The Purpose of This Study is to Evaluate the Efficacy and Safety of Aficamten (CK-3773274) Compared to Placebo in Adults With Symptomatic Non-obstructive Hypertrophic Cardiomyopathy

Study Overview
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Brief Summary
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This clinical trial will study the effects of aficamten (versus placebo) on the quality of life, exercise capacity, and clinical outcomes of patients with non-obstructive hypertrophic cardiomyopathy.

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 Placebo in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy

Conditions
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Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy

Intervention / Treatment
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* Drug: Aficamten
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 18-85 years of age Body mass index < 40 kg/m2 Diagnosed with nHCM and has a screening echocardiogram with the following: End-diastolic left ventricular (LV) wall thickness: ≥ 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 AND Resting LVOT-G < 30 mmHg AND Valsalva LVOT-G < 50 mmHg AND LVEF ≥ 60% Participants with a history of intracavitary obstruction are eligible. NYHA class II or III Respiratory exchange ratio of ≥ 1.00 at screening by cardiopulmonary exercise testing (CPET) and predicted peak oxygen uptake (pVO2) ≤ 90% for age and sex KCCQ-CSS score of ≥ 30 and ≤ 85 NT-proBNP of: NT-pro BNP ≥ 300 pg/mL or NT-proBNP ≥ 900 pg/mL if in atrial fibrillation or atrial flutter OR For Black participants, an NT-pro BNP ≥ 225 pg/mL or NT-proBNP ≥ 675 pg/mL if in atrial fibrillation or atrial flutter Exclusion Criteria: Significant valvular heart disease (per Investigator judgment) Moderate or severe valvular aortic stenosis or fixed subaortic obstruction Moderate or severe mitral regurgitation Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics nHCM (eg, Noonan syndrome, Fabry disease, amyloidosis) Known current unrevascularized coronary artery stenosis of ≥ 70% or documented history of myocardial infarction. History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations) Documented room air oxygen saturation reading < 90% at screening or history of significant chronic obstructive pulmonary disease or severe/significant pulmonary hypertension History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia with exercise within 3 months prior to screening History of resistant hypertension (persistently elevated blood pressure despite maximal doses of 3 or more classes of medications for hypertension control) Screening diastolic blood pressure ≥ 100 mmHg Received prior treatment with aficamten Received treatment with mavacamten within 3 months prior to screening (must be discussed with the medical monitor prior to screening) Undergone septal reduction therapy < 6 months prior to screening Is being considered for or is likely to be considered for heart transplant listing or left ventricular assist device placement during the study period Paroxysmal or permanent atrial fibrillation is excluded only if: rhythm restoring treatment (e.g., direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) has been required ≤ 3 months prior to screening rate control and anticoagulation have not been achieved for at least 3 months prior to screening.

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: Aficamten<br>Participants in this arm will receive a single daily oral dose of 5 mg, 10 mg, 15 mg, or 20 mg of aficamten with dose levels guided by echocardiography assessments, for up to 72 weeks. | Drug: Aficamten<br>* Oral Tablet<br>|
| Placebo Comparator: Placebo<br>Participants in this arm will receive placebo, for up to 72 weeks. | Drug: Placebo<br>* Oral Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) | Effect of aficamten compared with placebo on participant health status | Baseline to Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in composite of two Z-scores of CPET parameters (pVO2 and VE/VCO2 slope) | Effect of aficamten compared with placebo on global exercise capacity based on maximal and sub-maximal exercise performance | Baseline to Week 36 | 
| Proportion of participants with ≥ 1 class improvement in NYHA Functional Class | Effect of aficamten compared with placebo on NYHA Functional Classification | Baseline to Week 36 | 
| Change in NT-proBNP | Effect of aficamten compared with placebo on a biomarker of cardiac wall stress | Baseline to Week 36 | 
| Change in LAVI | Effect of aficamten compared with placebo on echocardiographic measures of structural remodeling | Baseline to Week 36 | 
| Time to first CV event (CV death; heart transplantation or left ventricular assist device; aborted sudden cardiac death; non-fatal stroke; heart failure hospitalization; or cardiac arrhythmia requiring treatment or hospitalization) | Effect of aficamten compared with placebo on cardiovascular events | Baseline to End of Study, Week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CK-3773274, CK-274, Aficamten, Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy, nHCM, ACACIA-HCM, ACACIA