Heart Failure With Preserved Ejection Fraction
Conditions
Brief summary
This is a study to evaluate whether macitentan is an effective and safe treatment for patients with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease. The primary objective is to evaluate whether macitentan 10 mg reduces N-terminal pro-brain natriuretic peptide (NT-pro-BNP) as compared to placebo in these patients.
Interventions
DRUGMacitentan
macitentan 10 mg; film-coated tablet; oral use
DRUGPlacebo
film-coated tablet (identical to the macitentan tablet); oral use
Sponsors
Actelion
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
* Signs or symptoms of Heart Failure (HF) (NYHA FC I I and II I ) requiring treatment with at least one oral diuretic (any type) * Left ventricular ejection fraction (LVEF) ≥ 40% (by echocardiography at Screening) * Structural heart disease consistent with heart failure with preserved ejection fraction (HFpEF) established by echocardiography at Screening * Elevated NT-proBNP * Pulmonary vascular disease or right ventricular dysfunction
Exclusion criteria
* Any prior valid measurement of LVEF \< 40%. An echocardiogram is considered valid if its quality is sufficient to allow accurate assessment of LVEF and if it is reflective of the true status of the subject * Cardiovascular co-morbidities (e.g., significant unrepaired structural valvular heart disease; acute coronary syndrome, coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) within 3 months of Screening; uncontrolled heart rate from atrial fibrillation or atrial flutter, history of serious life-threatening or hemodynamically significant arrhythmia; history of or anticipated heart transplant or ventricular assist device implantation, etc) * Systolic blood pressure (SBP) ≥ 180 mmHg, or diastolic blood pressure (DBP) ≥ 110 mmHg during Screening * Hemoglobin \< 100g/L (\< 10 g/dl) at Screening * Significant parenchymal lung disease (e.g., severe COPD, moderate or severe restrictive lung disease, diffuse interstitial fibrosis or alveolitis, pulmonary thromboembolism) * Severe renal dysfunction with an estimated Glomerular Filtration Rate (eGFR) \< 30 mL/min per 1.73 m2 * Severe hepatic impairment, e.g., Child Pugh Class C Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Baseline N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assessed at Week 24 | Week 24 | Percent of baseline NT-proBNP assessed at Week 24 was reported. Percent of baseline is calculated as the ratio of the Week 24 NT-proBNP value over baseline value, expressed in percentage. NT-proBNP is one of the best established cardiovascular response markers among all available surrogates in heart failure (HF). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in the Clinical Summary Score Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) Score | Baseline to Week 24 | The KCCQ is a validated health related quality of life measure for heart failure. The KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Clinical summary score is one of the quality of life variable of interest derived from KCCQ. Clinical summary score is the mean of domains: physical limitations score (6 items) and total symptom score (2 items \[symptoms frequency and symptom burden\]). The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status. |
| Change From Baseline to Week 24 in Accelerometer-assessed Proportion of Time Spent in Light to Vigourous Physical Activity | Baseline to Week 24 | Physical activity is assessed by accelerometer as the proportion of time spent in light to vigorous physical activity based on a threshold of greater than (\>)100 activity counts per minute and expressed as change from baseline to Week 24. |
| Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Weeks 16, 24, 36, 52 | Number of participants with WHF events were reported. A WHF event includes HF death, hospitalization for WHF or an urgent visit for WHF. |
Countries
Argentina, Austria, Brazil, Bulgaria, Czechia, Denmark, France, Germany, Hungary, Israel, Poland, Romania, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
Out of 143 enrolled participants, 1 participant was randomized by mistake and did not receive any dose of study drug. 142 participants received the study drug and were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Macitentan Participants received macitentan 10 milligrams (mg) tablet orally once a day starting from Day 1 up to Week 52. | 71 |
| Placebo Participants received placebo tablet orally once a day starting from Day 1 up to Week 52. | 71 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 5 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 5 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Macitentan | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 72.9 years STANDARD_DEVIATION 10.11 | 73.6 years STANDARD_DEVIATION 9.22 | 74.2 years STANDARD_DEVIATION 8.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants | 136 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 68 Participants | 135 Participants | 67 Participants |
| Region of Enrollment ARGENTINA | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment AUSTRIA | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment BRAZIL | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment BULGARIA | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment CZECH REPUBLIC | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment DENMARK | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment FRANCE | 2 Participants | 6 Participants | 4 Participants |
| Region of Enrollment GERMANY | 9 Participants | 13 Participants | 4 Participants |
| Region of Enrollment HUNGARY | 3 Participants | 9 Participants | 6 Participants |
| Region of Enrollment ISRAEL | 13 Participants | 27 Participants | 14 Participants |
| Region of Enrollment POLAND | 3 Participants | 8 Participants | 5 Participants |
| Region of Enrollment ROMANIA | 5 Participants | 7 Participants | 2 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 9 Participants | 20 Participants | 11 Participants |
| Region of Enrollment SPAIN | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment SWEDEN | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment UNITED KINGDOM | 4 Participants | 5 Participants | 1 Participants |
| Region of Enrollment UNITED STATES | 13 Participants | 24 Participants | 11 Participants |
| Sex: Female, Male Female | 46 Participants | 87 Participants | 41 Participants |
| Sex: Female, Male Male | 25 Participants | 55 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 71 | 5 / 71 |
| other Total, other adverse events | 57 / 71 | 54 / 71 |
| serious Total, serious adverse events | 29 / 71 | 23 / 71 |
Outcome results
Primary
Percent of Baseline N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assessed at Week 24
Percent of baseline NT-proBNP assessed at Week 24 was reported. Percent of baseline is calculated as the ratio of the Week 24 NT-proBNP value over baseline value, expressed in percentage. NT-proBNP is one of the best established cardiovascular response markers among all available surrogates in heart failure (HF).
Time frame: Week 24
Population: Full analysis set (FAS) included participants which were randomized to double-blind study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Macitentan | Percent of Baseline N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assessed at Week 24 | 108.39 percentage of baseline NT-proBNP | Geometric Coefficient of Variation 0.65 |
| Placebo | Percent of Baseline N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assessed at Week 24 | 106.27 percentage of baseline NT-proBNP | Geometric Coefficient of Variation 0.55 |
p-value: 0.792390% CI: [0.88, 1.19]ANCOVA
Secondary
Change From Baseline to Week 24 in Accelerometer-assessed Proportion of Time Spent in Light to Vigourous Physical Activity
Physical activity is assessed by accelerometer as the proportion of time spent in light to vigorous physical activity based on a threshold of greater than (\>)100 activity counts per minute and expressed as change from baseline to Week 24.
Time frame: Baseline to Week 24
Population: FAS included participants which were randomized to double-blind study treatment. Here, 'N' (number of participants analyzed) specifies all participants who were evaluated for this OM.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan | Change From Baseline to Week 24 in Accelerometer-assessed Proportion of Time Spent in Light to Vigourous Physical Activity | -0.024 proportion of time spent | Standard Deviation 0.084 |
| Placebo | Change From Baseline to Week 24 in Accelerometer-assessed Proportion of Time Spent in Light to Vigourous Physical Activity | -0.005 proportion of time spent | Standard Deviation 0.098 |
p-value: 0.366590% CI: [-0.05, 0.02]ANCOVA
Secondary
Change From Baseline to Week 24 in the Clinical Summary Score Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) Score
The KCCQ is a validated health related quality of life measure for heart failure. The KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Clinical summary score is one of the quality of life variable of interest derived from KCCQ. Clinical summary score is the mean of domains: physical limitations score (6 items) and total symptom score (2 items \[symptoms frequency and symptom burden\]). The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status.
Time frame: Baseline to Week 24
Population: FAS included participants which were randomized to double-blind study treatment. Here, 'N' (number of participants analyzed) specifies all participants who were evaluated for this outcome measure (OM).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Macitentan | Change From Baseline to Week 24 in the Clinical Summary Score Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) Score | -2.37 score on a scale | Standard Deviation 16.12 |
| Placebo | Change From Baseline to Week 24 in the Clinical Summary Score Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) Score | 0.89 score on a scale | Standard Deviation 17.72 |
p-value: 0.217290% CI: [-8.17, 1.17]ANCOVA
Secondary
Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks
Number of participants with WHF events were reported. A WHF event includes HF death, hospitalization for WHF or an urgent visit for WHF.
Time frame: Weeks 16, 24, 36, 52
Population: FAS included participants which were randomized to double-blind study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Week 16 | 12 Participants |
| Macitentan | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Week 24 | 14 Participants |
| Macitentan | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Week 36 | 17 Participants |
| Macitentan | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Week 52 | 18 Participants |
| Placebo | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Week 52 | 13 Participants |
| Placebo | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Week 16 | 5 Participants |
| Placebo | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Week 36 | 9 Participants |
| Placebo | Number of Participants With Worsening of Heart Failure (WHF) Events Over 52 Weeks | Week 24 | 6 Participants |