AFICAMTEN for Obstructive hypertrophic cardiomyopathy

Inclusion criteria

• {"criterion_text":"- P1: Males and females between 12 and < 18 years of age at screening and at Day 1.\n- P3: completed period 2\n- P1: 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.\n- P1: Diagnosed with oHCM per the following criteria, confirmed at the time of screening: Left ventricular (LV) hypertrophy with nondilated LV chamber in the absence of other cardiac disease. Core laboratory confirmation of LV end -diastolic wall thickness that meets a threshold of: Z-score (Ommen 2020)>2.5 in the absence of family history or Z-score (Ommen 2020)>2 in the presence of positive family history or positive genetic test. Core laboratory confirmation of LVEF ≥60% AND Valsalva LVOT-G ≥50mmHg.\n- P1: 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).\n- P1: New York Heart Association (NYHA) Class ≥ II at screening.\n- P1: Adequate acoustic windows for echocardiography.\n- P1: Participants on beta blockers, verapamil, diltiazem, or disopyramide should have been on stable doses or more than 4 weeks prior to randomization.\n- P2: 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.\n- P2: LVEF ≥ 55% after washout."}

Exclusion criteria

• {"criterion_text":"- P1: 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).\n- P1: 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.\n- P1: History of paroxysmal or persistent atrial fibrillation or atrial flutter.\n- P1: History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia within 3 months prior to screening.\n- P1: 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.\n- P1: 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]).\n- P1: 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.\n- P1: Implantable cardioverter defibrillator (ICD) implantation within 6 weeks of screening or planned ICD implantation during the trial period.\n- P1: Has received prior treatment with aficamten or mavacamten.\n- P1: Currently listed for heart transplantation or anticipated to be listed for heart transplantation in the next 12 months.\n- P1: Does not assent/consent to participate in the CMR substudy.\n- P1: Inability to tolerate CMR without sedation.\n- P1: Has an ICD or cardiac pacemaker.\n- P1: History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course.\n- P1: 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).\n- P1: Hypersensitivity to aficamten or any of the excipients"}

Primary endpoints

• {"endpoint_text":"- P1: Change in Valsalva LVOT-G from baseline to Week 12","definition_or_measurement_approach":"Change from baseline to Week 12 in Valsalva left ventricular outflow tract gradient (LVOT-G), measured by echocardiography (core/central laboratory and site echocardiography reads as specified)."}
• {"endpoint_text":"- P2: Participant incidence of AEs and SAEs through End of Study","definition_or_measurement_approach":"Incidence and recording of adverse events (AEs) and serious adverse events (SAEs) for each participant from baseline through end of study using standard safety reporting procedures."}

Secondary endpoints

• {"endpoint_text":"- P1: Change in resting LVOT-G from baseline to Week 12","definition_or_measurement_approach":"Change from baseline to Week 12 in resting LVOT gradient measured by echocardiography."}
• {"endpoint_text":"- P1: All participants: Observed Ctrough and C2h postdose of aficamten over the 12-week treatment period Intensive PK substudy: Observed Cmax, tmax, AUCtau, and Ctrough for aficamten.","definition_or_measurement_approach":"Pharmacokinetic measurements: observed trough (Ctrough), 2-hour post-dose concentrations (C2h) for all participants over 12 weeks; intensive PK substudy includes observed Cmax, tmax, AUCtau, and Ctrough using plasma assays."}
• {"endpoint_text":"- P1: Change in NT-proBNP from baseline to Week 12 Change in hs-cTnI from baseline to Week 12","definition_or_measurement_approach":"Change from baseline to Week 12 in cardiac biomarkers NT-proBNP and high-sensitivity cardiac troponin I (hs-cTnI) measured by laboratory assays."}
• {"endpoint_text":"- P1: Change in NYHA Functional Class from baseline to Week 12","definition_or_measurement_approach":"Change in New York Heart Association (NYHA) functional class from baseline to Week 12 assessed clinically."}
• {"endpoint_text":"- P1: Proportion of participants with ≥ 1 class improvement in NYHA Functional Class from baseline to Week 12","definition_or_measurement_approach":"Proportion of participants with at least one-class improvement in NYHA classification from baseline to Week 12 based on clinical assessment."}
• {"endpoint_text":"- P2: Change in the following measurements at 12-week intervals (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3): − Peak LVOT-G at rest and with Valsalva provocation.","definition_or_measurement_approach":"Serial change in peak LVOT gradient at rest and with Valsalva measured by echocardiography at scheduled intervals during extension periods."}
• {"endpoint_text":"- P2: Change in the following measurements at 12-week intervals (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3): Proportion of participants with resting LVOT-G < 30 mmHg","definition_or_measurement_approach":"Proportion of participants achieving resting LVOT gradient <30 mmHg at scheduled assessments during extension periods by echocardiography."}
• {"endpoint_text":"- P2: Change in the following measurements at 12-week intervals (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3): − Proportion of participants with Valsalva LVOT-G < 50 mmHg","definition_or_measurement_approach":"Proportion of participants achieving Valsalva LVOT gradient <50 mmHg at scheduled assessments during extension periods measured by echocardiography."}
• {"endpoint_text":"- P2: (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3): − Proportion of participants with Valsalva LVOT-G < 30 mmHg","definition_or_measurement_approach":"Proportion of participants achieving Valsalva LVOT gradient <30 mmHg at scheduled assessments during extension periods measured by echocardiography."}
• {"endpoint_text":"- P2: (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3):: − Proportion of participants with LVEF ≥ 50%, resting LVOT-G < 30 mmHg, and Valsalva LVOT-G < 50 mmHg","definition_or_measurement_approach":"Composite proportion of participants meeting LVEF ≥50% and specified LVOT gradient thresholds at scheduled assessments measured by echocardiography and LVEF assessment."}
• {"endpoint_text":"- P2: Time to the following event through last follow-up: − First resting LVOT-G < 30 mmHg − First Valsalva LVOT-G < 50 mmHg − First Valsalva LVOT-G < 30 mmHg − First LVEF ≥ 50%, resting LVOT-G < 30 mmHg, and Valsalva LVOT-G < 50 mmHg","definition_or_measurement_approach":"Time-to-event analyses for first occurrence of specified LVOT gradient and LVEF composite endpoints using scheduled assessment dates."}
• {"endpoint_text":"- P2: Change in NYHA Functional Class from Week 14 to Week 66 (Period 2) and end of treatment (Period 3)","definition_or_measurement_approach":"Change in NYHA functional class from Week 14 through Week 66 and end of treatment assessed clinically."}
• {"endpoint_text":"- P2: Proportion of participants with ≥ 1 class improvement in NYHA Functional Class from Week 14 to Week 66 (Period 2) and end of treatment (Period 3)","definition_or_measurement_approach":"Proportion of participants with at least one-class improvement in NYHA class between Week 14 and Week 66/end of treatment."}

Spain

Earliest CTIS Part Ii Submission Date

05-11-2024

Latest Decision Or Authorization Date

10-02-2026

Processing Time Days

462

Number Of Sites

2

Number Of Participants

2

Italy

Earliest CTIS Part Ii Submission Date

12-11-2024

Latest Decision Or Authorization Date

08-05-2026

Processing Time Days

542

Number Of Sites

2

Number Of Participants

2

Primary sponsor

Full Name

Cytokinetics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Sponsor duties codes: 1,12,13,2,5,8 (various clinical trial operational roles as listed)

Name

PPD International Holdings LLC

Responsibilities

Sponsor duties codes: 4

Third parties

• {"country":"United States","full_name":"The Brigham And Women’s Hospital Inc.","duties_or_roles":"Echocardiography","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"Sponsor duties codes: 3","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clario","duties_or_roles":"Electrocardiogram","organisation_type":"Industry"}
• {"country":"United States","full_name":"Advanced Clinical LLC","duties_or_roles":"Sponsor duties codes: 7","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"HEALTH IN CODE S. L.","duties_or_roles":"Genetic testing","organisation_type":"Industry"}
• {"country":"Belgium","full_name":"PPD International Holdings LLC","duties_or_roles":"Sponsor duties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Mycardium AI Limited","duties_or_roles":"Cardiovascular Magnetic Resonance","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Sponsor duties codes: 1,12,13,2,5,8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Primevigilance USA Inc.","duties_or_roles":"Sponsor duties codes: 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Celerion Inc.","duties_or_roles":"PK Analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"Sponsor duties codes: 14","organisation_type":"Pharmaceutical company"}