|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|obstructive hypertrophic cardiomyopathy (oHCM)
|Medical condition in easily understood language
|heart disease with thickening of the heart muscle
|Diseases [C] - Cardiovascular Diseases [C14]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|- To evaluate the effect of CK-3773274 on exercise capacity in patients with symptomatic oHCM
|Secondary objectives of the trial
|- To evaluate the effect of CK-3773274 on patient health status
- To evaluate the effect of CK-3773274 on New York Heart Association (NYHA) Functional Classification
- To evaluate the effect of CK-3773274 on post-Valsalva left ventricular outflow tract gradients (LVOT-G)
- To evaluate the effect of CK-3773274 on exercise capacity
- To evaluate the effect of CK-3773274 on duration of eligibility for septal reduction therapy
To evaluate the safety and tolerability profile of CK-3773274 in patients with symptomatic oHCM
|Trial contains a sub-study
|Full title, date and version of each sub-study and their related objectives
|A Cardiac Magnetic Resonance (CMR) imaging sub-study will be open to approximately 100 patients who consent to participate.
|Principal inclusion criteria
|- Males and females between 18 and 85 years of age, inclusive, at screening.
- Body mass index <35 kg/m^2.
- Diagnosed with HCM per the following criteria:
a. Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and
b. Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of:
• ≥15 mm in one or more myocardial segments OR
• ≥13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM
- Has resting LVOT-G ≥30 mmHg and post-Valsalva LVOT-G ≥50 mmHg during screening as determined by the echocardiography core laboratory
- LVEF ≥60% at screening as determined by the echocardiography core laboratory.
- New York Heart Association (NYHA) Functional Class II or III at screening
- Hemoglobin ≥10 g/dL at screening.
- Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the screening CPET per the core laboratory.
- Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on a stable doses for >6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial. Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker.
|Principal exclusion criteria
|- Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
- Significant valvular heart disease (per investigator judgment).
a) Moderate-severe valvular aortic stenosis.
b) Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve.
- History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time during their clinical course.
- Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations).
- Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period.
- Documented paroxysmal atrial fibrillation during the screening period.
- Paroxysmal or permanent atrial fibrillation is only excluded IF:
• rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy)has been required ≤6 months prior to screening.
• rate control and anticoagulation have not been achieved for at least 6 months prior to screening.
- History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
- Has received prior treatment with CK-3773274 or mavacamten.
Exclusion Criteria for CMR Sub-study
- Inability to tolerate CMR.
- Has an implantable cardioverter-defibrillator (ICD).
- Has a cardiac pacemaker.
|E.5 End points
|Primary end point(s)
|• Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET)
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|• Change in Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS)
• Proportion of patients with ≥1 class improvement in NYHA Functional Class
• Change in post-Valsalva LVOT-G
• Proportion of patients with post-Valsalva LVOT-G <30 mmHg
• Change in total workload during CPET
• Duration of eligibility for septal reduction therapy (SRT) in patients who are eligible for SRT at baseline
• Incidence of reported major adverse cardiac events (cardiovascular [CV] death, cardiac arrest, non-fatal stroke, non-fatal myocardial infarction, CV hospitalization)
• Incidence of new onset persistent atrial fibrillation
• Incidence of appropriate implantable cardiac defibrillator (ICD) discharges and aborted sudden cardiac death
• Incidence of left ventricular ejection fraction (LVEF) <50%
• Incidence of treatment emergent adverse events
|Timepoint(s) of evaluation of this end point
|KCCQ-CSS - baseline to Week 12 and Week 24
NYHA Functional Class -baseline to Week 12 and Week 24
Change in post-Valsalva LVOT-G - baseline to Week 12 and Week 24
Proportion of patients with post-Valsava LVOT-G <30 mmHg - Week 12 and Week 24
Total workload during CPET - baseline to Week 24
Duration of eligibility for SRT - baseline to Week 24
Safety - Throughout the study
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days