HOCM, Hypertrophic Obstructive Cardiomyopathy
Conditions
Brief summary
This is a randomized, double-blind, placebo-controlled, multi-center study in the United States (U.S.) that will evaluate the effect of mavacamten treatment on reducing the number of septal reduction therapy (SRT) procedures performed in subjects with symptomatic obstructive hypertrophic cardiomyopathy (oHCM \[also known as HOCM\]) who are eligible for SRT based on ACCF/AHA 2011 and/or ESC 2014 guidelines.
Interventions
DRUGMavacamten
Mavacamten Capsules Other names: MYK-461
DRUGPlacebo
Placebo
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a parallel group treatment study with 2 treatment groups; subjects and investigators are blinded to treatment and dose for the first 16 weeks of treatment. Mavacamten dose is blinded throughout the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * At least 18 years old at screening and body weight \> 45 kg at screening * Diagnosed with oHCM consistent with current ACCF/AHA 2011 and meet their recommendations for invasive therapies * Referred or under active consideration within the past 12 months for SRT procedure and willing to have SRT procedure * Has documented left ventricular ejection fraction (LVEF) ≥ 60% at Screening * Has documented oxygen saturation at rest ≥ 90% at Screening Key
Exclusion criteria
* Persistent or permanent atrial fibrillation and subject not on anticoagulation for ≥ 4 weeks prior to screening and/or not adequately rate controlled ≤ 6 months prior to screening * Previously treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation \[ASA\]) * For individuals on beta blockers, calcium channel blockers, or disopyramide, any dose adjustment of these medications \< 14 days prior to screening or an anticipated change in regimen during the first 16 weeks of the study * Any medical condition that precludes upright exercise stress testing * Paroxysmal, intermittent atrial fibrillation with atrial fibrillation present at screening * Prior treatment with cardiotoxic agents, such as doxorubicin or similar * Has a history or evidence of any other clinically significant disorder, condition, or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Decision to Proceed With Septal Reduction Therapy (SRT) and SRT Guideline Eligible at Week 16 | Week 16 | Participants who decided to proceed with SRT or were eligible for SRT at week 16. Participants with missing assessments were classified as meeting the primary endpoint (did not improve). SRT eligibility using the New York Heart Association Functional Class (NYHA) and left ventricular outflow tract (LVOT) assessments per the 2011 ACCF/AHA guideline clinical and hemodynamic criterion are below: * NYHA Class III or IV/ NYHA Class II with exertion-induced syncope/near syncope, AND * Dynamic LVOT gradient at rest or with provocation \>= 50 mmHg. NYHA Class II at week 16, the following rules will be applied: * NYHA Class II with history of exertional syncope/ syncope at baseline and at W16 is still NYHA Class II, they remain SRT eligible IF their maximal LVOT gradient is ≥ 50mmHg * NYHA Class III/IV at baseline and at W16 has improved to Class II, they are no longer SRT eligible UNLESS they have AE of exertional syncope or pre-syncope during the 16 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP) | Baseline and week 16 | A geometric mean ratio was used to assess the change from baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP). Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise. |
| Number of Participants With at Least One Class Improvement From Baseline in New York Heart Association (NYHA) Class at Week 16 | Baseline and week 16 | The NYHA functional classification of heart failure assigns participants to 1 of 4 categories based on the participants symptoms. Baseline values are defined generally as the last available value before the first administration of study drug of analysis interest. Participants with missing NYHA class assessments are treated as no improvement. Class 1: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). Class 2: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class 3: Marked limitation of physical activity. Comfortable at rest. Less-than ordinary-activity causes fatigue, palpitation, or dyspnea. Class 4: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. |
| Change From Baseline to Week 16 in Kansas City Cardiomyopathy Questionnaire 23-item Version, Clinical Summary Score (KCCQ-23, CSS) | Baseline and week 16 | The KCCQ-23 is a 23-item, self-administered questionnaire that measures the impact of a participant's cardiovascular disease or its treatment on 6 distinct domains using a 2-week recall period: symptoms/signs, physical limitation, quality of life (QoL), social limitations, self-efficacy, and symptom stability. The KCCQ 23 Clinical Summary Score (CSS) is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ 23. The CSS, TSS, and the PL score range from 0 to 100 with higher scores representing less severe symptoms and/or physical limitations. The CSS is a mean of the TSS and the PL score. |
| Change From Baseline to Week 16 in Cardiac Troponin | Baseline and week 16 | A geometric mean ratio was used to assess the change from baseline to week 16 in cardiac troponin. Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise. |
| Change From Baseline to Week 16 in Post-Exercise Left Ventricular Outflow Tract (LVOT) Gradient | Baseline and week 16 | Change from baseline to week 16 in post-exercise left ventricular outflow tract (LVOT) gradient. Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mavacamten Participants randomized to the mavacamten group started on 5 mg once daily and were titrated to receive 2.5, 5, 10, or 15 mg capsule orally once daily based on possible down-titration at Week 4 and up-titration at Weeks 8 and 12 (based on the LVEF and VLVOT gradient measured by TTE). Participants could be up- titrated at any scheduled visit after Week 32.
Participants went through 16 weeks of placebo-controlled treatment (Day 1 to Week 16), 16 weeks of active-controlled treatment (Weeks 16 to 32), and 96 weeks of LTE mavacamten (Weeks 32 to 128). | 56 |
| Placebo to Mavacamten One placebo-to-match mavacamten capsule once daily for 16 weeks and then switch to mavacamten. After Week 16 through Week 32, participants started on 5 mg once daily and were titrated to receive 2.5, 5, 10, or 15 mg capsule orally once daily based on possible down-titration at Week 20 and up-titration at Weeks 24 and 28 (based on the LVEF and VLVOT gradient measured by TTE). Participants could be up- titrated at any scheduled visit after Week 32.
Participants went through 16 weeks of placebo-controlled treatment (Day 1 to Week 16), 16 weeks of active-controlled treatment (Weeks 16 to 32), and 96 weeks of LTE mavacamten (Weeks 32 to 128). | 56 |
| Total | 112 |
Baseline characteristics
| Characteristic | Placebo to Mavacamten | Total | Mavacamten |
|---|---|---|---|
| Age, Continuous | 60.9 Years STANDARD_DEVIATION 10.55 | 60.3 Years STANDARD_DEVIATION 12.45 | 59.8 Years STANDARD_DEVIATION 14.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 110 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 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 | 3 Participants |
| Race (NIH/OMB) White | 52 Participants | 100 Participants | 48 Participants |
| Sex: Female, Male Female | 28 Participants | 55 Participants | 27 Participants |
| Sex: Female, Male Male | 28 Participants | 57 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 108 | 0 / 56 |
| other Total, other adverse events | 96 / 108 | 20 / 55 |
| serious Total, serious adverse events | 21 / 108 | 1 / 55 |
Outcome results
Primary
Composite of Decision to Proceed With Septal Reduction Therapy (SRT) and SRT Guideline Eligible at Week 16
Participants who decided to proceed with SRT or were eligible for SRT at week 16. Participants with missing assessments were classified as meeting the primary endpoint (did not improve). SRT eligibility using the New York Heart Association Functional Class (NYHA) and left ventricular outflow tract (LVOT) assessments per the 2011 ACCF/AHA guideline clinical and hemodynamic criterion are below: * NYHA Class III or IV/ NYHA Class II with exertion-induced syncope/near syncope, AND * Dynamic LVOT gradient at rest or with provocation \>= 50 mmHg. NYHA Class II at week 16, the following rules will be applied: * NYHA Class II with history of exertional syncope/ syncope at baseline and at W16 is still NYHA Class II, they remain SRT eligible IF their maximal LVOT gradient is ≥ 50mmHg * NYHA Class III/IV at baseline and at W16 has improved to Class II, they are no longer SRT eligible UNLESS they have AE of exertional syncope or pre-syncope during the 16 weeks.
Time frame: Week 16
Population: All randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten | Composite of Decision to Proceed With Septal Reduction Therapy (SRT) and SRT Guideline Eligible at Week 16 | 10 Participants |
| Placebo to Mavacamten | Composite of Decision to Proceed With Septal Reduction Therapy (SRT) and SRT Guideline Eligible at Week 16 | 43 Participants |
p-value: <0.000195% CI: [43.989, 73.868]Cochran-Mantel-Haenszel
Secondary
Change From Baseline to Week 16 in Cardiac Troponin
A geometric mean ratio was used to assess the change from baseline to week 16 in cardiac troponin. Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.
Time frame: Baseline and week 16
Population: All randomized participants with baseline and week 16 serum concentration data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mavacamten | Change From Baseline to Week 16 in Cardiac Troponin | 0.50 ng/L |
| Placebo to Mavacamten | Change From Baseline to Week 16 in Cardiac Troponin | 1.03 ng/L |
p-value: <0.000195% CI: [0.406, 0.7]Mixed Models Analysis
Secondary
Change From Baseline to Week 16 in Kansas City Cardiomyopathy Questionnaire 23-item Version, Clinical Summary Score (KCCQ-23, CSS)
The KCCQ-23 is a 23-item, self-administered questionnaire that measures the impact of a participant's cardiovascular disease or its treatment on 6 distinct domains using a 2-week recall period: symptoms/signs, physical limitation, quality of life (QoL), social limitations, self-efficacy, and symptom stability. The KCCQ 23 Clinical Summary Score (CSS) is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ 23. The CSS, TSS, and the PL score range from 0 to 100 with higher scores representing less severe symptoms and/or physical limitations. The CSS is a mean of the TSS and the PL score.
Time frame: Baseline and week 16
Population: All randomized participants with baseline and week 16 clinical summary scores
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mavacamten | Change From Baseline to Week 16 in Kansas City Cardiomyopathy Questionnaire 23-item Version, Clinical Summary Score (KCCQ-23, CSS) | 10.4 Score on a scale | Standard Deviation 16.06 |
| Placebo to Mavacamten | Change From Baseline to Week 16 in Kansas City Cardiomyopathy Questionnaire 23-item Version, Clinical Summary Score (KCCQ-23, CSS) | 1.8 Score on a scale | Standard Deviation 12.01 |
p-value: <0.000195% CI: [4.868, 14.041]Mixed Models Analysis
Secondary
Change From Baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP)
A geometric mean ratio was used to assess the change from baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP). Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.
Time frame: Baseline and week 16
Population: All randomized participants with baseline and week 16 serum concentration data
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mavacamten | Change From Baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP) | 0.35 ng/L |
| Placebo to Mavacamten | Change From Baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP) | 1.13 ng/L |
p-value: <0.000195% CI: [0.266, 0.421]Mixed Models Analysis
Secondary
Change From Baseline to Week 16 in Post-Exercise Left Ventricular Outflow Tract (LVOT) Gradient
Change from baseline to week 16 in post-exercise left ventricular outflow tract (LVOT) gradient. Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.
Time frame: Baseline and week 16
Population: All randomized participants with baseline and week 16 measurements
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mavacamten | Change From Baseline to Week 16 in Post-Exercise Left Ventricular Outflow Tract (LVOT) Gradient | -39.1 mmHg | Standard Deviation 36.51 |
| Placebo to Mavacamten | Change From Baseline to Week 16 in Post-Exercise Left Ventricular Outflow Tract (LVOT) Gradient | -1.8 mmHg | Standard Deviation 28.82 |
p-value: <0.000195% CI: [-48.08, -26.24]ANCOVA
Secondary
Number of Participants With at Least One Class Improvement From Baseline in New York Heart Association (NYHA) Class at Week 16
The NYHA functional classification of heart failure assigns participants to 1 of 4 categories based on the participants symptoms. Baseline values are defined generally as the last available value before the first administration of study drug of analysis interest. Participants with missing NYHA class assessments are treated as no improvement. Class 1: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). Class 2: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class 3: Marked limitation of physical activity. Comfortable at rest. Less-than ordinary-activity causes fatigue, palpitation, or dyspnea. Class 4: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Time frame: Baseline and week 16
Population: All randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten | Number of Participants With at Least One Class Improvement From Baseline in New York Heart Association (NYHA) Class at Week 16 | 35 Participants |
| Placebo to Mavacamten | Number of Participants With at Least One Class Improvement From Baseline in New York Heart Association (NYHA) Class at Week 16 | 12 Participants |
p-value: <0.000195% CI: [24.481, 57.662]Cochran-Mantel-Haenszel