Non-obstructive Hypertrophic Cardiomyopathy
Conditions
Brief summary
This is a multicenter, exploratory, randomized, double-blind study of the administration of mavacamten in 60 participants with symptomatic nHCM randomized to receive a 16-week course of mavacamten doses titrated to achieve 1 of 2 target drug concentrations.
Interventions
DRUGmavacamten
MYK-461
DRUGPlacebo
Placebo
Sponsors
MyoKardia, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosed with nHCM (hypertrophied and non-dilated left ventricle in absence of systemic or other known cause), with LV wall thickness ≥ 15mm at Screening or ≥ 13mm with a positive family history of HCM. * Age 18 and greater, Body weight \> 45kg * Documented LVEF ≥ 55% at the Screening as determined by echo central lab * LVOT gradient \< 30 mmHg at rest AND during Valsalva AND post-exercise * NYHA functional class II or III * Elevated NT-proBNP at rest Key
Exclusion criteria
* History of syncope, sustained ventricular tachyarrhythmia with exercise, obstructive coronary artery disease or myocardial infarction within the past 6 months * History of resuscitated sudden cardiac arrest at any time or known appropriate implantable cardioverter defibrillator (ICD) discharge within 6 months prior to Screening * Current treatment with disopyramide or ranolazine (within 14 days prior to Screening) * Current or planned treatment during the study with a combination of beta-blockers and calcium channel blockers * Has been treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation \[ASA\]) within 6 months prior to Screening * History of resting or post-exercise LVOT \>30 mmHg unless subsequently treated by septal reduction * Has QTc Fridericia (QTcF) \>480 ms or any other ECG abnormality considered by the investigator to pose a risk to participant safety (eg, second-degree atrioventricular block type II) * Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to Screening and/or not adequately rate-controlled within 1 year of Screening * History of clinically significant malignant disease within 10 years such as non-metastatic cutaneous squamous cell or basal cell carcinoma * History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator or MyoKardia physician, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced at Least One Treatment Emergent Adverse Event (TEAE) | From first dose to 8 weeks following last dose (Up to 24 weeks) | This is the percentage of participants who experienced at least one treatment emergent adverse event (TEAE) |
| Percentage of Participants Who Experienced at Least One Serious Treatment-emergent Adverse Event (STEAE) | From first dose to 8 weeks following last dose (Up to 24 weeks) | This is the percentage of participants who experienced at least one serious treatment-emergent adverse event (STEAE) |
Countries
United States
Participant flow
Recruitment details
In total, 157 participants were assessed for eligibility and 59 were enrolled from 35 sites in the United States.
Pre-assignment details
59 participants were randomized and 58 entered the treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Received active 16-week course of mavacamten doses titrated to achieve target drug concentrations of \
200 ng/ml. Dose adjustments were done at Week 6 based on PK | 19 |
| Group 2 Received active 16-week course of mavacamten doses titrated to achieve target drug concentrations of \
500 ng/ml. Dose adjustments were done at Week 6 based on PK | 21 |
| Placebo Placebo Group | 19 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Group 2 | Total | Group 1 | Placebo |
|---|---|---|---|---|
| Age, Continuous | 50.0 years STANDARD_DEVIATION 14.7 | 53.9 years STANDARD_DEVIATION 15.7 | 58.3 years STANDARD_DEVIATION 13.7 | 53.8 years STANDARD_DEVIATION 18.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 52 Participants | 18 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| New York Heart Association (NYHA) Functional Classification Class II | 18 Participants | 46 Participants | 15 Participants | 13 Participants |
| New York Heart Association (NYHA) Functional Classification Class III | 3 Participants | 13 Participants | 4 Participants | 6 Participants |
| NT-proBNP | 933.3 ng/L STANDARD_DEVIATION 719.41 | 1080.8 ng/L STANDARD_DEVIATION 791.97 | 1160.7 ng/L STANDARD_DEVIATION 859.02 | 1164.1 ng/L STANDARD_DEVIATION 817.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 18 Participants | 52 Participants | 17 Participants | 17 Participants |
| Sex: Female, Male Female | 12 Participants | 34 Participants | 9 Participants | 13 Participants |
| Sex: Female, Male Male | 9 Participants | 25 Participants | 10 Participants | 6 Participants |
| Troponin-I Detectable Not Elevated | 10 participants | 21 participants | 6 participants | 5 participants |
| Troponin-I Elevated | 7 participants | 19 participants | 6 participants | 6 participants |
| Troponin-I Missing | 0 participants | 1 participants | 1 participants | 0 participants |
| Troponin-I Undetectable | 4 participants | 18 participants | 6 participants | 8 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 21 | 0 / 39 | 0 / 19 |
| other Total, other adverse events | 16 / 18 | 18 / 21 | 34 / 39 | 11 / 19 |
| serious Total, serious adverse events | 2 / 18 | 2 / 21 | 4 / 39 | 4 / 19 |
Outcome results
Primary
Percentage of Participants Who Experienced at Least One Serious Treatment-emergent Adverse Event (STEAE)
This is the percentage of participants who experienced at least one serious treatment-emergent adverse event (STEAE)
Time frame: From first dose to 8 weeks following last dose (Up to 24 weeks)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Percentage of Participants Who Experienced at Least One Serious Treatment-emergent Adverse Event (STEAE) | 11.1 percentage of participants |
| Group 2 | Percentage of Participants Who Experienced at Least One Serious Treatment-emergent Adverse Event (STEAE) | 9.5 percentage of participants |
| Placebo | Percentage of Participants Who Experienced at Least One Serious Treatment-emergent Adverse Event (STEAE) | 21.1 percentage of participants |
Primary
Percentage of Participants Who Experienced at Least One Treatment Emergent Adverse Event (TEAE)
This is the percentage of participants who experienced at least one treatment emergent adverse event (TEAE)
Time frame: From first dose to 8 weeks following last dose (Up to 24 weeks)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Percentage of Participants Who Experienced at Least One Treatment Emergent Adverse Event (TEAE) | 88.9 percentage of participants |
| Group 2 | Percentage of Participants Who Experienced at Least One Treatment Emergent Adverse Event (TEAE) | 90.5 percentage of participants |
| Placebo | Percentage of Participants Who Experienced at Least One Treatment Emergent Adverse Event (TEAE) | 68.4 percentage of participants |