Pulmonary Arterial Hypertension
Conditions
Keywords
exercise capacity, Eisenmenger Syndrome
Brief summary
Clinical study to assess the efficacy, safety, and tolerability of macitentan in subjects with Eisenmenger Syndrome.
Interventions
DRUGMacitentan 10 mg
Macitentan 10 mg oral tablet once daily
DRUGPlacebo
Macitentan-matching placebo oral 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
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects: * not participating in the hemodynamic sub-study: males or females ≥ 12 years of age. * participating in the hemodynamic sub-study: males or females ≥ 18 years of age. * Subjects (including those with Down Syndrome \[DS\]) with confirmed Eisenmenger Syndrome \[ES\] (European Society of Cardiology \[ESC\] and the European Respiratory Society \[ERS\] guidelines): 1. Established by echocardiography as: * Large congenital shunting defect at atrial, ventricular or arterial level\* * and right to left shunt or bi-directional shunt with prevalent right to left direction. 2. Resting peripheral oxygen saturation (SpO2) ≤ 90% and \> 70% (pulse oximetry, room air). The lower limit is 65% if a subject is living at an altitude greater than 2500 m above sea level. \*Subjects with any of the following open defects are eligible for the study either as an isolated defect or in combination: * atrial septal defect (ASD) * ventricular septal defect (VSD) * partial or complete atrioventricular septal defect (AVSD) * patent ductus arteriosus (PDA) * aortopulmonary window (AP window) * total or partial anomalous pulmonary venous return (TAPVR, PAPVR) The defects may be either unoperated or previously palliated surgically (provided significant residual defect remains). The Steering Committee will review the echocardiography data of all subjects (main study and sub study) to confirm eligibility prior to Randomization. * Subjects with the following findings at cardiac catheterization: * Mean resting pulmonary arterial pressure (mPAP) \> 25 mmHg * Pulmonary capillary wedge pressure (PCWP) or mean left atrial pressure (LAP) or left ventricular end diastolic pressure (LVED) ≤ 15 mmHg * Pulmonary vascular resistance (PVR) ≥ 800 dyn∙s/cm5 or ≥ 10 Wood units * Subjects with WHO functional class ≥ II. * Subjects able to reliably perform the the 6-minute walk test (6MWT) with a minimum distance of 50 m and a maximum distance of 450 m.
Exclusion criteria
\- Main study and hemodynamic sub-study: Any of the following conditions previously known or identified via cardiac catheterization or echocardiography: * Pulmonary arterial or venous stenosis \> 25% size of native pulmonary artery (PA) or pulmonary vein * Severe tricuspid regurgitation in the setting of left to right shunt at the ventricular or atrial level * Greater than mild tricuspid stenosis * Intracavitary RV outflow obstruction * Greater than mild mitral stenosis * Intracavitary LV outflow obstruction * Subvalvular or supravalvular aortic stenosis * Aortic coarctation * Greater than moderate mitral regurgitation * Recognized extracardiac systemic venous collaterals to the pulmonary venous circulation * Recognized hepatic wedge pressure-inferior vena cava pressure gradient \>12 mm Hg * PCWP v waves \>20 mmHg * Tetralogy of Fallot * Truncus arteriosus * Interrupted aortic arch * Transposition of great arteries * Single ventricle defects: absent AV connection (mitral or tricuspid atresia), double inlet AV connections left or right ventricle, functional univentricular heart (unbalanced AVSD, hypoplastic RV, double outlet RV), hypoplastic left heart syndrome * Ebstein's anomaly * Severe aortic regurgitation * Pulmonary atresia * PAPVR or TAPVR, ONLY if there is lung hypoplasia or if documentation confirming the absence of lung hypoplasia does not exist. For subjects participating in the hemodynamic sub-study the following will also be considered
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) | From baseline to Week 16 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 16 in WHO Functional Class | From baseline to Week 16 | A shift in WHO functional classes is considered an 'improvement' when shifting to a lower class (e.g. from class III to class II) or a 'worsening' when shifting to a higher class (e.g. from class III to class IV). Definition of functional classes as follows - Class I: no symptoms with exercise or at rest. Class II: No symptoms at rest but uncomfortable and short of breath with normal activity such as 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 (e.g. doing normal chores around the house, have to take breaks while doing activities of daily living). Class IV: Symptoms at rest and severe symptoms with any activity. Most patients also have edema in the feet and ankles as result of right heart failure. |
| Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index | From baseline to Week 16 | This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 16 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement. |
| Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | From baseline to Week 16 | The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of the functional health and well-being scores (i.e., physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), as well as psychometrically based physical and mental health summary measures and a preference-based health utility (health rated as much better now than one year ago to much worse now than one year ago). It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group. For each of the domains and scores that the SF36 measures an aggregate percentage score is produced. The percentage scores range from 0% (lowest or worst possible level of functioning) to 100% (highest or best possible level of functioning). A higher score for the individual domains and summary component scores indicates a better condition of the subject. |
Countries
Austria, Bulgaria, Chile, China, France, Germany, Greece, Israel, Malaysia, Mexico, Philippines, Poland, Portugal, Romania, Russia, Serbia, Spain, Turkey (Türkiye), United Kingdom, United States, Vietnam
Participant flow
Recruitment details
The study was conducted at 71 sites in 26 countries (geographical regions: Asia-Pacific, Eastern Europe, Latin America, North America, Western Europe including Israel and Turkey, and South Africa), of which 55 sites in 21 countries randomized subjects.
Pre-assignment details
The screening period lasted a maximum of 30 days from Visit 1 up to Randomization (Visit 2). A total of 319 subjects were screened and 226 subjects were randomized to macitentan 10 mg and placebo.
Participants by arm
| Arm | Count |
|---|---|
| Macitentan Subjects receive macitentan 10 mg, oral tablet, to be taken once daily | 114 |
| Placebo Subjects receive macitentan-matching placebo, oral tablet, to be taken once daily | 112 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Pregnancy | 1 | 0 |
Baseline characteristics
| Characteristic | Macitentan | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 33.0 Years | 31.0 Years | 32.0 Years |
| Age, Customized 12 - 17 years | 13 Participants | 2 Participants | 15 Participants |
| Age, Customized 18 - 55 years | 90 Participants | 105 Participants | 195 Participants |
| Age, Customized ≥ 56 years | 11 Participants | 5 Participants | 16 Participants |
| Body Mass Index (BMI) | 21.15 kg/m^2 | 21.55 kg/m^2 | 21.35 kg/m^2 |
| Region of Enrollment Asia-Pacific | 47 Participants | 44 Participants | 91 Participants |
| Region of Enrollment Eastern Europe | 25 Participants | 27 Participants | 52 Participants |
| Region of Enrollment Latin America | 19 Participants | 18 Participants | 37 Participants |
| Region of Enrollment North America | 2 Participants | 5 Participants | 7 Participants |
| Region of Enrollment Western Europe - Israel | 21 Participants | 18 Participants | 39 Participants |
| Sex: Female, Male Female | 82 Participants | 68 Participants | 150 Participants |
| Sex: Female, Male Male | 32 Participants | 44 Participants | 76 Participants |
| WHO functional class class I | 0 Participants | 0 Participants | 0 Participants |
| WHO functional class class II | 69 Participants | 66 Participants | 135 Participants |
| WHO functional class class III | 45 Participants | 46 Participants | 91 Participants |
| WHO functional class class IV | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 114 | 0 / 112 |
| other Total, other adverse events | 31 / 114 | 30 / 112 |
| serious Total, serious adverse events | 7 / 114 | 2 / 112 |
Outcome results
Primary
Change From Baseline to Week 16 in Exercise Capacity, as Measured by 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 baseline to Week 16
Population: Full analysis set: The analysis was performed on the full analysis set (FAS), i.e., all randomized subjects in the treatment group to which they were randomized and by imputing missing values at Week 16 according to pre-defined rules.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan | Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) | Change in 6MWD from baseline to Week 16 | 18.3 meter | Standard Deviation 84.4 |
| Macitentan | Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) | 6MWD at baseline | 368.7 meter | Standard Deviation 74.5 |
| Macitentan | Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) | 6MWD at Week 16 | 387.1 meter | Standard Deviation 101.8 |
| Placebo | Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) | 6MWD at Week 16 | 399.9 meter | Standard Deviation 79.5 |
| Placebo | Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) | Change in 6MWD from baseline to Week 16 | 19.7 meter | Standard Deviation 53 |
| Placebo | Change From Baseline to Week 16 in Exercise Capacity, as Measured by 6-minute Walk Distance (6MWD) | 6MWD at baseline | 380.3 meter | Standard Deviation 76.3 |
Comparison: The null hypothesis was that there was no difference between macitentan and placebo for the mean change from baseline to Week 16 in 6MWD. Null hypothesis was tested by an analysis of covariance (ANCOVA).p-value: 0.61295% CI: [-22.8, 13.5]ANCOVA
Secondary
Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index
This outcome measures the difference in the Borg dyspnea index collected at the end of the 6-minute walk test (6MWT) at Week 16 compared to baseline. The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement.
Time frame: From baseline to Week 16
Population: Full analysis set: The analysis was performed on the full analysis set (FAS), i.e., all randomized subjects in the treatment group to which they were randomized and by imputing missing values at Week 16 according to pre-defined rules.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan | Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index | Borg dyspnea index score at baseline | 3.00 Score on a scale | Standard Deviation 1.95 |
| Macitentan | Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index | Borg dyspnea index score at Week 16 | 2.78 Score on a scale | Standard Deviation 2.1 |
| Macitentan | Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index | Change from baseline to Week 16 | -0.22 Score on a scale | Standard Deviation 1.56 |
| Placebo | Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index | Borg dyspnea index score at baseline | 2.94 Score on a scale | Standard Deviation 1.88 |
| Placebo | Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index | Borg dyspnea index score at Week 16 | 2.66 Score on a scale | Standard Deviation 1.64 |
| Placebo | Change From Baseline to Week 16 in Dyspnea, Assessed by the Borg Dyspnea Index | Change from baseline to Week 16 | -0.29 Score on a scale | Standard Deviation 1.5 |
Comparison: The null hypothesis was that the mean change from baseline to Week 16 in the Borg dyspnea index is the same in the macitentan and in the placebo group.p-value: 0.681895% CI: [-0.29, 0.44]ANCOVA
Secondary
Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire
The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of the functional health and well-being scores (i.e., physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), as well as psychometrically based physical and mental health summary measures and a preference-based health utility (health rated as much better now than one year ago to much worse now than one year ago). It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group. For each of the domains and scores that the SF36 measures an aggregate percentage score is produced. The percentage scores range from 0% (lowest or worst possible level of functioning) to 100% (highest or best possible level of functioning). A higher score for the individual domains and summary component scores indicates a better condition of the subject.
Time frame: From baseline to Week 16
Population: Full analysis set (excluding children \<14 years of age and Down Syndrome subjects)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in physical functioning (norm-based) | 1.9 Score on a scale | Standard Deviation 6.9 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score:general health perceptions at Week 16 | 40.3 Score on a scale | Standard Deviation 22.7 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: role-physical at baseline | 35.8 Score on a scale | Standard Deviation 10 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in physical functioning (domain score) | 4.6 Score on a scale | Standard Deviation 16.5 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: role-physical at Week 16 | 38.4 Score on a scale | Standard Deviation 10 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in general health perceptions(domain score) | 4.2 Score on a scale | Standard Deviation 16.4 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in role-physical (norm-based) | 2.6 Score on a scale | Standard Deviation 7.9 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: physical functioning at Week 16 | 38.7 Score on a scale | Standard Deviation 9.2 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: pain index at baseline | 45.9 Score on a scale | Standard Deviation 9.7 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: pain index at Week 16 | 47.4 Score on a scale | Standard Deviation 10 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: vitality at baseline | 49.0 Score on a scale | Standard Deviation 22.1 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in pain index (norm-based) | 1.5 Score on a scale | Standard Deviation 9.3 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: role-physical at baseline | 46.2 Score on a scale | Standard Deviation 25.5 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: general health perceptions at baseline | 33.4 Score on a scale | Standard Deviation 10 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: vitality at Week 16 | 56.1 Score on a scale | Standard Deviation 19.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: general health perceptions at Week 16 | 35.4 Score on a scale | Standard Deviation 10.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: role-physical at Week 16 | 52.8 Score on a scale | Standard Deviation 25.5 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in general health perceptions (norm-based) | 2.0 Score on a scale | Standard Deviation 7.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in vitality (domain score) | 7.1 Score on a scale | Standard Deviation 18.3 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: vitality at baseline | 45.4 Score on a scale | Standard Deviation 11.1 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in role-emotional (domain score) | 1.7 Score on a scale | Standard Deviation 22.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: vitality at Week 16 | 48.9 Score on a scale | Standard Deviation 9.9 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: social functioning at baseline | 64.7 Score on a scale | Standard Deviation 26.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in vitality (norm-based) | 3.6 Score on a scale | Standard Deviation 9.1 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in role-physical (domain score) | 6.6 Score on a scale | Standard Deviation 20.1 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: social functioning at Week 16 | 66.6 Score on a scale | Standard Deviation 25.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: social functioning at Week 16 | 42.3 Score on a scale | Standard Deviation 11.3 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: social functioning at baseline | 41.5 Score on a scale | Standard Deviation 11.7 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in social functioning (norm-based) | 0.8 Score on a scale | Standard Deviation 10 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in social functioning (domain score) | 1.9 Score on a scale | Standard Deviation 23 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: role-emotional at baseline | 37.9 Score on a scale | Standard Deviation 12.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: pain index at baseline | 61.7 Score on a scale | Standard Deviation 23 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: role-emotional at Week 16 | 38.8 Score on a scale | Standard Deviation 12.5 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: physical functioning at baseline | 51.9 Score on a scale | Standard Deviation 21.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in role-emotional (norm-based) | 0.8 Score on a scale | Standard Deviation 10.6 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: role-emotional at Week 16 | 63.3 Score on a scale | Standard Deviation 26.8 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: mental health index at baseline | 43.7 Score on a scale | Standard Deviation 11.9 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: pain index at Week 16 | 65.2 Score on a scale | Standard Deviation 23.6 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: mental health index at Week 16 | 44.8 Score on a scale | Standard Deviation 10.6 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: role-emotional at baseline | 61.6 Score on a scale | Standard Deviation 27.4 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in mental health index (norm-based) | 1.1 Score on a scale | Standard Deviation 9.1 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: mental health index at baseline | 63.8 Score on a scale | Standard Deviation 21.1 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Physical component summary score at baseline | 37.6 Score on a scale | Standard Deviation 7.5 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in pain index (domain score) | 3.5 Score on a scale | Standard Deviation 22.1 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Physical component summary score at Week 16 | 40.0 Score on a scale | Standard Deviation 8.4 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: mental health index at Week 16 | 65.7 Score on a scale | Standard Deviation 18.9 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in physical component summary score | 2.4 Score on a scale | Standard Deviation 6.4 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: physical functioning at Week 16 | 56.4 Score on a scale | Standard Deviation 21.9 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Mental component summary score at baseline | 43.8 Score on a scale | Standard Deviation 12.4 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: physical functioning at baseline | 36.8 Score on a scale | Standard Deviation 9.2 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Mental component summary score at Week 16 | 44.7 Score on a scale | Standard Deviation 11.7 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score:general health perceptions baseline | 36.1 Score on a scale | Standard Deviation 21 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in mental component summary score | 1.0 Score on a scale | Standard Deviation 9.3 |
| Macitentan | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in mental health index (domain score) | 1.9 Score on a scale | Standard Deviation 16.1 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in mental component summary score | 1.8 Score on a scale | Standard Deviation 9.3 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: mental health index at Week 16 | 67.7 Score on a scale | Standard Deviation 20.6 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: pain index at baseline | 47.2 Score on a scale | Standard Deviation 10.4 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: physical functioning at baseline | 52.7 Score on a scale | Standard Deviation 22.4 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: physical functioning at Week 16 | 58.0 Score on a scale | Standard Deviation 19.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in physical functioning (domain score) | 5.3 Score on a scale | Standard Deviation 15.4 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: role-physical at Week 16 | 55.9 Score on a scale | Standard Deviation 25.3 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in role-physical (domain score) | 7.4 Score on a scale | Standard Deviation 22.1 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: pain index at baseline | 64.6 Score on a scale | Standard Deviation 24.6 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: pain index at Week 16 | 66.2 Score on a scale | Standard Deviation 24.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in pain index (domain score) | 1.6 Score on a scale | Standard Deviation 27.1 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score:general health perceptions baseline | 37.2 Score on a scale | Standard Deviation 19.8 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score:general health perceptions at Week 16 | 37.6 Score on a scale | Standard Deviation 20.3 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in general health perceptions(domain score) | 0.5 Score on a scale | Standard Deviation 15.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: vitality at baseline | 51.9 Score on a scale | Standard Deviation 21.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: vitality at Week 16 | 56.3 Score on a scale | Standard Deviation 17.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in vitality (domain score) | 4.4 Score on a scale | Standard Deviation 18.2 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: social functioning at baseline | 66.9 Score on a scale | Standard Deviation 25 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: social functioning at Week 16 | 69.2 Score on a scale | Standard Deviation 23.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in social functioning (domain score) | 2.3 Score on a scale | Standard Deviation 24.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: role-emotional at baseline | 61.3 Score on a scale | Standard Deviation 28.8 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: role-emotional at Week 16 | 66.0 Score on a scale | Standard Deviation 25.6 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in role-emotional (domain score) | 4.7 Score on a scale | Standard Deviation 25 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: mental health index at baseline | 64.0 Score on a scale | Standard Deviation 20.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in mental health index (domain score) | 3.7 Score on a scale | Standard Deviation 16.6 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: physical functioning at baseline | 37.1 Score on a scale | Standard Deviation 9.4 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: physical functioning at Week 16 | 39.3 Score on a scale | Standard Deviation 8.3 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in physical functioning (norm-based) | 2.2 Score on a scale | Standard Deviation 6.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: role-physical at baseline | 36.6 Score on a scale | Standard Deviation 10.9 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: role-physical at Week 16 | 39.6 Score on a scale | Standard Deviation 9.9 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in role-physical (norm-based) | 2.9 Score on a scale | Standard Deviation 8.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: pain index at Week 16 | 47.8 Score on a scale | Standard Deviation 10.4 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in pain index (norm-based) | 0.7 Score on a scale | Standard Deviation 11.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: general health perceptions at baseline | 33.9 Score on a scale | Standard Deviation 9.4 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: general health perceptions at Week 16 | 34.2 Score on a scale | Standard Deviation 9.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in general health perceptions (norm-based) | 0.2 Score on a scale | Standard Deviation 7.4 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: vitality at baseline | 46.8 Score on a scale | Standard Deviation 10.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: vitality at Week 16 | 49.0 Score on a scale | Standard Deviation 8.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in vitality (norm-based) | 2.2 Score on a scale | Standard Deviation 9.1 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: social functioning at baseline | 42.4 Score on a scale | Standard Deviation 10.9 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: social functioning at Week 16 | 43.4 Score on a scale | Standard Deviation 10.3 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in social functioning (norm-based) | 1.0 Score on a scale | Standard Deviation 10.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: role-emotional at baseline | 37.8 Score on a scale | Standard Deviation 13.4 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: role-emotional at Week 16 | 40.0 Score on a scale | Standard Deviation 11.9 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in role-emotional (norm-based) | 2.2 Score on a scale | Standard Deviation 11.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: mental health index at baseline | 43.8 Score on a scale | Standard Deviation 11.6 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Norm-based: mental health index at Week 16 | 45.9 Score on a scale | Standard Deviation 11.6 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in mental health index (norm-based) | 2.1 Score on a scale | Standard Deviation 9.3 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Physical component summary score at baseline | 38.6 Score on a scale | Standard Deviation 8.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Physical component summary score at Week 16 | 40.0 Score on a scale | Standard Deviation 7.7 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Change in physical component summary score | 1.4 Score on a scale | Standard Deviation 6.5 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Mental component summary score at baseline | 44.1 Score on a scale | Standard Deviation 12.1 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Mental component summary score at Week 16 | 45.9 Score on a scale | Standard Deviation 10.9 |
| Placebo | Change From Baseline to Week 16 in Quality of Life (QoL), Assessed by the Short Form-36 (SF-36) Questionnaire | Domain score: role-physical at baseline | 48.4 Score on a scale | Standard Deviation 27.9 |
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Physical Functioning.p-value: 0.643195% CI: [-5, 3.1]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Role-Physical.p-value: 0.598895% CI: [-6.7, 3.9]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Pain Index.p-value: 0.964295% CI: [-5.9, 6.2]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of General Health Perceptions.p-value: 0.154295% CI: [-1.2, 7.3]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Vitality.p-value: 0.60295% CI: [-3.1, 5.3]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of General Health Perceptions (norm-based).p-value: 0.154295% CI: [-0.6, 3.5]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Social Functioning.p-value: 0.63495% CI: [-7.2, 4.4]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Role-Emotional.p-value: 0.338495% CI: [-8.7, 3]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Mental Health Index.p-value: 0.270495% CI: [-6.4, 1.8]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Physical Functioning (norm-based).p-value: 0.643195% CI: [-2.1, 1.3]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Role-Physical (norm-based).p-value: 0.598895% CI: [-2.6, 1.5]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Pain Index (norm-based).p-value: 0.964295% CI: [-2.5, 2.6]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Vitality (norm-based).p-value: 0.60295% CI: [-1.5, 2.6]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Social Functioning (norm-based).p-value: 0.63495% CI: [-3.1, 1.9]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Role-Emotional (norm-based).p-value: 0.338495% CI: [-4.1, 1.4]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the SF-36 domain score of Mental Health Index.p-value: 0.270495% CI: [-3.6, 1]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the Physical Component Summary Score.p-value: 0.433295% CI: [-1, 2.3]ANCOVA
Comparison: The null hypothesis is that the mean change from baseline to Week 16 is the same in the macitentan and the placebo group for the Mental Component Summary Score.p-value: 0.341695% CI: [-3.4, 1.2]ANCOVA
Secondary
Change From Baseline to Week 16 in WHO Functional Class
A shift in WHO functional classes is considered an 'improvement' when shifting to a lower class (e.g. from class III to class II) or a 'worsening' when shifting to a higher class (e.g. from class III to class IV). Definition of functional classes as follows - Class I: no symptoms with exercise or at rest. Class II: No symptoms at rest but uncomfortable and short of breath with normal activity such as 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 (e.g. doing normal chores around the house, have to take breaks while doing activities of daily living). Class IV: Symptoms at rest and severe symptoms with any activity. Most patients also have edema in the feet and ankles as result of right heart failure.
Time frame: From baseline to Week 16
Population: Full analysis set: The analysis was performed on the full analysis set (FAS), i.e., all randomized subjects in the treatment group to which they were randomized and by imputing missing values at Week 16 according to pre-defined rules.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan | Change From Baseline to Week 16 in WHO Functional Class | WHO functional class 3 at Week 16 | 38 Participants |
| Macitentan | Change From Baseline to Week 16 in WHO Functional Class | Unchanged from baseline to Week 16 | 103 Participants |
| Macitentan | Change From Baseline to Week 16 in WHO Functional Class | WHO functional class 2 at Week 16 | 72 Participants |
| Macitentan | Change From Baseline to Week 16 in WHO Functional Class | Improvement from baseline to Week 16 | 10 Participants |
| Macitentan | Change From Baseline to Week 16 in WHO Functional Class | WHO functional class 4 at Week 16 | 1 Participants |
| Macitentan | Change From Baseline to Week 16 in WHO Functional Class | Worsening from baseline to Week 16 | 1 Participants |
| Macitentan | Change From Baseline to Week 16 in WHO Functional Class | WHO functional class 1 at Week 16 | 3 Participants |
| Placebo | Change From Baseline to Week 16 in WHO Functional Class | Worsening from baseline to Week 16 | 1 Participants |
| Placebo | Change From Baseline to Week 16 in WHO Functional Class | WHO functional class 1 at Week 16 | 1 Participants |
| Placebo | Change From Baseline to Week 16 in WHO Functional Class | WHO functional class 2 at Week 16 | 79 Participants |
| Placebo | Change From Baseline to Week 16 in WHO Functional Class | WHO functional class 3 at Week 16 | 32 Participants |
| Placebo | Change From Baseline to Week 16 in WHO Functional Class | WHO functional class 4 at Week 16 | 0 Participants |
| Placebo | Change From Baseline to Week 16 in WHO Functional Class | Unchanged from baseline to Week 16 | 95 Participants |
| Placebo | Change From Baseline to Week 16 in WHO Functional Class | Improvement from baseline to Week 16 | 16 Participants |
Comparison: For this secondary endpoint of WHO functional class, the improvement from baseline to Week 16 in WHO functional class was evaluated. The null hypothesis is the odds of improvement are the same in the placebo and the macitentan group.p-value: 0.14595% CI: [0.23, 1.24]Regression, Logistic