E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
obstructive hypertrophic cardiomyopathy (oHCM) |
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E.1.1.1 | Medical condition in easily understood language |
heart disease with thickening of the heart muscle |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020871 |
E.1.2 | Term | Hypertrophic cardiomyopathy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To evaluate the effect of CK-3773274 on exercise capacity in patients with symptomatic oHCM |
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E.2.2 | 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
Safety
To evaluate the safety and tolerability profile of CK-3773274 in patients with symptomatic oHCM |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | 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. |
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E.3 | 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. |
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E.4 | 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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
Safety
• 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
• Incidence of LVEF <50% with at least one of the following:
- Signs and symptoms of heart failure (concomitant adverse event of heart failure or dyspnea), AND/OR
- Increase in NT-proBNP ( ≥30% increase), relative to results from the most recent previous visit and above the upper limit of normal, at the time of LVEF assessment <50%
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
China |
Israel |
United Kingdom |
United States |
Czechia |
Denmark |
France |
Germany |
Hungary |
Italy |
Netherlands |
Poland |
Portugal |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |