Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM (REDWOOD-HCM)

Cytokinetics

Status and phase: Completed; Phase 2

Conditions: Hypertrophic Cardiomyopathy (HCM)

Treatments: Drug: CK-3773274 (5 - 15 mg); Drug: Placebo for CK-3773274; Drug: CK-3773274 (10 - 30 mg)

Study type: Interventional

Funder types: Industry

Identifiers

NCT04219826

CY 6021

2019-002785-12 (EudraCT Number)

Details and patient eligibility

About

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

Enrollment: 96 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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96 participants in 6 patient groups, including a placebo group

CK-3773274 - Cohort 1 (Obstructive HCM)

Experimental group

Description:

Subjects will receive doses of 5 - 15 mg of CK-3773274 with dose levels guided by echocardiography assessments for up to 10 weeks

Treatment:

Drug: CK-3773274 (5 - 15 mg)

Placebo - Cohort 1 (Obstructive HCM)

Placebo Comparator group

Description:

Subjects will receive placebo for up to 10 weeks

Treatment:

Drug: Placebo for CK-3773274

CK-3773274 - Cohort 2 (Obstructive HCM)

Experimental group

Description:

Subjects will receive doses 10 - 30 mg of CK-3773274 with dose levels guided by echocardiography assessments for up to 10 weeks

Treatment:

Drug: CK-3773274 (10 - 30 mg)

Placebo - Cohort 2 (Obstructive HCM)

Placebo Comparator group

Description:

Subjects will receive placebo for up to 10 weeks

Treatment:

Drug: Placebo for CK-3773274

CK-3773274 & disopyramide - Cohort 3 (Obstructive HCM)

Experimental group

Description:

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

Treatment:

Drug: CK-3773274 (5 - 15 mg)

CK-3773274 - Cohort 4 (non-obstructive HCM)

Experimental group

Description:

Subjects will receive doses of 5 - 15 mg of CK-3773274 with dose levels guided by echocardiography assessments for up to 10 weeks

Treatment:

Drug: CK-3773274 (5 - 15 mg)