Hypertrophic Cardiomyopathy (HCM)
Conditions
Keywords
CK-3773274, CK-274, obstructive hypertrophic cardiomyopathy, oHCM, REDWOOD-HCM, non-obstructive hypertrophic cardiomyopathy, nHCM, hypertrophic cardiomyopathy, HCM, aficamten, CY 6021
Brief summary
This study is being performed to understand the effect of different doses of CK-3773274 on patients with hypertrophic cardiomyopathy (HCM).
Detailed description
This was a Phase 2, multi-center, randomized, placebo-controlled, double-blind, dose-finding study in participants with symptomatic HCM. The study consisted of 4 cohorts. For Cohorts 1 and 2, participants with obstructive HCM (oHCM) and not receiving disopyramide were randomized 2:1 to active or placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg once daily in Cohort 1 and 10, 20, and 30 mg once daily in Cohort 2) or placebo based on site-read echocardiographic guidance. Cohort 3 consisted of participants with oHCM whose background HCM therapy included disopyramide. All participants in Cohort 3 received up to 3 escalating doses of aficamten (5, 10, and 15 mg once daily) based on echocardiographic guidance. Cohort 4 consisted of participants with non-obstructive HCM (nHCM) on standard of care background therapy. Cohort 4 participants received up to 3 doses of aficamten (5, 10, and 15 mg once daily), titrated based on site-read echocardiographic guidance. In all 4 cohorts, treatment duration was 10 weeks with a 4-week follow-up period after the last dose.
Interventions
DRUGCK-3773274 (5 - 15 mg)
CK-3773274 tablets administered orally once daily
DRUGCK-3773274 (10 - 30 mg)
CK-3773274 tablets administered orally once daily
DRUGPlacebo for CK-3773274
Placebo administered orally once daily
Sponsors
Cytokinetics
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
* Males and females between 18 and 85 years of age at screening. * Body weight is ≥45 kg at screening. * Diagnosed with HCM per the following criteria: * Has left ventricular (LV) hypertrophy with non-dilated LV chamber in the absence of other cardiac disease. * Has minimal wall thickness ≥15 mm (minimal wall thickness ≥13 mm is acceptable with a positive family history of HCM or with a known disease-causing gene mutation). * Adequate acoustic windows for echocardiography. * For Cohorts 1, 2 and 3 has LVOT-G during screening as follows: * Resting gradient ≥50 mmHg OR * Resting gradient ≥30 mmHg and \<50 mmHg with post-Valsalva LVOT-G ≥50 mmHg * For Cohort 4 has resting and post-Valsalva LVOT-G \< 30 mmHg at the time of screening * For Cohort 4 has elevated NT-proBNP \> 300 pg/mL at the time of screening * LVEF ≥60% at screening. * New York Heart Association (NYHA) Class II or III at screening. * Patients on beta-blockers, verapamil, diltiazem, or ranolazine should have been on stable doses for \>4 weeks prior to randomization and anticipate remaining on the same medication regimen during the study. * For Cohort 3: Patients must be taking disopyramide. Patients should have been on stable disopyramide doses for \>4 weeks prior to screening and anticipate remaining on the same medication regimen during the study.
Exclusion criteria
* Aortic stenosis or fixed subaortic obstruction. * Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis). * History of LV systolic dysfunction (LVEF \<45%) at any time during their clinical course. * Documented history of current obstructive coronary artery disease (\>70% stenosis in one or more epicardial coronary arteries) or documented history of myocardial infarction. * Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the study period (Cohorts 1, 2, and 3 only). Patients having undergone septal reduction therapy \> 12 months prior to screening who remain symptomatic from nHCM, and who meet all other criteria for inclusion, may be enrolled in Cohort 4. * For Cohorts 1, 2 and 4: Has been treated with disopyramide or antiarrhythmic drugs that have negative inotropic activity within 4 weeks prior to screening. (For Cohort 3, use of disopyramide is required). * Has any ECG abnormality considered by the investigator to pose a risk to patient safety (eg, second degree atrioventricular block type II). * Paroxysmal atrial fibrillation or flutter documented during the screening period. * Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) ≤6 months prior to screening. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately rate-controlled for \>6 months). * History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening. * Has received prior treatment with CK-3773274 or mavacamten. * For Cohort 4: has any documented history of LVOT-G ≥ 30 mmHg at rest, with Valsalva, or with exercise (for subjects who have had prior septal reduction therapy, this
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) | 14 weeks | Participant incidence of reported AEs to determine the safety and tolerability of aficamten in participants with HCM. |
| Incidence of Left Ventricular Ejection Fraction (LVEF) < 50% | 14 weeks | Participant incidence of LVEF \< 50% as assessed by the core laboratory assessment. |
| Incidence of Serious Adverse Events (SAEs) | 14 weeks | Participant incidence of reported SAEs to determine the safety and tolerability of aficamten in participants with symptomatic HCM. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Slope of the Relationship of the Plasma Concentration of CK-3773274 to the Change From Baseline in the Resting Left Ventricular Outflow Track Gradient (LVOT-G) | Baseline and 10 weeks | Concentration-response relationship of CK-3773274 on the resting LVOT-G on echocardiogram over 10 weeks of treatment in participants with (oHCM) obstructive hypertrophic cardiomyopathy (oHCM) (Cohorts 1, 2, 3 only) |
| Slope of the Relationship of the Plasma Concentration of CK-3773274 to the Change From Baseline in the Post-Valsalva LVOT-G | Baseline and 10 Weeks | Concentration-response relationship of CK-3773274 on the post-Valsalva LVOT-G on echocardiogram over 10 weeks of treatment in participants with oHCM (Cohorts 1, 2, 3 only) |
| Change From Baseline in Resting LVOT-G Over Time as a Function of Dose. | Baseline and 10 Weeks | Dose response relationship on resting LVOT-G of CK-3773274 in participants with oHCM (Cohorts 1, 2, 3 only) |
| Change From Baseline in Post-Valsalva LVOT-G Over Time as a Function of Dose. | 10 weeks | Dose response relationship of CK-3773274 on post-Valsalva LVOT-G in participants with symptomatic oHCM (Cohorts 1, 2, 3 only) |
| Slope of the Relationship of the Plasma Concentration of CK-3773274 to the Change From Baseline in the Resting LVEF | Day 1 to End of Study (EOS) (Week 14) | Concentration-response relationship of CK-3773274 on LVEF over 10 weeks of treatment in participants with HCM |
Countries
Italy, Netherlands, Spain, United States
Contacts
STUDY_DIRECTORCytokinetics, MD
Cytokinetics
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 92 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| LVEF | 69.8 % STANDARD_DEVIATION 7.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment Italy | 3 Participants |
| Region of Enrollment Spain | 5 Participants |
| Region of Enrollment United States | 13 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 7 | 0 / 14 | 0 / 6 | 0 / 13 | 1 / 41 |
| other Total, other adverse events | 10 / 14 | 7 / 7 | 11 / 14 | 4 / 6 | 9 / 13 | 26 / 41 |
| serious Total, serious adverse events | 1 / 14 | 1 / 7 | 1 / 14 | 0 / 6 | 0 / 13 | 4 / 41 |
Outcome results
None listed