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

Официальное название

A Phase 2/3 Multicenter, Randomized, Double-Blind, Placebo-Controlled and Open-Label Extension Trial to Evaluate the Efficacy and Safety of Aficamten in a Pediatric Population With Symptomatic Obstructive Hypertrophic Cardiomyopathy

Обзор

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).

Подробное описание

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 3 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. 3. Period 3 is the long-term extension trial that will assess the long-term safety of aficamten in pediatric participants, and further assess efficacy and tolerability. Duration: 144 weeks.

Вмешательства

• Препарат Aficamten
  Oral Tablet
• Препарат Placebo
  Oral Tablet

Первичные конечные точки

• Change from baseline in Valsalva left ventricular outflow tract gradient (LVOT-G) [Срок оценки: Baseline to week 12]

Вторичные конечные точки (7)

• Change from baseline in resting LVOT-G [Срок оценки: Baseline to week 12]
• Change in values of NT-proBNP [Срок оценки: Baseline to week 12]
• Change in values of hs-cTnI [Срок оценки: Baseline to week 12]
• Change in New York Heart Association (NYHA) Functional Class [Срок оценки: Baseline to week 12]
• Proportion of patients with ≥1 class improvement in NYHA Functional Class [Срок оценки: Baseline to week 12]
• Trough observed plasma concentration (Ctrough) and C2h postdose of aficamten [Срок оценки: Baseline to week 12]
• Maximum observed concentration (Cmax), tmax, AUCtau, and Ctrough of aficamten [Срок оценки: Week 8 or Week 12]

Критерии участия

Критерии включения

• 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.
• Period 3: Long-term Extension • Completed Period 2.

Критерии исключения

• 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 membrane, aortic valve stenosis, 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) within the preceding 6 months 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 26 центров

• Phoenix Children's Hospital — Phoenix
• Children's Hospital Los Angeles — Los Angeles
• University of California, Los Angeles (UCLA) — Los Angeles
• UCSF Benioff Children's Hospital — San Francisco
• Children's Hospital Colorado — Aurora
• Children's National Hospital — Washington D.C.
• Nicklaus Children's Hospital — Miami
• Ann & Robert H. Lurie Children's Hospital — Chicago
• … и ещё 18 центров

Япония · 5 центров

• NHO Kagoshima Medical Center — Kagoshima
• University of Osaka Hospital — Osaka
• Kitasato University Hospital — Sagamihara
• National Cerebral and Cardiovascular Center — Suita
• Juntendo University Hospital — Tokyo

Великобритания · 3 центра

• Alder Hey Children's Hospital — Liverpool
• Evelina Children's Hospital — London
• Great Ormond Street Hospital for Children — London

Испания · 2 центра

• Unidad de Cardiología Infantil; Hospital Universitario da Coruña — A Coruña
• Hospital Sant Joan de Deu — Barcelona

Канада · 1 центр

• The Hospital for Sick Children (SickKids) — Toronto

Италия · 1 центр

• Azienda Ospedaliera Universitaria Meyer IRCCS — Florence

Публикации

• Kaski JP, Kantor PF, Nakano SJ, Olivotto I, Russell MW, Godown J, Chiu M, German P, Heitner SB, Jacoby DL, Kupfer S, Lutz J, Maharao N, Malik FI, Melloni C, Nieto Morales PF, Simkins T, Wei J, Ho CY; CEDAR-HCM Investigators. Efficacy and Safety of Aficamten in Children and Adolescents With Obstructive Hypertrophic Cardiomyopathy: Study Design and Rationale of CEDAR-HCM. Circ Heart Fail. 2026 Feb;1 PMID 41347307

Идентификаторы

NCT: NCT06412666 · CY 6023 · 2024-511377-30-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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