Pulmonary Hypertension
Conditions
Keywords
pre- and post-capillary pulmonary hypertension, CpcPH
Brief summary
Study to evaluate if macitentan is safe and tolerable enough to be used for treatment of subjects with combined pre- and post-capillary pulmonary hypertension (CpcPH) due to left ventricular dysfunction.
Interventions
DRUGMacitentan
oral tablet, 10 mg once daily
DRUGPlacebo
matching placebo
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
1. Males and Females \>=18 years of age 2. Subjects with combined pre-and post-capillary Pulmonary Hypertension (CpcPH) due to left ventricular dysfunction (subset of WHO groups 2.1 and 2.2) 3. Optimized diuretic therapy
Exclusion criteria
1. Types of Pulmonary Hypertension other than WHO groups 2.1 and 2.2 (Nice classification) 2. Administration of PAH-specific therapy (i.e., Endothelin receptor antagonists (ERAs), Prostanoids, Phosphodiesterase 5 (PDE-5) inhibitors, guanylate cyclase stimulators)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | From randomization up to End-of-Study (Week 12 + 30 days follow-up) plus 1 calendar day | The main endpoint is the number of participants who had at least one of the following: A) significant fluid retention, defined as increase in body weight at any time by ≥ 5% or ≥ 5 kg from baseline due to fluid overload and/or parenteral administration of diuretics. B) Worsening of NYHA functional class from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest | From randomization up to end of treatment period (Week 12) | Pulmonary vascular resistance (PVR) was assessed at rest by right heart catheterization (RHC). |
| Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | From randomization up to end of treatment period (Week 12) | — |
| Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | From randomization up to end of treatment period (Week 12) | — |
| NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest | From randomization up to end of treatment period (Week 12) | — |
| Change From Baseline to Week 12 in Cardiac Index (CI) | From randomization up to end of treatment period (Week 12) | — |
| Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) | From randomization up to end of treatment period (Week 12) | — |
| Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) | From randomization up to end of treatment period (Week 12) | — |
Countries
Austria, Belgium, Canada, Czechia, France, Germany, Israel, Italy, Spain, Switzerland, United States
Participant flow
Recruitment details
Participants were screened from 28 sites across Europe and North America in 11 countries (Austria, Belgium, Canada, Czech Republic, Germany, France, Israel, Italy, Spain, Switzerland, USA).
Pre-assignment details
Of the 88 participants screened 63 were randomized in a 1:1 ratio to macitentan 10 mg (N = 31) or placebo (N = 32).
Participants by arm
| Arm | Count |
|---|---|
| Macitentan Macitentan 10 mg to be taken once daily, oral use, film-coated tablet | 31 |
| Placebo Matching placebo to be taken once daily, oral use, film-coated tablet | 32 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Macitentan |
|---|---|---|---|
| 6-minute walk distance (6MWD) at baseline | 305.0 meter | 300.0 meter | 300.0 meter |
| Age, Continuous | 72.0 Years | 71.0 Years | 70.0 Years |
| Age, Customized 18-64 years | 3 Participants | 8 Participants | 5 Participants |
| Age, Customized 65-84 years | 28 Participants | 54 Participants | 26 Participants |
| Age, Customized ≥ 85 years | 1 Participants | 1 Participants | 0 Participants |
| Body Mass Index (BMI) at baseline | 31.15 kg/m^2 | 32.40 kg/m^2 | 33.30 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 61 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Left Ventricular Ejection Fraction (LEVF) at baseline as measured by Investigator < 50% | 9 Participants | 15 Participants | 6 Participants |
| Left Ventricular Ejection Fraction (LEVF) at baseline as measured by Investigator ≥ 50% | 23 Participants | 48 Participants | 25 Participants |
| New York Heart Association (NYHA) Functional Class at baseline Class I | 0 Participants | 0 Participants | 0 Participants |
| New York Heart Association (NYHA) Functional Class at baseline Class II | 10 Participants | 15 Participants | 5 Participants |
| New York Heart Association (NYHA) Functional Class at baseline Class III | 22 Participants | 48 Participants | 26 Participants |
| New York Heart Association (NYHA) Functional Class at baseline Class IV | 0 Participants | 0 Participants | 0 Participants |
| Participants with Atrial Fibrillation at baseline No | 8 Participants | 17 Participants | 9 Participants |
| Participants with Atrial Fibrillation at baseline Yes | 24 Participants | 46 Participants | 22 Participants |
| Participants with Chronic Kidney Disease (CKD) No | 26 Participants | 49 Participants | 23 Participants |
| Participants with Chronic Kidney Disease (CKD) Yes | 6 Participants | 14 Participants | 8 Participants |
| Participants with Diabetes Mellitus Type II No | 19 Participants | 36 Participants | 17 Participants |
| Participants with Diabetes Mellitus Type II Yes | 13 Participants | 27 Participants | 14 Participants |
| Participants with obesity (BMI > 30 kg/m^2) No | 12 Participants | 23 Participants | 11 Participants |
| Participants with obesity (BMI > 30 kg/m^2) Yes | 20 Participants | 40 Participants | 20 Participants |
| Participants with Right Heart Failure (RHF) No | 21 Participants | 45 Participants | 24 Participants |
| Participants with Right Heart Failure (RHF) Yes | 11 Participants | 18 Participants | 7 Participants |
| Participants with Systemic Hypertension No | 5 Participants | 6 Participants | 1 Participants |
| Participants with Systemic Hypertension Yes | 27 Participants | 57 Participants | 30 Participants |
| Pulmonary Vascular Resistance (PVR) at baseline | 483.5 dyn*sec/cm^5 | 462.0 dyn*sec/cm^5 | 450.0 dyn*sec/cm^5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 30 Participants | 60 Participants | 30 Participants |
| Sex: Female, Male Female | 16 Participants | 41 Participants | 25 Participants |
| Sex: Female, Male Male | 16 Participants | 22 Participants | 6 Participants |
| Time from Combined pre- and post-capillary Pulmonary Hypertension (CpcPH) diagnosis | 0.2 years | 0.2 years | 0.2 years |
| Time from Left Ventricular Dysfunction (LVD) diagnosis | 1.5 years | 1.3 years | 0.9 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 31 | 0 / 32 |
| other Total, other adverse events | 16 / 31 | 15 / 32 |
| serious Total, serious adverse events | 11 / 31 | 6 / 32 |
Outcome results
Primary
Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment
The main endpoint is the number of participants who had at least one of the following: A) significant fluid retention, defined as increase in body weight at any time by ≥ 5% or ≥ 5 kg from baseline due to fluid overload and/or parenteral administration of diuretics. B) Worsening of NYHA functional class from baseline.
Time frame: From randomization up to End-of-Study (Week 12 + 30 days follow-up) plus 1 calendar day
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | Participants with worsening in NYHA FC | 1 Participants |
| Macitentan | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | Total participants with at least one condition | 7 Participants |
| Macitentan | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | Participants with both conditions | 1 Participants |
| Macitentan | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | Participants with fluid retention | 7 Participants |
| Placebo | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | Participants with both conditions | 1 Participants |
| Placebo | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | Participants with worsening in NYHA FC | 2 Participants |
| Placebo | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | Total participants with at least one condition | 4 Participants |
| Placebo | Number of Participants Experiencing Significant Fluid Retention or Worsening in NYHA Functional Class (FC) up to End-of-treatment | Participants with fluid retention | 3 Participants |
p-value: 0.337295% CI: [-15.07, 33.26]Fisher Exact
Secondary
Change From Baseline to Week 12 in Cardiac Index (CI)
Time frame: From randomization up to end of treatment period (Week 12)
Population: The values of 11 patients in the macitentan group and of 8 patients in the placebo group are missing.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Macitentan | Change From Baseline to Week 12 in Cardiac Index (CI) | Change in CI from baseline to Week 12 | 0.37 L/min/m^2 |
| Macitentan | Change From Baseline to Week 12 in Cardiac Index (CI) | CI at baseline | 2.32 L/min/m^2 |
| Macitentan | Change From Baseline to Week 12 in Cardiac Index (CI) | CI at Week 12 | 2.69 L/min/m^2 |
| Placebo | Change From Baseline to Week 12 in Cardiac Index (CI) | CI at Week 12 | 2.30 L/min/m^2 |
| Placebo | Change From Baseline to Week 12 in Cardiac Index (CI) | CI at baseline | 2.33 L/min/m^2 |
| Placebo | Change From Baseline to Week 12 in Cardiac Index (CI) | Change in CI from baseline to Week 12 | -0.03 L/min/m^2 |
95% CI: [0.11, 0.69]
Secondary
Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG)
Time frame: From randomization up to end of treatment period (Week 12)
Population: The values of 11 patients in the macitentan group and of 8 patients in the placebo group are missing.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Macitentan | Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) | DPG at Week 12 | 7.0 mmHg |
| Macitentan | Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) | Change in DPG from baseline to Week 12 | -4.8 mmHg |
| Macitentan | Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) | DPG at baseline | 11.8 mmHg |
| Placebo | Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) | DPG at baseline | 11.4 mmHg |
| Placebo | Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) | DPG at Week 12 | 7.0 mmHg |
| Placebo | Change From Baseline to Week 12 in Diastolic Pulmonary Vascular Pressure Gradient (DPG) | Change in DPG from baseline to Week 12 | -4.3 mmHg |
95% CI: [-4.5, 3.6]
Secondary
Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP)
Time frame: From randomization up to end of treatment period (Week 12)
Population: The values of 10 patients in the macitentan group and of 7 patients in the placebo group are missing.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Macitentan | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | mPAP at Week 12 | 41.1 mmHg |
| Macitentan | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | Change in mPAP from baseline to Week 12 | -3.5 mmHg |
| Macitentan | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | mPAP at baseline | 44.6 mmHg |
| Placebo | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | mPAP at Week 12 | 42.1 mmHg |
| Placebo | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | Change in mPAP from baseline to Week 12 | -3.8 mmHg |
| Placebo | Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP) | mPAP at baseline | 45.9 mmHg |
95% CI: [-4.3, 4.9]
Secondary
Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
Time frame: From randomization up to end of treatment period (Week 12)
Population: The values of 10 patients in the macitentan group and of 7 patients in the placebo group are missing.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Macitentan | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | mRAP at baseline | 12.1 mmHg |
| Macitentan | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | mRAP at Week 12 | 11.2 mmHg |
| Macitentan | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | Change in mRAP from baseline to Week 12 | -0.9 mmHg |
| Placebo | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | mRAP at baseline | 13.0 mmHg |
| Placebo | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | mRAP at Week 12 | 11.3 mmHg |
| Placebo | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | Change in mRAP from baseline to Week 12 | -1.6 mmHg |
95% CI: [-2.2, 3.6]
Secondary
Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP)
Time frame: From randomization up to end of treatment period (Week 12)
Population: The values of 11 patients in the macitentan group and of 8 patients in the placebo group are missing.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Macitentan | Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) | PAWP at baseline | 19.1 mmHg |
| Macitentan | Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) | PAWP at Week 12 | 19.9 mmHg |
| Macitentan | Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) | Change in PAWP from baseline to Week 12 | 0.8 mmHg |
| Placebo | Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) | PAWP at baseline | 19.7 mmHg |
| Placebo | Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) | PAWP at Week 12 | 20.8 mmHg |
| Placebo | Change From Baseline to Week 12 in Pulmonary Artery Wedge Pressure (PAWP) | Change in PAWP from baseline to Week 12 | 1.1 mmHg |
95% CI: [-4.2, 3.7]
Secondary
NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest
Time frame: From randomization up to end of treatment period (Week 12)
Population: The values of 6 patients are missing in both the macitentan and the placebo group.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Macitentan | NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest | 91.56 percentage of baseline NT-proBNP |
| Placebo | NT-proBNP at Week 12 Expressed as Percent of Baseline NT-proBNP at Rest | 118.90 percentage of baseline NT-proBNP |
95% CI: [0.55, 1.08]
Secondary
PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest
Pulmonary vascular resistance (PVR) was assessed at rest by right heart catheterization (RHC).
Time frame: From randomization up to end of treatment period (Week 12)
Population: The values of 11 patients in the macitentan group and of 8 patients in the placebo group are missing.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Macitentan | PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest | 66.31 percentage of baseline PVR |
| Placebo | PVR at Rest at Week 12 Expressed as Percent of Baseline PVR at Rest | 71.23 percentage of baseline PVR |
95% CI: [0.64, 1.36]