Obstructive Hypertrophic Cardiomyopathy (oHCM)
Conditions
Keywords
Obstructive Hypertrophic Cardiomyopathy, oHCM, CK-3773274, CK-274, Aficamten, SEQUOIA-HCM, CY 6031, SEQUOIA
Brief summary
The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) versus placebo in adults with symptomatic hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction.
Detailed description
CY 6031 was a Phase 3, randomized, placebo-controlled, double-blind, multi-center trial in participants with symptomatic oHCM. Eligible participants were randomized in a 1:1 ratio to receive aficamten or placebo. Randomization was stratified by use of beta-blockers (yes or no) and cardiopulmonary exercise testing (CPET) exercise modality (treadmill or bicycle). Enrollment limits were applied as follows: participants taking beta-blockers were capped at approximately 70% of total enrollment; participants taking disopyramide were capped at approximately 10% of total enrollment; participants with persistent atrial fibrillation (AF) at screening were capped at approximately 15% of total enrollment; and participants using the bicycle CPET exercise modality were capped at approximately 50% of total enrollment. Investigational product (IP) was administered orally once daily (QD) with or without food for 24 weeks. During the initial 6 weeks of the treatment period, IP doses were individually titrated at Weeks 2, 4, and 6 based on echocardiography-guided criteria. Dose escalation at Weeks 2, 4, and 6 occurred only if a participant had a Valsalva left ventricular outflow tract gradient (LVOT-G) ≥ 30 mmHg and a biplane left ventricular ejection fraction (LVEF) ≥ 55%. Echocardiograms were performed at each subsequent visit during the trial, and the IP dose was down-titrated if the LVEF was \< 50%. The primary endpoint of peak oxygen uptake (pVO2) was measured by CPET at screening and at the end of treatment (Week 24). A participant's background HCM therapy was individually optimized according to local practice prior to enrollment in the study.
Interventions
DRUGAficamten (5 mg, 10 mg, 15 mg, and 20 mg)
Aficamten tablets were administered orally once daily.
Placebo tablets were administered orally once daily.
Sponsors
Cytokinetics
Corxel Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Males and females between 18 and 85 years of age, inclusive, at screening. * Body mass index \<35 kg/m2. * Diagnosed with HCM per the following criteria: * Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and * 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 ≥10g/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 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. Key
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). * Moderate-severe valvular aortic stenosis. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in pVO2 at Week 24 | Baseline to Week 24 | The effect of CK-3773274 on exercise capacity in participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) was determined through changes in peak oxygen uptake (pVO2) after 24 weeks of treatment. pVO2 was measured by cardiopulmonary exercise testing (CPET) on a treadmill or bicycle. A higher pVO2 indicates better cardiorespiratory fitness. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in KCCQ-CSS at Week 24 | Baseline to Week 24 | The effect of aficamten on patient health status was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), a patient-reported outcome designed to assess the physical limitations, symptoms, self-efficacy, social limitation, and quality of life of patients with heart failure symptoms. The KCCQ-Clinical Symptoms Score (KCCQ-CSS) is scored on a scale from 0 to 100, with higher scores indicating better physical functioning and symptoms. |
| Change From Baseline in KCCQ-CSS at Week 12 | Baseline to Week 12 | The effect of aficamten on patient health status was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), a patient-reported outcome designed to assess the physical limitations, symptoms, self-efficacy, social limitation, and quality of life of patients with heart failure symptoms. The KCCQ-Clinical Symptoms Score (KCCQ-CSS) is scored on a scale from 0 to 100, with higher scores indicating better physical functioning and symptoms. |
| Proportion of Participants With ≥1 Class Improvement in New York Heart Association (NYHA) Functional Class From Baseline to Week 24 | Baseline to Week 24 | The effect of aficamten on NYHA functional classification was evaluated through changes observed from baseline through 24 weeks of treatment. |
| Proportion of Participants With ≥1 Class Improvement in NYHA Functional Class From Baseline to Week 12 | Baseline to Week 12 | The effect of aficamten on NYHA functional classification was evaluated through changes observed from baseline through 12 weeks of treatment. |
| Change From Baseline in Valsalva Left Ventricular Outflow Tract Gradient (LVOT-G) at Week 24 | Baseline to Week 24 | The effect of aficamten treatment on Valsalva LVOT-G was evaluated through changes from baseline to Week 24. |
| Change From Baseline in Valsalva LVOT-G at Week 12 | Baseline to Week 12 | The effect of aficamten treatment on Valsalva LVOT-G was evaluated through changes from baseline to Week 12. |
| Proportion of Participants With Valsalva LVOT G <30 mmHg at Week 24 | Baseline to Week 24 | The effect of aficamten treatment on Valsalva LVOT-G was evaluated through changes from baseline to Week 24. |
| Proportion of Participants With Valsalva LVOT G <30 mmHg at Week 12 | Baseline to Week 12 | The effect of aficamten treatment on Valsalva LVOT-G was evaluated through changes from baseline to Week 12. |
| Duration of SRT Eligibility During the 24-week Treatment Period for Participants Who Were SRT Eligible at Baseline | Baseline to Week 24 | The effect of aficamten treatment on the duration of septal reduction therapy (SRT) eligibility was evaluated over the 24- week treatment period. |
| Change From Baseline to Week 24 in Total Workload During CPET | Baseline to Week 24 | Effect of aficamten on intensity of exercise (based on speed, incline, participant weight, etc.) during CPET. Workload is an indication of the energy expended during the exercise test. |
Countries
China, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORCytokinetics MD
Cytokinetics
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 60.0 Years |
| pVO2 per CPET | 18.4 mL/kg/min STANDARD_DEVIATION 4.5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 25 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized White | 223 Participants |
| Region of Enrollment China | 22 Participants |
| Region of Enrollment Czechia | 1 Participants |
| Region of Enrollment Denmark | 7 Participants |
| Region of Enrollment France | 8 Participants |
| Region of Enrollment Germany | 3 Participants |
| Region of Enrollment Hungary | 7 Participants |
| Region of Enrollment Israel | 5 Participants |
| Region of Enrollment Italy | 12 Participants |
| Region of Enrollment Netherlands | 6 Participants |
| Region of Enrollment Poland | 17 Participants |
| Region of Enrollment Portugal | 2 Participants |
| Region of Enrollment Spain | 32 Participants |
| Region of Enrollment United Kingdom | 8 Participants |
| Region of Enrollment United States | 45 Participants |
| Sex: Female, Male Female | 115 Participants |
| Sex: Female, Male Male | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 142 | 0 / 140 |
| other Total, other adverse events | 44 / 142 | 46 / 140 |
| serious Total, serious adverse events | 8 / 142 | 13 / 140 |
Outcome results
None listed