Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
HFpEF, NT-proBNP, Cardiac troponin T
Brief summary
This is a Phase 2a proof-of-concept study to assess safety, tolerability, and preliminary efficacy of mavacamten treatment on biomarker levels in participants with heart failure with preserved ejection fraction (HFpEF) and elevation of NT-proBNP with or without elevation of cTnT. Data from this study will inform future study designs of mavacamten in patients with HFpEF.
Interventions
DRUGmavacamten
mavacamten capsules
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Is at least 50 years old at Screening. 2. Body weight is greater than 45 kg at Screening. 3. Documented prior objective evidence of heart failure as shown by 1 or more of the following criteria: * Previous hospitalization for heart failure with documented radiographic evidence of pulmonary congestion. * Elevated LV end-diastolic pressure or pulmonary capillary wedge pressure at rest (≥15 mm Hg) or with exercise (≥25 mm Hg). * Elevated level of NT-proBNP (\>400 pg/mL) or brain natriuretic peptide (BNP) (\>200 pg/mL). * Echocardiographic evidence of medial E/e' ratio ≥ 15 or left atrial enlargement (left atrial volume index \>34 mL/m2) together with chronic treatment with spironolactone, eplerenone, or a loop diuretic. 4. Meets 1 or more of the following criteria: 1. A screening hs-cTnT ≥ 99th percentile AND a screening NT-proBNP \> 200 pg/mL (if not in atrial fibrillation or atrial flutter) or \> 500 pg/mL (if in atrial fibrillation or atrial flutter) OR if the screened participant is of African descent or has a body mass index (BMI) ≥ 30.0 kg/m2, a screening hs-cTnT ≥ 99th percentile, AND a screening NT-proBNP \> 160 pg/mL (if not in atrial fibrillation or atrial flutter) or \> 400 pg/mL (if in atrial fibrillation or atrial flutter). 2. A screening NT-proBNP \> 300 pg/mL (if not in atrial fibrillation or atrial flutter) or \> 750 pg/mL (if in atrial fibrillation or atrial flutter) OR if the screened participant is of African descent or has a BMI ≥ 30.0 kg/m2, a screening NT-proBNP \> 240 pg/mL (if not in atrial fibrillation or atrial flutter) or \> 600 pg/mL (if in atrial fibrillation or atrial flutter). 5. Has documented LVEF ≥60% at the Screening visit and no history of prior LVEF ≤ 45%. 6. Has maximal left ventricular wall thickness ≥12 mm OR documented elevated left ventricular mass index by 2-dimensional imaging (\>95 g/m2 if female and \>115 g/m2 if male). 7. Has high quality TTEs without or with echocardiographic contrast agents. 8. Has NYHA class II or III symptoms at Screening. Key
Exclusion criteria
1. Has a prior diagnosis of HCM OR a known infiltrative or storage disorder causing HFpEF and/or cardiac hypertrophy, such as amyloidosis, Fabry disease, or Noonan syndrome with LV hypertrophy OR a positive serum immunofixation result. 2. Has a history of syncope within the last 6 months or sustained ventricular tachycardia with exercise within the past 6 months. 3. Has a history of resuscitated sudden cardiac arrest at any time or known appropriate implantable cardioverter defibrillator discharge within 6 months prior to Screening. 4. Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to Screening and/or is not adequately rate controlled within 6 months prior to Screening. 5. Currently treated or planned treatment during the study with either: (a) a combination of beta blocker and verapamil or a combination of beta blocker and diltiazem, (b) disopyramide, or (c) biotin or biotin-containing supplements/multivitamins. 6. Has known moderate or severe aortic valve stenosis, hemodynamically significant mitral stenosis, or severe mitral or tricuspid regurgitation at Screening. 7. Has severe chronic obstructive pulmonary disease, or other severe pulmonary disease, requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy or hospitalized for pulmonary decompensation within 12 months. 8. Has body mass index ≥45.0 kg/m2. 9. Has left ventricular global longitudinal strain by TTE in the range from 0 to -12.0 (assessed by the central laboratory). 10. Has NT-proBNP at Screening \>2000 pg/mL. 11. Has acute decompensated heart failure events requiring intravenous (IV) diuretics, IV inotropes, IV vasodilators, or a left ventricular assist device within 30 days prior to Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days) | Treatment-emergent Adverse event (TEAE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. |
| Number of Participants With Adverse Events of Special Interest (AESIs) | From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days) | Adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. AEs of special interest include: Symptomatic overdose, teratogenicity, and LVEF ≤30% |
| Number of Participants With Treatment-Emergent Serious Adverse Events (TESAEs) | From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days) | Treatment-emergent serious adverse event (TESAE) is defined as any untoward medical occurrence at any dose that: Results in death, Is immediately life-threatening (places the participant at immediate risk of death from the event as it occurred), Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions, Results in a congenital abnormality or birth defect, Is an important medical event that may not result in death, be life-threatening, or require hospitalization, but may be considered an SAE when, based upon appropriate medical judgment, it may require medical or surgical intervention to prevent any of the outcomes listed above. |
| Number of Participants With Laboratory Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs) | From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days) | Blood samples were collected to assess the abnormalities in laboratory parameters. |
| Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs) | From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days) | Treatment-emergent Adverse event (TEAE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. |
| Number of Participants With Cardiac Rhythm Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs) | From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days) | Treatment-emergent Adverse event (TEAE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. |
| Ratio to Baseline at Week 26 in Resting N-Terminal Pro B-Type Natriuretic Peptide (NT-proBNP) Levels | At Week 26 | Ratio to baseline in N-terminal pro B-type natriuretic peptide levels. The baseline value is defined as the last available value before the first administration of study drug. |
| Ratio to Baseline at Week 26 in Resting High Sensitivity Cardiac Troponin T (Hs-cTnT) Levels Assessed by High-Sensitivity Assay | At Week 26 | Ratio to Baseline in resting high sensitivity cardiac troponin T (hs-cTnT) levels. The baseline value is defined as the last available value before the first administration of study drug. |
Countries
Canada, United States
Participant flow
Pre-assignment details
30 participants enrolled and treated
Participants by arm
| Arm | Count |
|---|---|
| Mavacamten Mavacamten | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Left ventricular ejection fraction (LVEF) Criteria Met | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Mavacamten |
|---|---|
| Age, Continuous | 75.0 Years STANDARD_DEVIATION 7.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 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 | 1 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 30 |
| other Total, other adverse events | 18 / 30 |
| serious Total, serious adverse events | 5 / 30 |
Outcome results
Primary
Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs)
Treatment-emergent Adverse event (TEAE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment.
Time frame: From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days)
Population: Safety Analysis Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten | Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs) | 4 Participants |
Primary
Number of Participants With Adverse Events of Special Interest (AESIs)
Adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. AEs of special interest include: Symptomatic overdose, teratogenicity, and LVEF ≤30%
Time frame: From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days)
Population: Safety Analysis Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mavacamten | Number of Participants With Adverse Events of Special Interest (AESIs) | Symptomatic Overdose | 0 Participants |
| Mavacamten | Number of Participants With Adverse Events of Special Interest (AESIs) | Outcomes of Pregnancy | 0 Participants |
| Mavacamten | Number of Participants With Adverse Events of Special Interest (AESIs) | Left Ventricular Ejection Fraction (LVEF) ≤30% | 0 Participants |
Primary
Number of Participants With Cardiac Rhythm Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs)
Treatment-emergent Adverse event (TEAE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment.
Time frame: From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days)
Population: Safety Analysis Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten | Number of Participants With Cardiac Rhythm Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs) | 5 Participants |
Primary
Number of Participants With Laboratory Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs)
Blood samples were collected to assess the abnormalities in laboratory parameters.
Time frame: From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days)
Population: Safety Analysis Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten | Number of Participants With Laboratory Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs) | 4 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Treatment-emergent Adverse event (TEAE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment.
Time frame: From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days)
Population: Safety Analysis Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 23 Participants |
Primary
Number of Participants With Treatment-Emergent Serious Adverse Events (TESAEs)
Treatment-emergent serious adverse event (TESAE) is defined as any untoward medical occurrence at any dose that: Results in death, Is immediately life-threatening (places the participant at immediate risk of death from the event as it occurred), Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions, Results in a congenital abnormality or birth defect, Is an important medical event that may not result in death, be life-threatening, or require hospitalization, but may be considered an SAE when, based upon appropriate medical judgment, it may require medical or surgical intervention to prevent any of the outcomes listed above.
Time frame: From the first dose of study drug through 56 days following last dose of study drug (assessed for an average of 225 days up to a max of approximately 270 days)
Population: Safety Analysis Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mavacamten | Number of Participants With Treatment-Emergent Serious Adverse Events (TESAEs) | 5 Participants |
Primary
Ratio to Baseline at Week 26 in Resting High Sensitivity Cardiac Troponin T (Hs-cTnT) Levels Assessed by High-Sensitivity Assay
Ratio to Baseline in resting high sensitivity cardiac troponin T (hs-cTnT) levels. The baseline value is defined as the last available value before the first administration of study drug.
Time frame: At Week 26
Population: All Intention-To-Treat Participants
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mavacamten | Ratio to Baseline at Week 26 in Resting High Sensitivity Cardiac Troponin T (Hs-cTnT) Levels Assessed by High-Sensitivity Assay | 0.8645 Ratio |
Primary
Ratio to Baseline at Week 26 in Resting N-Terminal Pro B-Type Natriuretic Peptide (NT-proBNP) Levels
Ratio to baseline in N-terminal pro B-type natriuretic peptide levels. The baseline value is defined as the last available value before the first administration of study drug.
Time frame: At Week 26
Population: All Intention-To-Treat Participants
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mavacamten | Ratio to Baseline at Week 26 in Resting N-Terminal Pro B-Type Natriuretic Peptide (NT-proBNP) Levels | 0.7354 Ratio |