A Study to Evaluate the Effect of Aficamten in Pediatric Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy (oHCM).

Phase 2

Recruiting

• Conditions: Pediatric; Symptomatic Obstructive Hypertrophic Cardiomyopathy
• Interventions: Drug: Aficamten; Drug: Placebo

• Registration Number: NCT06412666
• Lead Sponsor: Cytokinetics

Brief Summary

The purpose of this study is to evaluate the efficacy, safety and PK of aficamten in a pediatric population with symptomatic obstructive hypertrophic cardiomyopathy (oHCM).

Detailed Description

The overall objective of the trial is to determine the efficacy, safety, and tolerability of administration of aficamten in adolescents (12 to \< 18 years old) and children (6 to \< 12 years old) with symptomatic oHCM. Adolescents and children will be studied in a staged approach involving established favorable pharmacodynamic and safety profiles of aficamten in adolescents followed by further pharmacokinetic modeling to inform the dosing regimen in children. Only the 12 to \<18 years old cohort is currently open for enrollment.

The trial will consist of 2 periods:

1. Period 1 is the randomized, double-blind, placebo-controlled treatment period that will assess the efficacy, safety and tolerability of aficamten in pediatric participants. Duration: 12 weeks.

2. Period 2 is the open-label extension trial that will assess the long-term safety of aficamten in pediatric participants, and further assess efficacy and tolerability. Duration: 52 weeks.

Study Timeline

• Study First Submitted: 2024-05-09
• Study First Submitted QC: 2024-05-09
• Study First Posted: 2024-05-14
• Study Start: 2024-05-29
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-06
• Last Update Posted: 2025-01-08
• Primary Completion: 2028-12
• Study Completion: 2028-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• Period 1: Treatment Period

  • Males and females between 12 and < 18 years of age at screening and at Day 1.
  • Body weight ≥ 45 kg for the initial cohort and then body weight ≥ 35 kg after at least 10 participants in the initial cohort have undergone dose titration up to Week 4 without observed events of LVEF < 50% at the starting dose of 5 mg qd.
  • Core laboratory confirmation of the following oHCM echocardiographic criteria at screening:

• Left ventricular (LV) hypertrophy with nondilated LV chamber in the absence of other cardiac disease.

• LV end-diastolic wall thickness that meets a threshold of:

  • Z-score > 2.5 in the absence of family history OR
  • Z-score > 2 in the presence of positive family history or positive genetic test.

• LVEF ≥ 60% AND Valsalva LVOT-G ≥ 50 mmHg.

  • oHCM of sarcomeric origin confirmed by genetic testing or, if unable to confirm by genetic testing, oHCM of sarcomeric origin may be presumed in the absence of history of metabolic disorders, mitochondrial cardiomyopathies, neuromuscular disease, malformation syndromes, infiltrative diseases/inflammation, and endocrine disorders (such as Fabry's disease, Noonan syndrome with left ventricular hypertrophy, and amyloid-cardiomyopathy).
  • New York Heart Association (NYHA) Class ≥ II at screening.
  • Adequate acoustic windows for echocardiography.
  • Participants on beta blockers, verapamil, diltiazem, or disopyramide should have been on stable doses for more than 4 weeks prior to randomization.

Period 2: Open-Label Extension

• Completed Period 1. If unable to complete Period 1 due to circumstances not related to compliance or safety, the Medical Monitor may review and determine eligibility.
• LVEF ≥ 55% after washout.

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Exclusion Criteria

• Period 1: Treatment Period

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

• Significant valvular heart disease.

  • Moderate or severe valvular aortic stenosis or fixed subaortic obstruction.
  • Mitral regurgitation that is greater than mild in severity and not due to systolic anterior motion of the mitral valve (per judgment of Principal Investigator or designee).
  • Evidence of fixed left-sided obstruction (eg, subaortic, aortic valve, or coarctation of the aorta).

• History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course.

• History of congenital heart disease other than oHCM (may be enrolled if not hemodynamically significant in the judgement of the Principal Investigator and study Medical Monitor).

• Has been treated with SRT (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period.

• History of paroxysmal or persistent atrial fibrillation or atrial flutter.

• History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia within 3 months prior to screening.

• History or evidence of any other clinically significant disorder, malignancy, active infection, other condition, or disease that, in the opinion of the Principal Investigator (or designee) or the Medical Monitor, would pose a risk to participant safety or interfere with the trial evaluation, procedures, or completion.

• Current or previous use of drugs known to cause cardiomyopathy (eg, anthracyclines, monoclonal antibodies [trastuzumab], alkylating agents [cyclophosphamide], and tyrosine kinase inhibitors [sunitinib and imatinib]).

• Currently participating in another investigational device or drug trial or received an investigational device or drug < 1 month (or 5 half-lives for drugs, whichever is longer) prior to screening.

• Implantable cardioverter defibrillator (ICD) implantation within 6 weeks of screening or planned ICD implantation during the trial period.

• Has received prior treatment with aficamten or mavacamten.

• Currently listed for heart transplantation or anticipated to be listed for heart transplantation in the next 12 months.

Period 2:

Exclusion Criteria:

Had a confirmed LVEF < 40% with an associated dose interruption during participation in Period 1.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Aficamten	Aficamten	Participants in this arm will receive a single daily oral dose of aficamten with dose levels (5 mg to 20 mg) guided by echocardiography assessments, for 12 weeks during the double-blinded period, and then for another 52 weeks during the open-label extension period.
Placebo	Aficamten	Participants in this arm will receive placebo for 12 weeks during the double-blinded period, and then will receive aficamten for 52 weeks during the open-label extension period.
Placebo	Placebo	Participants in this arm will receive placebo for 12 weeks during the double-blinded period, and then will receive aficamten for 52 weeks during the open-label extension period.

Primary Outcome Measures

Name	Time	Method
Change from baseline in Valsalva left ventricular outflow tract gradient (LVOT-G)	Baseline to week 12

Secondary Outcome Measures

Name	Time	Method
Change from baseline in resting LVOT-G	Baseline to week 12
Change in values of NT-proBNP	Baseline to week 12
Change in values of hs-cTnI	Baseline to week 12
Change in New York Heart Association (NYHA) Functional Class	Baseline to week 12
Proportion of patients with ≥1 class improvement in NYHA Functional Class	Baseline to week 12
Trough observed plasma concentration (Ctrough) of aficamten	Baseline to week 12
Maximum observed concentration (Cmax), tmax, AUCtau, and Ctrough of aficamten	Week 8 or Week 12	A voluntary intensive PK substudy may occur at Week 8 or Week 12

Trial Locations

Locations (26)

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

University of California, Los Angeles (UCLA); 🇺🇸 Los Angeles, California, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Children's National Hospital; 🇺🇸 Washington, District of Columbia, United States

Baptist Health South Florida; 🇺🇸 Miami, Florida, United States

Ann & Robert H. Lurie Children's Hospital; 🇺🇸 Chicago, Illinois, United States

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

Children's Hospital New Orleans; 🇺🇸 New Orleans, Louisiana, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Children's Hospital of Michigan; 🇺🇸 Detroit, Michigan, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Children's Mercy Hospital; 🇺🇸 Kansas City, Missouri, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

Columbia University; 🇺🇸 New York, New York, United States

Duke Clinical Research Institute; 🇺🇸 Durham, North Carolina, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

LeBonheur Children's Hospital; 🇺🇸 Memphis, Tennessee, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

UT Southwestern; 🇺🇸 Dallas, Texas, United States

The Hospital for Sick Children (SickKids); 🇨🇦 Toronto, Ontario, Canada

Careggi University Hospital; 🇮🇹 Florence, Italy

Unidad de Cardiología Infantil; Hospital Universitario da Coruña; 🇪🇸 A Coruña, Spain

Alder Hey Children's Hospital; 🇬🇧 Liverpool, United Kingdom

Great Ormond Street Hospital for Children; 🇬🇧 London, United Kingdom