Portopulmonary Hypertension
Conditions
Brief summary
24-week study to evaluate the efficacy and safety of macitentan for the treatment of portopulmonary hypertension.
Interventions
DRUGMacitentan
Macitentan film-coated tablet 10 mg once daily.
OTHERPlacebo
Matching placebo tablet once daily.
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
Main Inclusion Criteria: * Male or female of at least 18 years of age * Confirmed diagnosis of portopulmonary hypertension Main
Exclusion criteria
* Severe hepatic impairment * Severe obstructive or restrictive lung disease * Pulmonary veno-occlusive disease * Systolic blood pressure (SBP) \< 90 mmHg at Screening * ALT/AST \>= 3 x ULN * Bilirubin \>= 3 mg/dL at Screening * Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR). | From enrollment/baseline to Week 12 in the Double Blind (DB) treatment period | The relative change from baseline to Week 12 in PVR is expressed as a ratio of Week 12 to baseline PVR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in WHO Functional Class (FC) | From enrollment/baseline to Week 12 in the DB treatment period | Changes from baseline to Week 12 in WHO FC were dichotomized as worsening (i.e., change \> 0) versus no change or improvement (i.e., change ≤ 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure. |
| Change From Baseline to Week 12 in the Biomarker N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | From enrollment/baseline to Week 12 in the DB treatment period | NT-proBNP functions as a strong indicator of prognosis in patients with pulmonary hypertension (PH). The relative change from baseline to Week 12 in NT-proBNP is expressed as a ratio of Week 12 to baseline NT-proBNP. |
| Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | From enrollment/baseline to Week 12 in the DB treatment period | mRAP is the mean blood pressure in the right atrium of the heart. |
| Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD) | From enrollment/baseline to Week 12 in the DB treatment period | The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. |
| Change From Baseline to Week 12 in Cardiac Index | From enrollment/baseline to Week 12 in the DB treatment period | The cardiac index is an assessment of the function of the heart and relates the cardiac output to the patient's body size (the patient's body surface area). |
| Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | From enrollment/baseline to Week 12 in the DB treatment period | TPR is the resistance the pulmonary circulation that must be overcome in order for the blood flow to occur. It takes into account the blood pressure in the pulmonary arteries and the cardiac output. It is an important measurement to monitor the function of the pulmonary circulation and detect disease progression or improvement. |
| Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2) | From enrollment/baseline to Week 12 in the DB treatment period | SVO2 help assess tissue oxygen delivery. It describes the percentage of oxygen bound to hemoglobin in the blood which returns to the heart. This reflects the amount of residual oxygen in the blood after oxygen extraction by the tissues throughout the body. |
| Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP) | From enrollment/baseline to Week 12 in the DB treatment period | mPAP is the mean blood pressure inside the pulmonary artery which moves the blood from the heart to the lungs. Monitoring of mPAP can detect small changes in the function of the heart. |
Countries
Brazil, Czechia, France, Germany, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants at 39 sites in 7 countries were screened and were randomized at 36 sites in these 7 countries (Brazil, Czech Republic, France, Germany, Spain, UK and US).
Pre-assignment details
A total of 119 participants were screened and 85 participants were randomized (43 to macitentan 10 mg once daily and 42 to matching placebo) and received double-blind (DB) study treatment. Overall, 80 participants who completed DB treatment period entered the open-label (OL) treatment period and 33 participants in open-label extension (OLE) period.
Participants by arm
| Arm | Count |
|---|---|
| Macitentan 10 mg Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. | 43 |
| Placebo Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. | 42 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind (DB) Treatment Period | Lack of Efficacy | 1 | 0 |
| Double-blind (DB) Treatment Period | Physician Decision | 3 | 0 |
| Double-blind (DB) Treatment Period | Withdrawal by Subject | 0 | 1 |
| OL Extension Period | Death | 2 | 0 |
| OL Extension Period | Physician Decision | 3 | 0 |
| OL Extension Period | Withdrawal by Subject | 1 | 0 |
| Open-label (OL) Treatment Period | Death | 4 | 0 |
| Open-label (OL) Treatment Period | Physician Decision | 3 | 0 |
| Open-label (OL) Treatment Period | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Macitentan 10 mg | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 13 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 29 Participants | 64 Participants |
| Age, Continuous | 58.0 years STANDARD_DEVIATION 8.7 | 59.0 years STANDARD_DEVIATION 9.5 | 58.5 years STANDARD_DEVIATION 9.1 |
| Body Mass Index (BMI) at baseline | 29.01 Kilogram per meter^2 (Kg/m^2) STANDARD_DEVIATION 4.79 | 29.33 Kilogram per meter^2 (Kg/m^2) STANDARD_DEVIATION 4.04 | 29.17 Kilogram per meter^2 (Kg/m^2) STANDARD_DEVIATION 4.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 15 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 21 Participants | 39 Participants |
| Pulmonary arterial hypertension (PAH)-specific therapy No | 16 Participants | 15 Participants | 31 Participants |
| Pulmonary arterial hypertension (PAH)-specific therapy Yes | 27 Participants | 27 Participants | 54 Participants |
| Pulmonary vascular resistance (PVR) at baseline (calculated) | 552.4 Dyn*sec/cm^5 STANDARD_DEVIATION 192.8 | 521.7 Dyn*sec/cm^5 STANDARD_DEVIATION 163.3 | 537.2 Dyn*sec/cm^5 STANDARD_DEVIATION 178.4 |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Applicable | 18 Participants | 21 Participants | 39 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 23 Participants | 21 Participants | 44 Participants |
| Region of Enrollment Brazil | 2 Participants | 3 Participants | 5 Participants |
| Region of Enrollment Czech Republic | 1 Participants | 3 Participants | 4 Participants |
| Region of Enrollment France | 18 Participants | 21 Participants | 39 Participants |
| Region of Enrollment Germany | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Spain | 4 Participants | 0 Participants | 4 Participants |
| Region of Enrollment United Kingdom | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Female | 21 Participants | 20 Participants | 41 Participants |
| Sex: Female, Male Male | 22 Participants | 22 Participants | 44 Participants |
| Time since PAH diagnosis | 7 Months | 12 Months | 10 Months |
| Time since portal hypertension diagnosis | 23 Months | 31 Months | 25 Months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 42 | 4 / 80 | 2 / 33 |
| other Total, other adverse events | 34 / 43 | 32 / 42 | 62 / 80 | 30 / 33 |
| serious Total, serious adverse events | 9 / 43 | 6 / 42 | 18 / 80 | 11 / 33 |
Outcome results
Primary
Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR).
The relative change from baseline to Week 12 in PVR is expressed as a ratio of Week 12 to baseline PVR.
Time frame: From enrollment/baseline to Week 12 in the Double Blind (DB) treatment period
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Macitentan 10 mg | Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR). | 0.63 ratio |
| Placebo | Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR). | 0.98 ratio |
Comparison: The null hypothesis (change of PVR at Week 12 as a ratio of baseline PVR in subjects treated with placebo or macitentan is the same) is tested on the primary endpoint by means of an analysis of covariance (ANCOVA) model on the log(e) transformed ratio of PVR at Week 12 to baseline PVR.p-value: 0.000195% CI: [0.59, 0.72]ANCOVA
Secondary
Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD)
The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.
Time frame: From enrollment/baseline to Week 12 in the DB treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD) | 6MWD at baseline | 385.8 meter | Standard Deviation 99.97 |
| Macitentan 10 mg | Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD) | 6MWD at Week 12 | 392.2 meter | Standard Deviation 98.46 |
| Macitentan 10 mg | Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD) | Change of 6MWD from baseline to Week 12 | 6.4 meter | Standard Deviation 65.74 |
| Placebo | Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD) | 6MWD at baseline | 383.2 meter | Standard Deviation 108.9 |
| Placebo | Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD) | 6MWD at Week 12 | 380.8 meter | Standard Deviation 114.98 |
| Placebo | Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD) | Change of 6MWD from baseline to Week 12 | -2.4 meter | Standard Deviation 43.65 |
Comparison: The main analysis on 6MWD was performed using a mixed-effect model repeated measure (MMRM) adjusted for treatment, visit, region, PAH-specific therapy at baseline, and treatment-by-visit interaction as factors, and baseline 6MWD and WHO functional class (FC) as covariates.p-value: 0.426495% CI: [-14.5, 33.95]mixed-effect model repeated measure
Secondary
Change From Baseline to Week 12 in Cardiac Index
The cardiac index is an assessment of the function of the heart and relates the cardiac output to the patient's body size (the patient's body surface area).
Time frame: From enrollment/baseline to Week 12 in the DB treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline to Week 12 in Cardiac Index | Cardiac index at baseline | 3.1 L/min/m^2 | Standard Deviation 0.83 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Cardiac Index | Cardiac index at Week 12 | 3.7 L/min/m^2 | Standard Deviation 1.04 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Cardiac Index | Change in cardiac index at Week 12 | 0.6 L/min/m^2 | Standard Deviation 0.8 |
| Placebo | Change From Baseline to Week 12 in Cardiac Index | Cardiac index at baseline | 2.9 L/min/m^2 | Standard Deviation 0.76 |
| Placebo | Change From Baseline to Week 12 in Cardiac Index | Cardiac index at Week 12 | 3.0 L/min/m^2 | Standard Deviation 0.82 |
| Placebo | Change From Baseline to Week 12 in Cardiac Index | Change in cardiac index at Week 12 | 0.1 L/min/m^2 | Standard Deviation 0.6 |
p-value: 0.000995% CI: [0.22, 0.81]ANCOVA
Secondary
Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP)
mPAP is the mean blood pressure inside the pulmonary artery which moves the blood from the heart to the lungs. Monitoring of mPAP can detect small changes in the function of the heart.
Time frame: From enrollment/baseline to Week 12 in the DB treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP) | mPAP at baseline | 46.4 mmHg | Standard Deviation 7.89 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP) | mPAP at Week 12 | 40.0 mmHg | Standard Deviation 7.61 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP) | Change in mPAP at Week 12 | -6.4 mmHg | Standard Deviation 4.94 |
| Placebo | Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP) | mPAP at baseline | 43.8 mmHg | Standard Deviation 8.52 |
| Placebo | Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP) | mPAP at Week 12 | 44.2 mmHg | Standard Deviation 8.26 |
| Placebo | Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP) | Change in mPAP at Week 12 | 0.4 mmHg | Standard Deviation 7.04 |
p-value: 0.000195% CI: [-8.4, -3.57]ANCOVA
Secondary
Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
mRAP is the mean blood pressure in the right atrium of the heart.
Time frame: From enrollment/baseline to Week 12 in the DB treatment period
Population: Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, 'N'(number of participants analyzed included population included participants with available baseline data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | mRAP at baseline | 7.3 mmHg | Standard Deviation 3.74 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | mRAP at Week 12 | 9.0 mmHg | Standard Deviation 5.32 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | Change in mRAP from baseline to Week 12 | 1.6 mmHg | Standard Deviation 5.55 |
| Placebo | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | mRAP at baseline | 6.7 mmHg | Standard Deviation 3.6 |
| Placebo | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | mRAP at Week 12 | 7.0 mmHg | Standard Deviation 2.93 |
| Placebo | Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP) | Change in mRAP from baseline to Week 12 | 0.3 mmHg | Standard Deviation 3.29 |
p-value: 0.063795% CI: [-0.1, 3.44]ANCOVA
Secondary
Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2)
SVO2 help assess tissue oxygen delivery. It describes the percentage of oxygen bound to hemoglobin in the blood which returns to the heart. This reflects the amount of residual oxygen in the blood after oxygen extraction by the tissues throughout the body.
Time frame: From enrollment/baseline to Week 12 in the DB treatment period
Population: Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, 'N'(number of participants analyzed included population included participants with available baseline data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2) | SVO2 at baseline | 69.2 percent of oxygen bound to hemoglobin | Standard Deviation 9.87 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2) | SVO2 at Week 12 | 70.3 percent of oxygen bound to hemoglobin | Standard Deviation 7.07 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2) | Change in SVO2 from baseline to Week 12 | 1.1 percent of oxygen bound to hemoglobin | Standard Deviation 6.7 |
| Placebo | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2) | SVO2 at baseline | 69.9 percent of oxygen bound to hemoglobin | Standard Deviation 5.34 |
| Placebo | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2) | SVO2 at Week 12 | 70.7 percent of oxygen bound to hemoglobin | Standard Deviation 8.58 |
| Placebo | Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2) | Change in SVO2 from baseline to Week 12 | 0.8 percent of oxygen bound to hemoglobin | Standard Deviation 7.81 |
p-value: 0.984495% CI: [-2.85, 2.91]ANCOVA
Secondary
Change From Baseline to Week 12 in the Biomarker N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)
NT-proBNP functions as a strong indicator of prognosis in patients with pulmonary hypertension (PH). The relative change from baseline to Week 12 in NT-proBNP is expressed as a ratio of Week 12 to baseline NT-proBNP.
Time frame: From enrollment/baseline to Week 12 in the DB treatment period
Population: Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, 'N'(number of participants analyzed included population included participants with available baseline data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Macitentan 10 mg | Change From Baseline to Week 12 in the Biomarker N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | 0.86 ratio |
| Placebo | Change From Baseline to Week 12 in the Biomarker N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | 1.04 ratio |
p-value: 0.395195% CI: [0.639, 1.196]ANCOVA
Secondary
Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR)
TPR is the resistance the pulmonary circulation that must be overcome in order for the blood flow to occur. It takes into account the blood pressure in the pulmonary arteries and the cardiac output. It is an important measurement to monitor the function of the pulmonary circulation and detect disease progression or improvement.
Time frame: From enrollment/baseline to Week 12 in the DB treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan 10 mg | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | TPR at baseline | 689.3 dyn*sec/cm^5 | Standard Deviation 228.59 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | TPR at Week 12 | 489.4 dyn*sec/cm^5 | Standard Deviation 157.13 |
| Macitentan 10 mg | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | Change in TPR from baseline to Week 12 | -199.8 dyn*sec/cm^5 | Standard Deviation 163.06 |
| Placebo | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | TPR at baseline | 671.5 dyn*sec/cm^5 | Standard Deviation 199.73 |
| Placebo | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | TPR at Week 12 | 653.1 dyn*sec/cm^5 | Standard Deviation 197.88 |
| Placebo | Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR) | Change in TPR from baseline to Week 12 | -18.3 dyn*sec/cm^5 | Standard Deviation 135.28 |
p-value: 0.000195% CI: [-223.67, -119.3]ANCOVA
Secondary
Change From Baseline to Week 12 in WHO Functional Class (FC)
Changes from baseline to Week 12 in WHO FC were dichotomized as worsening (i.e., change \> 0) versus no change or improvement (i.e., change ≤ 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure.
Time frame: From enrollment/baseline to Week 12 in the DB treatment period
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC IV at baseline | 0 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC III at Week 12 | 13 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC III at baseline | 15 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC IV at Week 12 | 0 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC I at Week 12 | 3 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | Improved from baseline to Week 12 | 9 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC II at baseline | 27 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | Worsened from baseline to Week 12 | 6 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC II at Week 12 | 27 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | Unchanged from baseline to Week 12 | 28 Participants |
| Macitentan 10 mg | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC I at baseline | 1 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | Unchanged from baseline to Week 12 | 34 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC I at baseline | 1 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC II at baseline | 23 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC III at baseline | 18 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC IV at baseline | 0 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC I at Week 12 | 4 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC II at Week 12 | 23 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC III at Week 12 | 15 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | WHO FC IV at Week 12 | 0 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | Improved from baseline to Week 12 | 7 Participants |
| Placebo | Change From Baseline to Week 12 in WHO Functional Class (FC) | Worsened from baseline to Week 12 | 1 Participants |
Comparison: A logistic regression model (exact) adjusted for treatment, PAH-specific therapy at baseline, and region as covariates was used to analyze worsening in WHO FC.p-value: 0.127895% CI: [0.714, 298.376]Regression, Logistic