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

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

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

Study Overview

• Status: Completed
• Conditions: Hypertrophic Cardiomyopathy (HCM)
• Intervention / Treatment: Drug: CK-3773274 (5 - 15 mg); Drug: Placebo for CK-3773274; Drug: CK-3773274 (10 - 30 mg)

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Firenze, Italy
    • Azienda Ospedaliero Universitaria Careggi
• Netherlands
  • Rotterdam, Netherlands
    • Erasmus University Medical Center (Erasmus MC)
• Spain
  • A Coruña, Spain, 15003
    • Complejo Hospitalario Universitario A Coruña
  • Madrid, Spain
    • Hospital Universitario Puerta de Hierro de Majadahonda
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedar-Sinai Medical Center
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
  • Illinois
    • Evanston, Illinois, United States, 60208
      • Northwestern University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Michigan Medicine - University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10016
      • New York University Langone Health Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center
    • Durham, North Carolina, United States, 27713
      • Duke Cardiology at Southpoint
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania (University of Pennsylvania School of Medicine)
    • Pittsburgh, Pennsylvania, United States, 15213
      • UMPC Heart and Vascular Institute
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Health System

Participation Criteria

Eligibility Criteria

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

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Cytokinetics
• Investigators: Study Director: Cytokinetics, MD, Cytokinetics

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2020
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: January 3, 2020
• First Submitted That Met QC Criteria: January 3, 2020
• First Posted (Actual): January 7, 2020

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: HCM; hypertrophic cardiomyopathy; oHCM; CK-3773274; CK-274; nHCM; obstructive hypertrophic cardiomyopathy; REDWOOD-HCM; non-obstructive hypertrophic cardiomyopathy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Hypertrophy; Cardiomyopathies; Cardiomyopathy, Hypertrophic
• Other Study ID Numbers: CY 6021; 2019-002785-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No