A Phase 3 trial to measure how safe and effective CK-3773274 is in Adults with obstructive hypertrophic cardiomyopathy (oHCM)

• Register: EUCTR
• Last refreshed on: 21 May 2024
• Main ID: EUCTR2021-003536-92-PL
• Date of registration: 20/04/2022
• Prospective Registration: Yes
• Primary sponsor: Cytokinetics, Incorporated
• Public title: A Phase 3 trial to measure how safe and effective CK-3773274 is in Adults with obstructive hypertrophic cardiomyopathy (oHCM)
• Scientific title: A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults with Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction
• Date of first enrolment: 30/05/2022
• Target sample size: 282
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-003536-92
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

China, Czech Republic, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom, United States

Contacts

• Name: Medical Affairs
• Affiliation: Cytokinetics, Incorporated

• Name: Medical Affairs
• Affiliation: Cytokinetics, Incorporated

Key inclusion & exclusion criteria

Inclusion criteria:
- Males and females between 18 and 85 years of age, inclusive, at screening.
- Body mass index <35 kg/m^2.
- Diagnosed with HCM per the following criteria:
a. Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and
b. Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of:
• =15 mm in one or more myocardial segments OR
• =13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM
- Has resting LVOT-G =30 mmHg and post-Valsalva LVOT-G =50 mmHg during screening as determined by the echocardiography core laboratory
- LVEF =60% at screening as determined by the echocardiography core laboratory.
- New York Heart Association (NYHA) Functional Class II or III at screening
- Hemoglobin =10 g/dL at screening.
- Respiratory exchange ratio (RER) =1.05 and pVO2 =90% predicted on the screening CPET per the core laboratory.
- Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on a stable doses for >6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial. Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 169
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 113

Exclusion criteria:
- Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
- Significant valvular heart disease (per investigator judgment).
a) Moderate-severe valvular aortic stenosis.
b) Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve.
- 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).
- Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period.
- Documented paroxysmal atrial fibrillation during the screening period.
- Paroxysmal or permanent atrial fibrillation is only excluded IF:
• rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy)has been required =6 months prior to screening.
• rate control and anticoagulation have not been achieved for at least 6 months prior to screening.

- History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
- Has received prior treatment with CK-3773274 or mavacamten.
Exclusion Criteria for CMR Sub-study
- Inability to tolerate CMR.
- Has an implantable cardioverter-defibrillator (ICD).
- Has a cardiac pacemaker.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

obstructive hypertrophic cardiomyopathy (oHCM)
MedDRA version: 27.0 Level: PT Classification code 10020871 Term: Hypertrophic cardiomyopathy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: aficamten
Product Code: CK-3773274
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: aficamten
CAS Number: 2364554-48-1
Current Sponsor code: CK-3773274
Other descriptive name: (R)-N-(5-(5-ETHYL-1,2,4-OXADIAZOL-3-YL)-2,3-DIHYDRO-1H-INDEN-1-YL)-1-METHYL-1H-PYRAZOLE-4-CARBOXAMIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: - To evaluate the effect of CK-3773274 on exercise capacity in patients with symptomatic oHCM

Primary end point(s): • Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET)

Secondary Objective: - To evaluate the effect of CK-3773274 on patient health status
- To evaluate the effect of CK-3773274 on New York Heart Association (NYHA) Functional Classification
- To evaluate the effect of CK-3773274 on post-Valsalva left ventricular outflow tract gradients (LVOT-G)
- To evaluate the effect of CK-3773274 on exercise capacity
- To evaluate the effect of CK-3773274 on duration of eligibility for septal reduction therapy

Safety
To evaluate the safety and tolerability profile of CK-3773274 in patients with symptomatic oHCM

Timepoint(s) of evaluation of this end point: from baseline to Week 24

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: KCCQ-CSS - baseline to Week 12 and Week 24
NYHA Functional Class -baseline to Week 12 and Week 24
Change in post-Valsalva LVOT-G - baseline to Week 12 and Week 24
Proportion of patients with post-Valsava LVOT-G <30 mmHg - Week 12 and Week 24
Total workload during CPET - baseline to Week 24
Duration of eligibility for SRT - baseline to Week 24
Safety - Throughout the study

Secondary end point(s): • Change in Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS)
• Proportion of patients with =1 class improvement in NYHA Functional Class
• Change in post-Valsalva LVOT-G
• Proportion of patients with post-Valsalva LVOT-G <30 mmHg
• Change in total workload during CPET
• Duration of eligibility for septal reduction therapy (SRT) in patients who are eligible for SRT at baseline

Safety
• Incidence of reported major adverse cardiac events (cardiovascular [CV] death, cardiac arrest, non-fatal stroke, non-fatal myocardial infarction, CV hospitalization)
• Incidence of new onset persistent atrial fibrillation
• Incidence of appropriate implantable cardiac defibrillator (ICD) discharges and aborted sudden cardiac death
• Incidence of left ventricular ejection fraction (LVEF) <50%
• Incidence of treatment emergent adverse events

Secondary ID(s)

CY6031

2021-003536-92-HU

NCT05186818

Source(s) of Monetary Support

Cytokinetics, Incorporated

Ethics review

Status: Approved
Approval date: 25/04/2022
Contact: