REDWOOD-HCM: Randomized Evaluation of Dosing With CK-3773274 in HCM

Study Overview
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Brief Summary
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This study is being performed to understand the effect of different doses of CK-3773274 on patients with hypertrophic cardiomyopathy (HCM).

Official Title
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A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy

Conditions
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Hypertrophic Cardiomyopathy (HCM)

Intervention / Treatment
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* Drug: CK-3773274 (5 - 15 mg)
* Drug: CK-3773274 (10 - 30 mg)
* Drug: Placebo for CK-3773274


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Males and females between 18 and 85 years of age at screening. Body weight is ≥45 kg at screening. Diagnosed with HCM per the following criteria: Has left ventricular (LV) hypertrophy with non-dilated LV chamber in the absence of other cardiac disease. Has minimal wall thickness ≥15 mm (minimal wall thickness ≥13 mm is acceptable with a positive family history of HCM or with a known disease-causing gene mutation). Adequate acoustic windows for echocardiography. For Cohorts 1, 2 and 3 has LVOT-G during screening as follows: Resting gradient ≥50 mmHg OR Resting gradient ≥30 mmHg and <50 mmHg with post-Valsalva LVOT-G ≥50 mmHg For Cohort 4 has resting and post-Valsalva LVOT-G < 30 mmHg at the time of screening For Cohort 4 has elevated NT-proBNP > 300 pg/mL at the time of screening LVEF ≥60% at screening. New York Heart Association (NYHA) Class II or III at screening. Patients on beta-blockers, verapamil, diltiazem, or ranolazine should have been on stable doses for >4 weeks prior to randomization and anticipate remaining on the same medication regimen during the study. For Cohort 3: Patients must be taking disopyramide. Patients should have been on stable disopyramide doses for >4 weeks prior to screening and anticipate remaining on the same medication regimen during the study. Exclusion Criteria Aortic stenosis or fixed subaortic obstruction. Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis). History of LV systolic dysfunction (LVEF <45%) at any time during their clinical course. Documented history of current obstructive coronary artery disease (>70% stenosis in one or more epicardial coronary arteries) or documented history of myocardial infarction. Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the study period (Cohorts 1, 2, and 3 only). Patients having undergone septal reduction therapy > 12 months prior to screening who remain symptomatic from nHCM, and who meet all other criteria for inclusion, may be enrolled in Cohort 4. For Cohorts 1, 2 and 4: Has been treated with disopyramide or antiarrhythmic drugs that have negative inotropic activity within 4 weeks prior to screening. (For Cohort 3, use of disopyramide is required). Has any ECG abnormality considered by the investigator to pose a risk to patient safety (eg, second degree atrioventricular block type II). Paroxysmal atrial fibrillation or flutter documented during the screening period. Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) ≤6 months prior to screening. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately rate-controlled for >6 months). History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening. Has received prior treatment with CK-3773274 or mavacamten. For Cohort 4: has any documented history of LVOT-G ≥ 30 mmHg at rest, with Valsalva, or with exercise (for subjects who have had prior septal reduction therapy, this exclusion criteria only applies to gradients detected following septal reduction therapy).

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 - Cohort 1 (Obstructive HCM)<br>Subjects will receive doses of 5 - 15 mg of CK-3773274 with dose levels guided by echocardiography assessments for up to 10 weeks | Drug: CK-3773274 (5 - 15 mg)<br>* CK-3773274 tablets administered orally<br>|
| Placebo Comparator: Placebo - Cohort 1 (Obstructive HCM)<br>Subjects will receive placebo for up to 10 weeks | Drug: Placebo for CK-3773274<br>* Placebo administered orally<br>|
| Experimental: CK-3773274 - Cohort 2 (Obstructive HCM)<br>Subjects will receive doses 10 - 30 mg of CK-3773274 with dose levels guided by echocardiography assessments for up to 10 weeks | Drug: CK-3773274 (10 - 30 mg)<br>* CK-3773274 tablets administered orally<br>|
| Placebo Comparator: Placebo - Cohort 2 (Obstructive HCM)<br>Subjects will receive placebo for up to 10 weeks | Drug: Placebo for CK-3773274<br>* Placebo administered orally<br>|
| Experimental: CK-3773274 & disopyramide - Cohort 3 (Obstructive HCM)<br>Subjects will receive doses 5 - 15 mg of CK-3773274 with dose levels guided by echocardiography assessments for up to 10 weeks while taking disopyramide | Drug: CK-3773274 (5 - 15 mg)<br>* CK-3773274 tablets administered orally<br>|
| Experimental: CK-3773274 - Cohort 4 (non-obstructive HCM)<br>Subjects will receive doses of 5 - 15 mg of CK-3773274 with dose levels guided by echocardiography assessments for up to 10 weeks | Drug: CK-3773274 (5 - 15 mg)<br>* CK-3773274 tablets administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events observed during dosing of CK--3773274 in patients with HCM | Patient incidence of reported adverse events (AEs) | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of left ventricular ejection fraction (LVEF) < 50% observed during dosing of CK-3773274 in patients with HCM | Patient incidence of left ventricular ejection fraction (LVEF) < 50% | 14 weeks | 
| Incidence of serious adverse events observed during dosing of CK-3773274 in patients with HCM | Patient incidence of reported serious adverse events (SAEs) | 14 weeks | 
| Concentration-response relationship of CK-3773274 on the resting left ventricular outflow tract gradient (LVOT-G) on echocardiogram over 10 weeks of treatment in patients with oHCM (Cohorts 1, 2, 3 only) | Slope of the relationship of the plasma concentration of CK-3773274 to the change from baseline in the resting LVOT-G | 10 weeks | 
| Concentration-response relationship of CK-3773274 on the post-Valsalva left ventricular outflow tract gradient (LVOT-G) on echocardiogram over 10 weeks of treatment in patients with oHCM (Cohorts 1, 2, 3 only) | Slope of the relationship of the plasma concentration of CK-3773274 to the change from baseline in the post-Valsalva LVOT-G | 10 weeks | 
| Dose response relationship on LVOT-G of CK-3773274 in patients with oHCM at rest (Cohorts 1, 2, 3 only) | Change from baseline in resting LVOT-G over time as a function of dose | 10 weeks | 
| Dose response relationship on LVOT-G of CK-3773274 in patients with oHCM post-Valsalva (Cohorts 1, 2, 3 only) | Change from baseline in post-Valsalva LVOT-G over time as a function of dose | 10 weeks | 
| Concentration-response relationship of CK-3773274 on left ventricular ejection fraction (LVEF) over 10 weeks of treatment in patients with HCM | Change from baseline in the resting LVEF | Day 1 to End of Study (EOS) (Week 14) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CK-3773274, CK-274, obstructive hypertrophic cardiomyopathy, oHCM, REDWOOD-HCM, non-obstructive hypertrophic cardiomyopathy, nHCM, hypertrophic cardiomyopathy, HCM