Clinical trial NCT06412666: A Study to Evaluate the Effect of Aficamten in Pediatric Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy (oHCM).
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Pediatric
Symptomatic Obstructive Hypertrophic Cardiomyopathy
Keywords: CK-3773274
CK-274
Aficamten
Symptomatic Obstructive Hypertrophic Cardiomyopathy
oHCM
CEDAR
CEDAR-HCM
CY 6023
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
First posted: 2024-05-14
Enrollment: 40
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

Eligibility criteria: 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.

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 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.

Primary outcomes:
measure: Change from baseline in Valsalva left ventricular outflow tract gradient (LVOT-G)
timeFrame: Baseline to week 12
Secondary outcomes:
measure: Change from baseline in resting LVOT-G
timeFrame: Baseline to week 12
measure: Change in values of NT-proBNP
timeFrame: Baseline to week 12
measure: Change in values of hs-cTnI
timeFrame: Baseline to week 12
measure: Change in New York Heart Association (NYHA) Functional Class
timeFrame: Baseline to week 12
measure: Proportion of patients with ≥1 class improvement in NYHA Functional Class
timeFrame: Baseline to week 12
measure: Trough observed plasma concentration (Ctrough) and C2h postdose of aficamten
timeFrame: Baseline to week 12
measure: Maximum observed concentration (Cmax), tmax, AUCtau, and Ctrough of aficamten
timeFrame: Week 8 or Week 12
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles (UCLA)
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Hospital
state: District of Columbia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: New Orleans
country: United States
facility: Children's Hospital New Orleans
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New York
country: United States
facility: NYP/Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke Clinical Research Institute
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: LeBonheur Children's Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Milwaukee
country: United States
facility: Children's Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: The Hospital for Sick Children (SickKids)
state: Ontario
city: Florence
country: Italy
facility: Careggi University Hospital
city: A Coruña
country: Spain
facility: Unidad de Cardiología Infantil; Hospital Universitario da Coruña
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
Study officials:
affiliation: Cytokinetics
name: Cytokinetics MD
role: STUDY_DIRECTOR
References: