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

Hypertrophic Cardiomyopathy (HCM) Clinical Trial

— REDWOOD-HCM  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04219826
• Other study ID #: CY 6021
• Secondary ID: 2019-002785-12
• Status: Completed
• Phase: Phase 2
• Start date: January 10, 2020
• Est. completion date: February 28, 2023

Study information

• Verified date: November 2023
• Source: Cytokinetics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 96
• Est. completion date: February 28, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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).

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Hypertrophic
• Hypertrophic Cardiomyopathy (HCM)
• Hypertrophy

Intervention

Drug:
• CK-3773274 (5 - 15 mg)
CK-3773274 tablets administered orally
• CK-3773274 (10 - 30 mg)
CK-3773274 tablets administered orally
• Placebo for CK-3773274
Placebo administered orally

Locations

Country	Name	City	State
Italy	Azienda Ospedaliero Universitaria Careggi	Firenze
Netherlands	Erasmus University Medical Center (Erasmus MC)	Rotterdam
Spain	Complejo Hospitalario Universitario A Coruña	A Coruña
Spain	Hospital Universitario Puerta de Hierro de Majadahonda	Madrid
United States	Michigan Medicine - University of Michigan	Ann Arbor	Michigan
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Duke Cardiology at Southpoint	Durham	North Carolina
United States	Northwestern University	Evanston	Illinois
United States	Houston Methodist Hospital	Houston	Texas
United States	Cedar-Sinai Medical Center	Los Angeles	California
United States	Intermountain Medical Center	Murray	Utah
United States	New York University Langone Health Medical Center	New York	New York
United States	Hospital of the University of Pennsylvania (University of Pennsylvania School of Medicine)	Philadelphia	Pennsylvania
United States	UMPC Heart and Vascular Institute	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	UCSF Medical Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Cytokinetics

Countries where clinical trial is conducted

United States,  Italy,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of adverse events observed during dosing of CK--3773274 in patients with HCM	Patient incidence of reported adverse events (AEs)	14 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)