Obstructive Hypertrophic Cardiomyopathy
Conditions
Keywords
Symptomatic, left ventricular outflow tract gradient
Brief summary
This is a multicenter, international, double-blind study of the administration of mavacamten in participants with symptomatic obstructive HCM (oHCM). Approximately 220 participants will be randomized to receive placebo or mavacamten.
Interventions
DRUGmavacamten
mavacamten capsules
DRUGPlacebo
placebo oral capsule
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: * Age 18 and greater, body weight ≥ 45kg * Has adequate acoustic windows to enable accurate transthoracic echocardiograms (TTEs) * Diagnosed with oHCM consistent with current American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guidelines and satisfy both criteria: * Has documented left ventricular ejection fraction (LVEF) ≥55% * NYHA Class II or III * Has documented oxygen saturation at rest ≥90% at Screening * Is able to perform an upright CPET and has a respiratory exchange ratio (RER) ≥1.0 at Screening per central reading Key
Exclusion criteria
* Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy * History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to Screening * History of resuscitated sudden cardiac arrest (at any time) or known history of appropriate implantable cardioverter defibrillator (ICD) discharge for life-threatening ventricular arrhythmia within 6 months prior to Screening * Paroxysmal, intermittent atrial fibrillation with atrial fibrillation present at Screening * Persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to Screening and/or not adequately rate controlled within 6 months prior to Screening * Treatment (within 14 days prior to Screening) or planned treatment during the study with disopyramide or ranolazine * Treatment (within 14 days prior to Screening) or planned treatment during the study with a combination of β-blockers and calcium channel blockers * LVOT gradient with Valsalva maneuver \<30 mmHg at Screening * Has been successfully treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation \[ASA\]) within 6 months prior to Screening or plans to have either of these treatments during the study * ICD placement within 2 months prior to Screening or planned ICD placement during the study * Has a history or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator, would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion * Prior treatment with cardiotoxic agents such as doxorubicin or similar
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving A Clinical Response | 30 weeks | A positive clinical response (value=YES) is defined as having achieved either an improvement of at least 1.5 mL/kg/min in peak oxygen consumption (pVO2) as determined by cardiopulmonary exercise testing (CPET) and a reduction of one or more class in New York Heart Association (NYHA) functional classification (e.g.I, II, III, or IV) -OR- an improvement of 3.0 mL/kg/min or more in pVO2 with no worsening in NYHA Functional Class. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes From Baseline to Week 30 in Post Exercise in LVOT Peak Gradient. | 30 weeks | The post-exercise LVOT gradient was measured from echocardiograms obtained at baseline and week 30 following a study-specified exercise protocol and read by the Cardiovascular Imaging Core Laboratory (CICL, Boston MA). Change from baseline was determined as per the study statistical analysis plan and compared between treatment arms. |
| Change From Baseline to Week 30 in pVO2 as Assessed by CPET | 30 weeks | Cardiopulmonary exercise testing (CPET) was performed at baseline and week 30 following a study-specified protocol and peak oxygen consumption (pVO2) was determined by the Cardiovascular Metabolic Disease Research Institute (CMDRI, Palo Alto, CA). Change from baseline was determined as per the study statistical analysis plan and compared between treatment arms. |
| Proportion of Participants With at Least 1 Class Improvement in NYHA Functional Class From Baseline to Week 30 | 30 weeks | New York Heart Association (NYHA) functional classification was determined by the principal investigator at baseline and at specified timepoints in the study. At baseline, all subjects were NYHA Class II or III. For the secondary outcome, NYHA class at Week 30 was compared to baseline and the proportion of subjects with an improvement of at least one class was determined, and the difference between treatment groups was analyzed. The proportion was also multiplied by 100 to provide the result as a percent. |
| Change From Baseline to Week 30 in Participant-reported Health-related Quality of Life as Assessed by the KCCQ Score | 30 weeks | The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient reported outcome instrument with minimum score = 0 and maximum score = 100 where higher score indicates better health status. There are no units to the score. The instrument utilizes a recall period of 2 weeks over which patients describe the frequency and severity of their symptoms, their physical and social limitations, and how they perceive their heart failure symptoms to affect their quality of life. The KCCQ clinical summary (KCCQ-CS) score, a prespecified secondary outcome of EXPLORER-HCM, combines the physical limitation and total symptom scores. |
| Change From Baseline to Week 30 in Participant-reported Severity of HCM Symptoms as Assessed by the HCMSQ Score | 30 weeks | The Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) is a patient reported outcome instrument that is a daily self-administered 11-item questionnaire. The HCMSQ assesses the core symptoms of HCM (tiredness/fatigue, heart palpitations, chest pain, dizziness, and shortness of breath). The Shortness of Breath domain score, a pre-specified secondary outcome of EXPLORER-HCM, assesses the frequency and severity of shortness of breath. The minimum score = 0 and maximum score = 18 where lower score indicates better health status. There are no units to the score. |
Countries
Belgium, Czechia, Denmark, France, Germany, Israel, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom, United States
Participant flow
Recruitment details
Subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled into the study and were randomized 1:1 to receive mavacamten (2.5, 5, 10, or 15 mg capsule) or placebo once daily for 30 weeks, followed by an 8 week post-treatment period. In total, 429 participants were assessed for eligibility and 251 were enrolled from 68 sites in the United States and EMEA.
Participants by arm
| Arm | Count |
|---|---|
| Mavacamten (MYK-461) mavacamten: mavacamten capsules | 123 |
| Placebo Placebo: placebo oral capsule | 128 |
| Total | 251 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Did not complete Week 30 assessments due to scheduling conflict | 1 | 0 |
| Overall Study | Week 30 not completed due to circumstances surrounding the COVID-19 pandemic | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Mavacamten (MYK-461) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 45 Participants | 40 Participants | 85 Participants |
| Age, Categorical Between 18 and 65 years | 78 Participants | 88 Participants | 166 Participants |
| Age, Continuous | 60 years | 60 years | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 4 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 114 Participants | 119 Participants | 233 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) White | 115 Participants | 114 Participants | 229 Participants |
| Sex: Female, Male Female | 57 Participants | 45 Participants | 102 Participants |
| Sex: Female, Male Male | 66 Participants | 83 Participants | 149 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 123 | 1 / 128 |
| other Total, other adverse events | 108 / 123 | 104 / 128 |
| serious Total, serious adverse events | 14 / 123 | 12 / 128 |
Outcome results
Primary
Percentage of Participants Achieving A Clinical Response
A positive clinical response (value=YES) is defined as having achieved either an improvement of at least 1.5 mL/kg/min in peak oxygen consumption (pVO2) as determined by cardiopulmonary exercise testing (CPET) and a reduction of one or more class in New York Heart Association (NYHA) functional classification (e.g.I, II, III, or IV) -OR- an improvement of 3.0 mL/kg/min or more in pVO2 with no worsening in NYHA Functional Class.
Time frame: 30 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten (MYK-461) | Percentage of Participants Achieving A Clinical Response | 45 Participants |
| Placebo | Percentage of Participants Achieving A Clinical Response | 22 Participants |
Secondary
Change From Baseline to Week 30 in Participant-reported Health-related Quality of Life as Assessed by the KCCQ Score
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient reported outcome instrument with minimum score = 0 and maximum score = 100 where higher score indicates better health status. There are no units to the score. The instrument utilizes a recall period of 2 weeks over which patients describe the frequency and severity of their symptoms, their physical and social limitations, and how they perceive their heart failure symptoms to affect their quality of life. The KCCQ clinical summary (KCCQ-CS) score, a prespecified secondary outcome of EXPLORER-HCM, combines the physical limitation and total symptom scores.
Time frame: 30 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mavacamten (MYK-461) | Change From Baseline to Week 30 in Participant-reported Health-related Quality of Life as Assessed by the KCCQ Score | 13.6 Scores on Scale | Standard Deviation 14.42 |
| Placebo | Change From Baseline to Week 30 in Participant-reported Health-related Quality of Life as Assessed by the KCCQ Score | 4.2 Scores on Scale | Standard Deviation 13.68 |
Secondary
Change From Baseline to Week 30 in Participant-reported Severity of HCM Symptoms as Assessed by the HCMSQ Score
The Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) is a patient reported outcome instrument that is a daily self-administered 11-item questionnaire. The HCMSQ assesses the core symptoms of HCM (tiredness/fatigue, heart palpitations, chest pain, dizziness, and shortness of breath). The Shortness of Breath domain score, a pre-specified secondary outcome of EXPLORER-HCM, assesses the frequency and severity of shortness of breath. The minimum score = 0 and maximum score = 18 where lower score indicates better health status. There are no units to the score.
Time frame: 30 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mavacamten (MYK-461) | Change From Baseline to Week 30 in Participant-reported Severity of HCM Symptoms as Assessed by the HCMSQ Score | -2.8 Scores on Scale | Standard Deviation 2.68 |
| Placebo | Change From Baseline to Week 30 in Participant-reported Severity of HCM Symptoms as Assessed by the HCMSQ Score | -0.9 Scores on Scale | Standard Deviation 2.41 |
Secondary
Change From Baseline to Week 30 in pVO2 as Assessed by CPET
Cardiopulmonary exercise testing (CPET) was performed at baseline and week 30 following a study-specified protocol and peak oxygen consumption (pVO2) was determined by the Cardiovascular Metabolic Disease Research Institute (CMDRI, Palo Alto, CA). Change from baseline was determined as per the study statistical analysis plan and compared between treatment arms.
Time frame: 30 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mavacamten (MYK-461) | Change From Baseline to Week 30 in pVO2 as Assessed by CPET | 1.4 mL/kg/min | Standard Deviation 3.12 |
| Placebo | Change From Baseline to Week 30 in pVO2 as Assessed by CPET | -0.05 mL/kg/min | Standard Deviation 3.02 |
Secondary
Changes From Baseline to Week 30 in Post Exercise in LVOT Peak Gradient.
The post-exercise LVOT gradient was measured from echocardiograms obtained at baseline and week 30 following a study-specified exercise protocol and read by the Cardiovascular Imaging Core Laboratory (CICL, Boston MA). Change from baseline was determined as per the study statistical analysis plan and compared between treatment arms.
Time frame: 30 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mavacamten (MYK-461) | Changes From Baseline to Week 30 in Post Exercise in LVOT Peak Gradient. | -47 mmHg | Standard Deviation 40.3 |
| Placebo | Changes From Baseline to Week 30 in Post Exercise in LVOT Peak Gradient. | -10 mmHg | Standard Deviation 29.6 |
Secondary
Proportion of Participants With at Least 1 Class Improvement in NYHA Functional Class From Baseline to Week 30
New York Heart Association (NYHA) functional classification was determined by the principal investigator at baseline and at specified timepoints in the study. At baseline, all subjects were NYHA Class II or III. For the secondary outcome, NYHA class at Week 30 was compared to baseline and the proportion of subjects with an improvement of at least one class was determined, and the difference between treatment groups was analyzed. The proportion was also multiplied by 100 to provide the result as a percent.
Time frame: 30 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten (MYK-461) | Proportion of Participants With at Least 1 Class Improvement in NYHA Functional Class From Baseline to Week 30 | 80 Participants |
| Placebo | Proportion of Participants With at Least 1 Class Improvement in NYHA Functional Class From Baseline to Week 30 | 40 Participants |