CY 6031 Study Will Evaluate the Effects of Treatment With Aficamten (CK-3773274) Over a 24-week Period on Cardiopulmonary Exercise Capacity and Health Status in Patients With Symptomatic oHCM

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction

Official Title
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A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction

Conditions
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Obstructive Hypertrophic Cardiomyopathy (oHCM)

Intervention / Treatment
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* Drug: CK-3773274 (5 mg, 10 mg, 15 mg and 20 mg)
* Drug: Placebo to match CK-3773274


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males and females between 18 and 85 years of age, inclusive, at screening. Body mass index <35 kg/m2. Diagnosed with HCM per the following criteria: Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and 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. NYHA Functional Class II or III at screening. Hemoglobin ≥10g/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 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. Key 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). Moderate-severe valvular aortic stenosis. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CK-3773274 up to 20 mg<br>Patients will receive doses of 5 mg, 10 mg, 15 mg or 20 mg of CK-3773274 with dose levels guided by echocardiography assessments for up to 24 weeks | Drug: CK-3773274 (5 mg, 10 mg, 15 mg and 20 mg)<br>* CK-3773274 tablets administered orally<br>|
| Placebo Comparator: Placebo to match CK-3773274<br>Patients will receive placebo for up to 24 weeks | Drug: Placebo to match CK-3773274<br>* Placebo administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET) | Effect of CK-3773274 on exercise capacity in patients with symptomatic oHCM | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) | Effect of CK-3773274 on patient health status | Baseline to Week 12 and Week 24 | 
| Proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) Functional Class | Effect of CK-3773274 on NYHA Functional Classification | Baseline to Week 12 and Week 24 | 
| Change in post-Valsalva left ventricular outflow tract gradients (LVOT-G) | Effect of CK-3773274 on post-Valsalva LVOT-G | Baseline to Week 12 and Week 24 | 
| Proportion of patients with post-Valsalva LVOT G <30 mmHg | Effect of CK-3773274 on post-Valsalva LVOT-G | Baseline to Week 12 and Week 24 | 
| Change in total workload during CPET | Effect of CK-3773274 on exercise capacity | Baseline to Week 24 | 
| Duration of eligibility for septal reduction therapy (SRT) | Effect of CK-3773274 on duration of eligibility for septal reduction therapy | Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obstructive Hypertrophic Cardiomyopathy, oHCM, CK-3773274, CK-274, Aficamten, SEQUOIA-HCM, CY 6031, SEQUOIA