Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM (MAPLE-HCM)

• ClinicalTrials.gov Identifier: NCT05767346
• Recruitment Status: Recruiting
• First Posted: March 14, 2023
• Last Update Posted: May 13, 2024
• Sponsor: Cytokinetics
• Information provided by (Responsible Party): Cytokinetics

Tracking Information

• First Submitted Date: March 2, 2023
• First Posted Date: March 14, 2023
• Last Update Posted Date: May 13, 2024
• Actual Study Start Date: June 19, 2023
• Estimated Primary Completion Date: July 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 2, 2023)

Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET) [ Time Frame: Baseline to Week 24 ]

Effect of aficamten compared with metoprolol succinate on exercise capacity in patients with symptomatic oHCM

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 3, 2023)

• Proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) Functional Class [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten compared with metoprolol succinate on NYHA Functional Classification
• Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten compared with metoprolol succinate on patient health status
• Change in left ventricular mass index (LVMI) [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten on mass of the heart as compared with metoprolol succinate
• Change in left atrial volume index (LAVI) [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten on size of the heart as compared with metoprolol succinate
• Change from baseline values in NT-proBNP from baseline to Week 24 [ Time Frame: Baseline to Week 24 ]
  Effect of CK-¬3773274 on NT-proBNP
• Change in post-Valsalva LVOT-G from baseline to Week 24 [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten on post-Valsalva LVOT-G

Original Secondary Outcome Measures (submitted: March 2, 2023)

• Proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) Functional Class [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten compared with metoprolol succinate on NYHA Functional Classification
• Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten compared with metoprolol succinate on patient health status
• Change in left ventricular mass index (LVMI) [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten on mass of the heart as compared with metoprolol succinate
• Change in left atrial volume index (LAVI) [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten on size of the heart as compared with metoprolol succinate
• Proportion of patients with post-Valsalva LVOT G <30 mmHg [ Time Frame: Baseline to Week 24 ]
  Effect of aficamten on post-Valsalva LVOT-G

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
• Official Title: A Phase 3, Multi-center, Randomized, Double-blind Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
• Brief Summary: The purpose of this study is to compare the efficacy and safety of aficamten (CK-3773274) compared with metoprolol succinate in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Obstructive Hypertrophic Cardiomyopathy (oHCM)

Intervention

• Drug: Aficamten (CK-3773274) (5 mg, 10 mg, 15 mg and 20 mg)
  Aficamten (CK-3773274) tablets administered orally
• Drug: Placebo to match aficamten
  Placebo for aficamten (CK-3773274) administered orally
• Drug: Metoprolol succinate (50 mg, 100 mg, 150 mg and 200 mg)
  Metoprolol succinate tablets administered orally
• Drug: Placebo to match metoprolol succinate
  Placebo for metoprolol succinate administered orally

Study Arms

• Experimental: Aficamten up to 20 mg plus placebo for metoprolol
  Patients will receive doses of 5 mg, 10 mg, 15 mg or 20 mg of aficamten (CK-3773274) plus placebo for metoprolol succinate with dose levels guided by echocardiography assessments for up to 24 weeks.
  Interventions:

  • Drug: Aficamten (CK-3773274) (5 mg, 10 mg, 15 mg and 20 mg)
  • Drug: Placebo to match metoprolol succinate
• Active Comparator: Metoprolol succinate up to 200 mg plus placebo for aficamten
  Patients will receive 50 mg, 100 mg, 150 mg or 200 mg of metoprolol succinate plus placebo for aficamten (CK-3773274) with dose levels guided by echocardiography and heart rate assessments for up to 24 weeks.
  Interventions:

  • Drug: Placebo to match aficamten
  • Drug: Metoprolol succinate (50 mg, 100 mg, 150 mg and 200 mg)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 2, 2023): 170
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2025
• Estimated Primary Completion Date: July 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants who meet all the following criteria at screening may be included in the trial:

  • Males and females between 18 to 85 years of age, inclusive, at screening
  • Body mass index < 35 kg/m2

  • Diagnosed with oHCM per the following criteria by cardiac magnetic resonance imaging (CMR) or echocardiography -

    • Has left ventricular (LV) hypertrophy with non-dilated LV chamber in the absence of other cardiac disease and

    • Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory:

      1. ≥ 15 mm in one or more myocardial segments OR
      2. ≥ 13 mm in one or more wall segments and a known disease-causing gene mutation or positive family history of HCM
  • NYHA class II or III

  • Has a screening echocardiogram with the following determined by the echocardiography core laboratory:

    • Resting LVOT-G > 30 mm Hg and/or post-Valsalva LVOT-G ≥ 50 mmHg at screening AND
    • LVEF ≥ 60%
  • Hemoglobin ≥ 10g/dL
  • Patients previously exposed to mavacamten are allowed to participate but must be off mavacamten for at least 8 weeks

Exclusion Criteria:

• Any of the following criteria will exclude potential participants from the trial:

  • Medical indication for either beta blocker or calcium-channel blockers prohibiting drug discontinuation other than oHCM
  • History of intolerance or medical contraindication to beta blocker therapy
  • Resting SBP of > 160 mmHg
  • Resting heart rate of > 100 bpm

  • Significant valvular heart disease

    1. Moderate-severe valvular aortic stenosis or fixed subaortic obstruction
    2. Mitral regurgitation not due to systolic anterior motion of the mitral valve (per Investigator judgment)
  • Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis)
  • History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course
  • Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations)
  • Documented room air oxygen saturation reading < 90% at screening
  • Planned septal reduction treatment that cannot be deferred during the trial period
  • History of septal reduction therapy (surgical myectomy or alcohol septal ablation) within 6 months of screening
  • History of paroxysmal or persistent atrial fibrillation or atrial flutter. Atrial flutter treated with radio frequency ablation without recurrence within the last 6 months prior to screening is allowed.
  • Current or recent (< 4 weeks) therapy with disopyramide
  • History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening
  • Has received prior treatment with aficamten or previously intolerant (reduced LVEF requiring permanent drug discontinuation) to mavacamten

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Cytokinetics MD; 650-624-2929; medicalaffairs@cytokinetics.com

• Listed Location Countries: Canada, China, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT05767346
• Other Study ID Numbers: CY 6032; 2023-504809-37-00 ( Other Identifier: EU CTR Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Cytokinetics
• Original Responsible Party: Same as current
• Current Study Sponsor: Cytokinetics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Scientific Leadership; Cytokinetics

• PRS Account: Cytokinetics
• Verification Date: December 2023