (IUD) - intrauterine hormone-releasing system (IUS) - bilateral tubal occlusion - 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 levels are in the postmenopausal range Male partners must also use a contraceptive (eg barrier, condom or vasectomy)
Exclusion criteria
Exclusion criteria: 1.Previously participated in a clinical study with mavacamten 2.Hypersensitivity to any of the components of the mavacamten formulation 3.Participated in a clinical trial in which the participant received any investigational drug (or is currently using an investigational device) within 30 days of Screening, or at least 5x the respective elimination half life (whichever is longer) 4.Infiltrative or storage disorder causing CH that mimics oHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LVH 5.Medical condition that precludes upright exercise stress testing 6.History of syncope within 6 months prior to Screening or history of sustained VT with exercise within 6 months prior to Screening 7.History of resuscitated sudden CA (at any time) or history of appropriate ICD discharge/shock for life-threatening VA within 6 months prior to Screening 8.Has paroxysmal, intermittent AF with AF present per the investigator's evaluation of the participant's ECG at time of Screening 9.Has persistent/permanent AF not on anticoagulation for at least 4 weeks to Screening &/or not adequately rate controlled within 6 months prior to Screening 10.Current treatment (within 14 days to Screening) or planned treatment during the study with disopyramide or ranolazine 11.Current treatment (within 14 days prior to Screening) or planned treatment during the study with a combination of *-blockers and verapamil or a combination of *-blockers and diltiazem 12.Individuals on *-blockers, verapamil, or diltiazem, any dose adjustment of that medication 500 ms at screening or other ECG abnormality considered by investigator to pose risk to participant safety (eg, second-degree atrioventricular block type II) 16.Documented OCAD (>70% stenosis in one or more epicardial coronary arteries) or history of MI 17.Moderate or severe (as per investigator's judgment) AVS at Screening 18.Acute or serious comorbid condition (eg, major infection or hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction) that, in the judgment of the investigator, could lead to premature termination of study participation or interfere with the measurement or interpretation of the efficacy & safety assessments in the study 19.Has pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation 20.History of malignant disease within 10 years of Screening: 21.Has safety laboratory parameters (chemistry, hematology, coagulation, & urinalysis) outside normal limits (according to the central laboratory reference range) at Screening as assessed by the central laboratory; however, participant with safety laboratory parameters outside normal limits may be included if he or she meets all of the following criteria: *Safety laboratory parameter outside normal limits is considered by the investigator to be clinical
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| * Clinical response defined as achieving (1) an improvement of at least 1.5 mL/kg/min or more in peak oxygen consumption (pVO2) as determined by CPET and a reduction of one or more class in NYHA Functional Classification or 2) an improvement of 3.0 mL/kg/min or more in pVO2 with no worsening in NYHA Functional Class. | — |
Secondary
| Measure | Time frame |
|---|---|
| * Change from baseline to Week 30 in post-exercise LVOT peak gradient * Proportion of participants with at least 1 class improvement in NYHA functional class from baseline to Week 30 * Change from baseline to Week 30 in peak oxygen consumption (pVO2) as determined by CPET * Change from baseline to Week 30 in participant-reported health-related quality of life as assessed by the KCCQ score * Change from baseline to Week 30 in patient-reported severity of HCM symptoms as assessed by the HCM Symptom Questionnaire score | — |
Countries
Netherlands
Outcome results
None listed