The Purpose of This Study is to Compare the Efficacy and Safety of Aficamten (CK-3773274) Compared With Metoprolol Succinate in Adults With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of aficamten (CK-3773274) compared with metoprolol succinate 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 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy

Conditions
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Obstructive Hypertrophic Cardiomyopathy (oHCM)

Intervention / Treatment
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* Drug: Aficamten (CK-3773274) (5 mg, 10 mg, 15 mg and 20 mg)
* Drug: Placebo to match aficamten
* Drug: Metoprolol succinate (50 mg, 100 mg, 150 mg and 200 mg)
* Drug: Placebo to match metoprolol succinate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who meet all the following criteria at screening may be included in the trial: Males and females between 18 to 85 years of age, inclusive, at screening Body mass index < 35 kg/m2 Diagnosed with oHCM per the following criteria by cardiac magnetic resonance imaging (CMR) or echocardiography - Has left ventricular (LV) hypertrophy with 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: ≥ 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 NYHA class II or III Has a screening echocardiogram with the following determined by the echocardiography core laboratory: Resting LVOT-G > 30 mm Hg and/or post-Valsalva LVOT-G ≥ 50 mmHg at screening AND LVEF ≥ 60% Hemoglobin ≥ 10g/dL Patients previously exposed to mavacamten are allowed to participate but must be off mavacamten for at least 8 weeks Exclusion Criteria: Any of the following criteria will exclude potential participants from the trial: Medical indication for either beta blocker or calcium-channel blockers prohibiting drug discontinuation other than oHCM History of intolerance or medical contraindication to beta blocker therapy Resting SBP of > 160 mmHg Resting heart rate of > 100 bpm Significant valvular heart disease Moderate-severe valvular aortic stenosis or fixed subaortic obstruction Mitral regurgitation not due to systolic anterior motion of the mitral valve (per Investigator judgment) Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis) 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) Documented room air oxygen saturation reading < 90% at screening Planned septal reduction treatment that cannot be deferred during the trial period History of septal reduction therapy (surgical myectomy or alcohol septal ablation) within 6 months of screening History of paroxysmal or persistent atrial fibrillation or atrial flutter. Atrial flutter treated with radio frequency ablation without recurrence within the last 6 months prior to screening is allowed. Current or recent (< 4 weeks) therapy with disopyramide History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening Has received prior treatment with aficamten or previously intolerant (reduced LVEF requiring permanent drug discontinuation) to 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aficamten up to 20 mg plus placebo for metoprolol<br>Patients will receive doses of 5 mg, 10 mg, 15 mg or 20 mg of aficamten (CK-3773274) plus placebo for metoprolol succinate with dose levels guided by echocardiography assessments for up to 24 weeks. | Drug: Aficamten (CK-3773274) (5 mg, 10 mg, 15 mg and 20 mg)<br>* Aficamten (CK-3773274) tablets administered orally<br>Drug: Placebo to match metoprolol succinate<br>* Placebo for metoprolol succinate administered orally<br>|
| Active Comparator: Metoprolol succinate up to 200 mg plus placebo for aficamten<br>Patients will receive 50 mg, 100 mg, 150 mg or 200 mg of metoprolol succinate plus placebo for aficamten (CK-3773274) with dose levels guided by echocardiography and heart rate assessments for up to 24 weeks. | Drug: Placebo to match aficamten<br>* Placebo for aficamten (CK-3773274) administered orally<br>Drug: Metoprolol succinate (50 mg, 100 mg, 150 mg and 200 mg)<br>* Metoprolol succinate tablets 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 aficamten compared with metoprolol succinate on exercise capacity in patients with symptomatic oHCM | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) Functional Class | Effect of aficamten compared with metoprolol succinate on NYHA Functional Classification | Baseline to Week 24 | 
| Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) | Effect of aficamten compared with metoprolol succinate on patient health status | Baseline to Week 24 | 
| Change in left ventricular mass index (LVMI) | Effect of aficamten on mass of the heart as compared with metoprolol succinate | Baseline to Week 24 | 
| Change in left atrial volume index (LAVI) | Effect of aficamten on size of the heart as compared with metoprolol succinate | Baseline to Week 24 | 
| Change from baseline values in NT-proBNP from baseline to Week 24 | Effect of CK-¬3773274 on NT-proBNP | Baseline to Week 24 | 
| Change in post-Valsalva LVOT-G from baseline to Week 24 | Effect of aficamten on post-Valsalva LVOT-G | 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, Aficamten, Metoprolol, oHCM, CK-3773274, CK-274, MAPLE-HCM, MAPLE, CY 6032