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

• ClinicalTrials.gov Identifier: NCT04219826
• Recruitment Status: Active, not recruiting
• First Posted: January 7, 2020
• Last Update Posted: November 7, 2022
• Sponsor: Cytokinetics
• Information provided by (Responsible Party): Cytokinetics

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Hypertrophic Cardiomyopathy (HCM)	Drug: CK-3773274 (5 - 15 mg); Drug: CK-3773274 (10 - 30 mg); Drug: Placebo for CK-3773274	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 95 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 10, 2020
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: June 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: CK-3773274 - Cohort 1 (Obstructive HCM); 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); CK-3773274 tablets administered orally
Placebo Comparator: Placebo - Cohort 1 (Obstructive HCM); Subjects will receive placebo for up to 10 weeks	Drug: Placebo for CK-3773274; Placebo administered orally
Experimental: CK-3773274 - Cohort 2 (Obstructive HCM); 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); CK-3773274 tablets administered orally
Placebo Comparator: Placebo - Cohort 2 (Obstructive HCM); Subjects will receive placebo for up to 10 weeks	Drug: Placebo for CK-3773274; Placebo administered orally
Experimental: CK-3773274 & disopyramide - Cohort 3 (Obstructive HCM); 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); CK-3773274 tablets administered orally
Experimental: CK-3773274 - Cohort 4 (non-obstructive HCM); 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); CK-3773274 tablets administered orally

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverse events observed during dosing of CK--3773274 in patients with HCM [ Time Frame: 14 weeks ]
   Patient incidence of reported adverse events (AEs)

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

United States, California

Cedar-Sinai Medical Center

Los Angeles, California, United States, 90048

UCSF Medical Center

San Francisco, California, United States, 94143

United States, Illinois

Northwestern University

Evanston, Illinois, United States, 60208

United States, Massachusetts

Tufts Medical Center

Boston, Massachusetts, United States, 02111

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

United States, Michigan

Michigan Medicine - University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

New York University Langone Health Medical Center

New York, New York, United States, 10016

United States, North Carolina

Carolinas Medical Center

Charlotte, North Carolina, United States, 28203

Duke Cardiology at Southpoint

Durham, North Carolina, United States, 27713

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Hospital of the University of Pennsylvania (University of Pennsylvania School of Medicine)

Philadelphia, Pennsylvania, United States, 19104

UMPC Heart and Vascular Institute

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

UT Southwestern Medical Center

Dallas, Texas, United States, 75390

Houston Methodist Hospital

Houston, Texas, United States, 77030

United States, Utah

Intermountain Medical Center

Murray, Utah, United States, 84107

United States, Virginia

University of Virginia Health System

Charlottesville, Virginia, United States, 22903

Italy

Azienda Ospedaliero Universitaria Careggi

Firenze, Italy

Netherlands

Erasmus University Medical Center (Erasmus MC)

Rotterdam, Netherlands

Spain

Complejo Hospitalario Universitario A Coruña

A Coruña, Spain, 15003

Hospital Universitario Puerta de Hierro de Majadahonda

Madrid, Spain

Sponsors and Collaborators

Cytokinetics

Investigators

• Study Director: Cytokinetics, MD; Cytokinetics

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zampieri M, Argiro A, Marchi A, Berteotti M, Targetti M, Fornaro A, Tomberli A, Stefano P, Marchionni N, Olivotto I. Mavacamten, a Novel Therapeutic Strategy for Obstructive Hypertrophic Cardiomyopathy. Curr Cardiol Rep. 2021 Jun 3;23(7):79. doi: 10.1007/s11886-021-01508-0.

• Responsible Party: Cytokinetics
• ClinicalTrials.gov Identifier: NCT04219826
• Other Study ID Numbers: CY 6021; 2019-002785-12 ( EudraCT Number )
• First Posted: January 7, 2020
• Last Update Posted: November 7, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cytokinetics:

CK-3773274; CK-274; obstructive hypertrophic cardiomyopathy; oHCM; REDWOOD-HCM; non-obstructive hypertrophic cardiomyopathy; nHCM; hypertrophic cardiomyopathy; HCM

Additional relevant MeSH terms:

Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy; Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases