Obstructive Hypertrophic Cardiomyopathy (oHCM)
Conditions
Keywords
Obstructive Hypertrophic Cardiomyopathy, Aficamten, Metoprolol, oHCM, CK-3773274, CK-274, MAPLE-HCM, MAPLE, CY 6032
Brief summary
The purpose of this study is to compare the efficacy and safety of aficamten (CK-3773274) compared with metoprolol succinate in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction
Interventions
DRUGAficamten (CK-3773274) (5 mg, 10 mg, 15 mg and 20 mg)
Aficamten (CK-3773274) tablets administered orally
Placebo for aficamten (CK-3773274) administered orally
DRUGMetoprolol succinate (50 mg, 100 mg, 150 mg and 200 mg)
Metoprolol succinate tablets administered orally
Placebo for metoprolol succinate administered orally
Sponsors
Cytokinetics
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Participants who meet all the following criteria at screening may be included in the trial: * Males and females between 18 to 85 years of age, inclusive, at screening * Body mass index \< 35 kg/m2 * Diagnosed with oHCM per the following criteria by cardiac magnetic resonance imaging (CMR) or echocardiography - * Has left ventricular (LV) hypertrophy with 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: 1. ≥ 15 mm in one or more myocardial segments OR 2. ≥ 13 mm in one or more wall segments and a known disease-causing gene mutation or positive family history of HCM * New York Heart Association (NYHA) class II or III * Has a Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) score of ≤ 90 at screening * Has a screening echocardiogram with the following determined by the echocardiography core laboratory: * Resting left ventricular outflow tract gradient (LVOT-G) \> 30 mm Hg and/or post-Valsalva LVOT-G ≥ 50 mmHg at screening AND * LVEF ≥ 60% * Hemoglobin ≥ 10g/dL * Respiratory exchange ratio (RER) ≥ 1.05 and peak oxygen uptake (pVO2) \< 100% predicted on the screening cardiopulmonary exercise testing (CPET) per the core laboratory * Patients previously exposed to mavacamten are allowed to participate but must be off mavacamten for at least 8 weeks
Exclusion criteria
* Any of the following criteria will exclude potential participants from the trial: * Medical indication for either beta blocker or calcium-channel blockers prohibiting drug discontinuation other than oHCM * History of intolerance or medical contraindication to beta blocker therapy * Resting Systolic Blood Pressure (SBP) of \> 160 mmHg * Resting heart rate of \> 100 bpm * Significant valvular heart disease 1. Moderate-severe valvular aortic stenosis or fixed subaortic obstruction 2. Mitral regurgitation not due to systolic anterior motion of the mitral valve (per Investigator judgment) * Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis) * 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) * Documented room air oxygen saturation reading \< 90% at screening * Planned septal reduction treatment that cannot be deferred during the trial period * History of septal reduction therapy (surgical myectomy or alcohol septal ablation) within 6 months of screening * History of paroxysmal or persistent atrial fibrillation or atrial flutter. Atrial flutter treated with radio frequency ablation without recurrence within the last 6 months prior to screening is allowed. * Current or recent (\< 4 weeks) therapy with disopyramide * History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening * Has received prior treatment with aficamten or previously intolerant (reduced LVEF requiring permanent drug discontinuation) to mavacamten
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak Oxygen Uptake (pVO2) by Cardiopulmonary Exercise Testing (CPET) | Baseline to Week 24 | Effect of aficamten compared with metoprolol succinate on exercise capacity in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Exercise capacity 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 |
|---|---|---|
| Proportion of Patients With ≥1 Class Improvement in New York Heart Association (NYHA) Functional Class | Baseline to Week 24 | Effect of aficamten compared with metoprolol succinate on NYHA Functional Classification |
| Change in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) | Baseline to Week 24 | Effect of aficamten compared with metoprolol succinate on participant health status was measured by change in KCCQ-CSS. The KCCQ is a patient-reported outcome designed to assess the physical limitations, symptoms, self-efficacy, quality of life, and social limitation of patients with heart failure symptoms. The CSS is the sum of the physical limitation score and the total symptom score. 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 in Left Ventricular Mass Index (LVMI) | Baseline to Week 24 | Effect of aficamten on mass of the heart as compared with metoprolol succinate |
| Change in Left Atrial Volume Index (LAVI) | Baseline to Week 24 | Effect of aficamten on size of the heart as compared with metoprolol succinate |
| Change From Baseline Values in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) | Baseline to Week 24 | Effect of aficamten on NT-proBNP as compared with metoprolol succinate. For change in NT-proBNP from baseline to Week 24, the log transformed proportional change up to Week 24 was analyzed using a mixed model for repeated measures (MMRM) then the estimate was back transformed to obtain the ratio. |
| Change in Post-Valsalva Left Ventricular Outflow Tract Gradient (LVOT-G) | Baseline to Week 24 | Effect of aficamten on post-Valsalva LVOT-G as compared with metoprolol succinate |
Countries
Brazil, Canada, China, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORScientific Leadership
Cytokinetics
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 57.7 Years STANDARD_DEVIATION 13.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 146 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CSS) | 65.8 Points on a Scale STANDARD_DEVIATION 16.47 |
| Peak Oxygen Uptake (pVO2) by Cardiopulmonary Exercise Testing (CPET) | 19.52 mL/kg/min STANDARD_DEVIATION 4.786 |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 13 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race Not Reported | 4 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants |
| Race/Ethnicity, Customized Race Unknown | 2 Participants |
| Race/Ethnicity, Customized Race White | 140 Participants |
| Region of Enrollment Brazil | 1 Participants |
| Region of Enrollment Canada | 2 Participants |
| Region of Enrollment China | 22 Participants |
| Region of Enrollment Denmark | 5 Participants |
| Region of Enrollment France | 4 Participants |
| Region of Enrollment Germany | 1 Participants |
| Region of Enrollment Hungary | 11 Participants |
| Region of Enrollment Israel | 3 Participants |
| Region of Enrollment Italy | 4 Participants |
| Region of Enrollment Netherlands | 4 Participants |
| Region of Enrollment Spain | 28 Participants |
| Region of Enrollment United Kingdom | 8 Participants |
| Region of Enrollment United States | 82 Participants |
| Sex: Female, Male Female | 37 Participants |
| Sex: Female, Male Male | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 88 | 0 / 87 |
| other Total, other adverse events | 46 / 88 | 43 / 87 |
| serious Total, serious adverse events | 7 / 88 | 6 / 87 |
Outcome results
None listed