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    Clinical Trial Results:
    A Prospective, Randomized, Double-Blind, Multicenter, Placebo-Controlled, Parallel Group, Adaptive Phase 3 Study with Open-Label Extension to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension

    Summary
    EudraCT number
    		 2019-004131-24
    Trial protocol
    		 CZ   DE   GB   HU   PL   ES   AT   SK   LT   FR   IT   PT   DK  
    Global end of trial date
    20 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2025
    First version publication date
    05 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    67896062CTP3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04271475
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    16 Gewerbestrasse, Allschwil, Switzerland, 4123
    Public contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd,, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd,, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to evaluate the effect of macitentan 75 milligrams (mg) versus placebo on exercise capacity at Week 28 in subjects with chronic thromboembolic pulmonary hypertension (CTEPH).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jul 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 13
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Türkiye: 6
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    China: 17
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Japan: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Saudi Arabia: 2
    Country: Number of subjects enrolled
    Thailand: 2
    Worldwide total number of subjects
    127
    EEA total number of subjects
    47
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    56
    From 65 to 84 years
    71
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study comprised of screening, double-blind (DB), open-label (OL) and safety follow-up (FU) periods. The DB period started with an 8-week up-titration phase and lasted until all subjects either completed the Week 28 visit or prematurely discontinued the study.

    Period 1
    Period 1 title
    DB Period: Day 1 up to EODBT
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Double blind

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double Blind (DB) Period: Macitentan
    Arm description
    		 During the 8-week up-titration phase, subjects received macitentan doses orally once daily (QD): 10 mg tablet for 4 weeks followed by 37.5 mg tablet for another 4 weeks prior to reaching the target maintenance phase dose of macitentan 75 mg QD. Subjects were to remain on double-blind maintenance treatment until the last subject randomised completed the Week 28 visit. Subjects who prematurely discontinued DB study treatment prior to Week 28 but did not withdraw consent were asked to enter post-treatment observation period (PTOP) from DB period last dose until Week 28. Median exposure to DB treatment was 24.50 weeks (minimum: 3.9 weeks; maximum: 160.4 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    ACT-064992
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received macitentan 10 mg QD for 4 weeks followed by macitentan 37.5 mg QD for another 4 weeks during the up-titration phase, prior to reaching the target maintenance dose of macitentan 75 mg QD. Subject remained on DB maintenance treatment until the last subject randomised completed the Week 28 visit.

    Arm title
    		 DB Period: Placebo
    Arm description
    		 Subjects received placebo matched to macitentan dose levels during the DB treatment period. Subjects who prematurely discontinued DB study treatment prior to Week 28 but did not withdraw consent were asked to enter PTOP from DB period last dose until Week 28. Median exposure to DB treatment was 44 weeks (minimum: 4 weeks; maximum: 147.9 weeks).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to macitentan dose levels during the DB treatment period.

    Number of subjects in period 1
    		Double Blind (DB) Period: Macitentan DB Period: Placebo
    Started
    64
    63
    Completed
    1
    1
    Not completed
    63
    62
         Adverse event, serious fatal
    1
    -
         Physician decision
    8
    1
         Consent withdrawn by subject
    5
    4
         Study terminated by sponsor
    41
    52
         Unspecified
    8
    5
    Period 2
    Period 2 title
    OL Period:Day 1 upto End of OL Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Open Label (OL) Period: DB Macitentan
    Arm description
    		 Subjects who were treated with macitentan in the DB period and had reached the target dose of macitentan 75 mg and completed the DB period as per protocol were considered eligible to transition into the 104-week OL period and they continued macitentan 75 mg tablet orally QD from end of double blind treatment (EODBT) until study termination. Subjects who experienced a clinical worsening event confirmed by the clinical event committee (CEC), were allowed to transition to the OL period at any time after Week 28. Median exposure to OL treatment was 72 weeks (minimum: 8.1 weeks; maximum: 84.6 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    ACT-064992
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects continued macitentan 75 mg QD from EODBT until study termination.

    Arm title
    		 OL Period: DB Placebo
    Arm description
    		 Subjects who were treated with placebo in the DB period and had completed the DB period as per protocol were considered eligible to transition into the 104-week OL period and were up-titrated to the target dose of macitentan 75 mg (macitentan 10 mg for 4 weeks, followed by macitentan 37.5 mg for another 4 weeks). Subjects who experienced a clinical worsening event confirmed by the CEC, were allowed to transition to the OL period at any time after Week 28. Median exposure to OL treatment was 72 weeks (minimum: 8.1 weeks; maximum: 84.6 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    ACT-064992
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were up-titrated to the target dose of macitentan 75 mg (macitentan 10 mg for 4 weeks, followed by macitentan 37.5 mg for another 4 weeks).

    Number of subjects in period 2
    		Open Label (OL) Period: DB Macitentan OL Period: DB Placebo
    Started
    1
    1
    Completed
    0
    0
    Not completed
    1
    1
         Study terminated by sponsor
    1
    -
         Unspecified
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double Blind (DB) Period: Macitentan
    Reporting group description
    		 During the 8-week up-titration phase, subjects received macitentan doses orally once daily (QD): 10 mg tablet for 4 weeks followed by 37.5 mg tablet for another 4 weeks prior to reaching the target maintenance phase dose of macitentan 75 mg QD. Subjects were to remain on double-blind maintenance treatment until the last subject randomised completed the Week 28 visit. Subjects who prematurely discontinued DB study treatment prior to Week 28 but did not withdraw consent were asked to enter post-treatment observation period (PTOP) from DB period last dose until Week 28. Median exposure to DB treatment was 24.50 weeks (minimum: 3.9 weeks; maximum: 160.4 weeks).

    Reporting group title
    DB Period: Placebo
    Reporting group description
    		 Subjects received placebo matched to macitentan dose levels during the DB treatment period. Subjects who prematurely discontinued DB study treatment prior to Week 28 but did not withdraw consent were asked to enter PTOP from DB period last dose until Week 28. Median exposure to DB treatment was 44 weeks (minimum: 4 weeks; maximum: 147.9 weeks).

    Reporting group values
    		 Double Blind (DB) Period: Macitentan DB Period: Placebo Total
    Number of subjects
    		 64 63 127
    Age categorical
    Units: Subjects
        In Utero
    		 0 0 0
        Preterm newborn infants (gestional age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days - 23 months)
    		 0 0 0
        Children (2 - 11 years)
    		 0 0 0
        12 - 17 years
    		 0 0 0
        Adults (18 - 64 years)
    		 23 33 56
        From 65 - 84 years
    		 41 30 71
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.7 ( 11.69 ) 60.3 ( 12.84 ) -
    Gender categorical
    Units: Subjects
        Male
    		 27 21 48
        Female
    		 37 42 79

    End points

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    End points reporting groups
    Reporting group title
    Double Blind (DB) Period: Macitentan
    Reporting group description
    		 During the 8-week up-titration phase, subjects received macitentan doses orally once daily (QD): 10 mg tablet for 4 weeks followed by 37.5 mg tablet for another 4 weeks prior to reaching the target maintenance phase dose of macitentan 75 mg QD. Subjects were to remain on double-blind maintenance treatment until the last subject randomised completed the Week 28 visit. Subjects who prematurely discontinued DB study treatment prior to Week 28 but did not withdraw consent were asked to enter post-treatment observation period (PTOP) from DB period last dose until Week 28. Median exposure to DB treatment was 24.50 weeks (minimum: 3.9 weeks; maximum: 160.4 weeks).

    Reporting group title
    DB Period: Placebo
    Reporting group description
    		 Subjects received placebo matched to macitentan dose levels during the DB treatment period. Subjects who prematurely discontinued DB study treatment prior to Week 28 but did not withdraw consent were asked to enter PTOP from DB period last dose until Week 28. Median exposure to DB treatment was 44 weeks (minimum: 4 weeks; maximum: 147.9 weeks).
    Reporting group title
    Open Label (OL) Period: DB Macitentan
    Reporting group description
    		 Subjects who were treated with macitentan in the DB period and had reached the target dose of macitentan 75 mg and completed the DB period as per protocol were considered eligible to transition into the 104-week OL period and they continued macitentan 75 mg tablet orally QD from end of double blind treatment (EODBT) until study termination. Subjects who experienced a clinical worsening event confirmed by the clinical event committee (CEC), were allowed to transition to the OL period at any time after Week 28. Median exposure to OL treatment was 72 weeks (minimum: 8.1 weeks; maximum: 84.6 weeks).

    Reporting group title
    OL Period: DB Placebo
    Reporting group description
    		 Subjects who were treated with placebo in the DB period and had completed the DB period as per protocol were considered eligible to transition into the 104-week OL period and were up-titrated to the target dose of macitentan 75 mg (macitentan 10 mg for 4 weeks, followed by macitentan 37.5 mg for another 4 weeks). Subjects who experienced a clinical worsening event confirmed by the CEC, were allowed to transition to the OL period at any time after Week 28. Median exposure to OL treatment was 72 weeks (minimum: 8.1 weeks; maximum: 84.6 weeks).

    Primary: Change From Baseline in 6-minute Walk Distance (6MWD) at Week 28

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    End point title
    		 Change From Baseline in 6-minute Walk Distance (6MWD) at Week 28
    End point description
    Change from baseline in 6MWD as measured by 6-minute walk test (6MWT)) at Week 28 was reported. The purpose of the 6MWT was to quantify exercise tolerance and capacity. This standardized test measured the distance an individual was able to walk over a total of six minutes on a hard, flat surface with no obstacles. The goal was for the individual to walk as far as possible in 6 minutes. Full analysis set (FAS) included all randomised subjects assigned to a study intervention and were analysed according to the intervention they had been assigned to via interactive web response system (IWRS). Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this end point.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Week 28
    End point values
    		 Double Blind (DB) Period: Macitentan DB Period: Placebo
    Number of subjects analysed
    47
    48
    Units: Meters
        least squares mean (standard error)
    9.7 ( 5.81 )
    25.8 ( 5.78 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Estimated by mixed model repeated measurements method.
    Comparison groups
    DB Period: Placebo v Double Blind (DB) Period: Macitentan
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.974
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least square mean
    Point estimate
    -16.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.34
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.2

    Secondary: Time First Clinical Event Committee (CEC) Confirmed to Clinical Worsening up to End-of Double-blind-treatment (EODBT) Period

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    End point title
    		 Time First Clinical Event Committee (CEC) Confirmed to Clinical Worsening up to End-of Double-blind-treatment (EODBT) Period
    End point description
    Time (months) to first CEC-confirmed clinical worsening up to EODBT were reported. Clinical worsening: occurrence of at least 1 of following: 1) All-cause death; 2) Heart and/or lung transplantation; 3) Hospitalization or Deterioration from baseline due to unplanned pulmonary hypertension (PH) identified by at least 1 of following: a) Persistent increase in World Health Organization functional class (WHO FC) that could not be explained by another cause (like viral infection); b) Persistent deterioration by at least 15 percent exercise capacity; (by 6MWD); c) New/worsened signs/symptoms of right heart failure; 5) Rescue pulmonary endarterectomy(PEA) and/or balloon pulmonary angioplasty(BPA) procedure. FAS: randomised subjects assigned to study intervention and were analysed according to received intervention via IWRS. 99999 signifies data could not be calculated due to low number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to EODBT: median 24.5 weeks [min 3.9 weeks; max 160.4 weeks] for macitentan, median 44 weeks (min 4 weeks; max 147.9 weeks) for placebo
    End point values
    		 Double Blind (DB) Period: Macitentan DB Period: Placebo
    Number of subjects analysed
    64
    63
    Units: Months
        median (confidence interval 95%)
    99999 (19.0 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score

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    End point title
    		 Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score
    End point description
    The cardiopulmonary symptoms domain consisted 6 items: dyspnea, fatigue, lack of energy, swelling in ankles/legs/stomach area and cough, on a scale from 0 no symptom at all) to 4 (very severe symptoms). The symptoms part of the PAH-SYMPACT was administered daily over a 7-day period. The recall period of symptom items was the last 24 hours. An average cardiopulmonary symptoms domain score was determined based on daily scores of the 6 items. The mean individual symptom item score was determined for each of 6 items and domain score was calculated by summing the mean individual symptom item scores, dividing by number of items, ranged from 0=no cardiopulmonary symptoms, 4=severe cardiopulmonary symptoms. Higher score indicated severe symptoms. FAS: all randomised subjects assigned to a study intervention and analysed according to the intervention received via IWRS. Per change in planned analysis, data for this endpoint was not collected and analysed due to study termination.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 28
    End point values
    		 Double Blind (DB) Period: Macitentan DB Period: Placebo
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [1] - The study was terminated for futility, no subjects were analysed for this endpoint.
    [2] - The study was terminated for futility, no subjects were analysed for this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects with Improvement in World Health Organisation Functional Class (WHO FC) From Baseline to Week 28

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    End point title
    		 Number of Subjects with Improvement in World Health Organisation Functional Class (WHO FC) From Baseline to Week 28
    End point description
    Number of subjects with improvement in WHO FC from baseline to Week 28 were reported. Improvement (decrease) in WHO FC from baseline to Week 28 was calculated for each subject. WHO FC test was used to assess disease severity. Four FC were defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). For analysis purpose, these WHO FC class values were transformed to a scale with scores ranged from 1 to 4; where a score 1 corresponded to WHO FC Class I and a score 4 corresponded to WHO FC Class IV. The higher scores indicated greater symptom severity or worse impact. Improvement was considered when a subject changed from a higher class to a lower class. FAS: all randomised subjects assigned to a study intervention and were analysed according to the intervention they had been assigned to via IWRS. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 28
    End point values
    		 Double Blind (DB) Period: Macitentan DB Period: Placebo
    Number of subjects analysed
    37
    43
    Units: Subjects
    7
    6
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity

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    End point title
    		 Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity
    End point description
    Change from baseline to week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity were assessed. The daily life physical activity of the subject was assessed using an accelerometer which was provided to the subject at screening and was worn daily during walking hours up to Week 28. For each scheduled visit, the 14 days prior to the visit was considered as the assessment period for physical activity. A complete day was defined as a record of at least 7 waking hours of data. During these periods, the time spent in different level of activity: sedentary/light/moderate/vigorous was determined based on activity counts per minutes and expressed as proportion relative to the period duration. FAS: all randomised subjects assigned to a study intervention and were analysed according to the intervention they had been assigned to via IWRS. Per change in planned analysis, data for this endpoint was not collected and analysed due to study termination.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 28
    End point values
    		 Double Blind (DB) Period: Macitentan DB Period: Placebo
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Days
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [3] - The study was terminated for futility, no subjects were analysed for this endpoint.
    [4] - The study was terminated for futility, no subjects were analysed for this endpoint.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score

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    End point title
    		 Change from Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score
    End point description
    The cardiovascular symptoms domain consisted 5 items: fluttering, rapid heartbeat, chest pain, chest tightness, and lightheadedness, on a scale from 0 (no symptoms at all) to 4 (very severe symptoms). The symptoms part of PAH-SYMPACT was administered daily over 7-day period. The recall period of symptom items was the last 24 hours. An average cardiovascular symptoms domain score was determined based on daily scores of the 5 items. Mean individual symptom item score was determined for each of the 5 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items, ranged from 0=no cardiovascular symptoms to 4=severe cardiovascular symptoms. Higher score indicated more severe symptoms. FAS: all randomised subjects assigned to a study intervention and were analysed according to the intervention received via IWRS. Per change in planned analysis, data for this endpoint was not collected and analysed due to study termination.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 28
    End point values
    		 Double Blind (DB) Period: Macitentan DB Period: Placebo
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [5] - The study was terminated for futility, no subjects were analysed for this endpoint
    [6] - The study was terminated for futility, no subjects were analysed for this endpoint.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 28 in Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L) Utility Score

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    End point title
    		 Change from Baseline to Week 28 in Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L) Utility Score
    End point description
    The EQ-5D-5L was a generic measure of health status, a 5-item questionnaire that assessed 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale (VAS). Each questionnaire had 5 response levels: 1 =no problems, 2 =slight problems, 3 =moderate problems, 4 =severe problems and 5 =extreme problems. The scores for the 5 questionnaires were used to compute a single utility score ranged from 0 to 1 representing the general health status of the individual. Higher score indicated better health status. FAS included all randomised subjects assigned to a study intervention and were analysed according to the intervention they had been assigned to via IWRS. Per change in planned analysis, data for this endpoint was not collected and analysed due to study termination.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to Week 28
    End point values
    		 Double Blind (DB) Period: Macitentan DB Period: Placebo
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [7] - The study was terminated for futility, no subjects were analysed for this endpoint.
    [8] - The study was terminated for futility, no subjects were analysed for this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DB period:DB Day 1 to 30 days post EODBT (median exposure[ME]:24.5 weeks[wks], [min 3.9 wks; max 160.4 wks] on macitentan, ME:44 wks [min 4 wks; max 147.9 wks] on placebo); OL period: OL Day 1 to study termination (ME:72 wks [min 8.1 wks; max 84.6 wks]).
    Adverse event reporting additional description
    Safety analysis was based on safety analysis set which included all participants who received at least one dose of study intervention in this study and were analysed according to the intervention they actually received.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Double Blind (DB) Period: Macitentan
    Reporting group description
    		 During the 8-week up-titration phase, subjects received macitentan doses orally once daily (QD): 10 mg tablet for 4 weeks followed by 37.5 mg tablet for another 4 weeks prior to reaching the target maintenance phase dose of macitentan 75 mg QD. Subjects were to remain on double-blind maintenance treatment until the last subject randomised completed the Week 28 visit. Subjects who prematurely discontinued DB study treatment prior to Week 28 but did not withdraw consent were asked to enter post-treatment observation period (PTOP) from DB period last dose until Week 28. Median exposure to DB treatment was 24.50 weeks (minimum: 3.9 weeks; maximum: 160.4 weeks).

    Reporting group title
    OL Period: DB Placebo
    Reporting group description
    		 Subjects who were treated with placebo in the DB period and had completed the DB period as per protocol were considered eligible to transition into the 104-week OL period and were up-titrated to the target dose of macitentan 75 mg (macitentan 10 mg for 4 weeks, followed by macitentan 37.5 mg for another 4 weeks). Subjects who experienced a clinical worsening event confirmed by the CEC, were allowed to transition to the OL period at any time after Week 28. Median exposure to OL treatment was 72 weeks (minimum: 8.1 weeks; maximum: 84.6 weeks).

    Reporting group title
    Open Label (OL) Period: DB Macitentan
    Reporting group description
    		 Subjects who were treated with macitentan in the DB period and had reached the target dose of macitentan 75 mg and completed the DB period as per protocol were considered eligible to transition into the 104-week OL period and they continued macitentan 75 mg tablet orally QD from EODBT until study termination. Subjects who experienced a clinical worsening event confirmed by the CEC, were allowed to transition to the OL period at any time after Week 28. Median exposure to OL treatment was 72 weeks (minimum: 8.1 weeks; maximum: 84.6 weeks).

    Reporting group title
    DB Period: Placebo
    Reporting group description
    		 Subjects received placebo matched to macitentan dose levels during the DB treatment period. Subjects who prematurely discontinued DB study treatment prior to Week 28 but did not withdraw consent were asked to enter PTOP from DB period last dose until Week 28. Median exposure to DB treatment was 44 weeks (minimum: 4 weeks; maximum: 147.9 weeks).

    Serious adverse events
    		 Double Blind (DB) Period: Macitentan OL Period: DB Placebo Open Label (OL) Period: DB Macitentan DB Period: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 64 (26.56%)
    4 / 6 (66.67%)
    0 / 1 (0.00%)
    14 / 63 (22.22%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast Cancer
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cancer Metastatic
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post Thrombotic Syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Ovarian Cystectomy
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema Peripheral
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Abnormal Uterine Bleeding
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Organising Pneumonia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 6 (33.33%)
    0 / 1 (0.00%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal Polyps
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Postoperative Hypertension
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Tachycardia
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo Positional
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dental Caries
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum Intestinal Haemorrhagic
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urge Incontinence
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar Spinal Stenosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid Retention
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double Blind (DB) Period: Macitentan OL Period: DB Placebo Open Label (OL) Period: DB Macitentan DB Period: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 64 (73.44%)
    5 / 6 (83.33%)
    1 / 1 (100.00%)
    38 / 63 (60.32%)
    Investigations
    Haemoglobin Decreased
         subjects affected / exposed
    7 / 64 (10.94%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    7
    1
    0
    0
    Injury, poisoning and procedural complications
    Ligament Sprain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    2 / 63 (3.17%)
         occurrences all number
    1
    0
    1
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    9 / 64 (14.06%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    9
    1
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    3
    0
    0
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 64 (14.06%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    10 / 63 (15.87%)
         occurrences all number
    13
    1
    0
    11
    Dizziness
         subjects affected / exposed
    5 / 64 (7.81%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    6
    0
    0
    3
    Memory Impairment
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    0
    1
    General disorders and administration site conditions
    Oedema Peripheral
         subjects affected / exposed
    18 / 64 (28.13%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    30
    1
    0
    5
    Pyrexia
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    4
    0
    0
    4
    Swelling
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    4
    0
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    6
    1
    0
    2
    Iron Deficiency Anaemia
         subjects affected / exposed
    6 / 64 (9.38%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    9
    0
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    2
    0
    0
    4
    Stomatitis
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    6 / 63 (9.52%)
         occurrences all number
    6
    1
    0
    9
    Dyspnoea
         subjects affected / exposed
    7 / 64 (10.94%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    7
    2
    0
    5
    Nasal Congestion
         subjects affected / exposed
    8 / 64 (12.50%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    10
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    1
    1
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    3
    1
    0
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    6
    0
    0
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    0
    0
    0
    9
    Nasopharyngitis
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    8 / 63 (12.70%)
         occurrences all number
    5
    1
    0
    8
    Covid-19
         subjects affected / exposed
    15 / 64 (23.44%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    14 / 63 (22.22%)
         occurrences all number
    17
    1
    0
    14
    Metabolism and nutrition disorders
    Iron Deficiency
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    0
    1
    Fluid retention
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    4
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Apr 2020
    The purpose of this amendment was to ensure that all subjects, for whom standard of care with riociguat was appropriate, received riociguat in the study. Furthermore, information on the ongoing drug-drug interaction (DDI) study with riociguat was provided, and the criteria for concomitant riociguat therapy (in the absence of a clinically relevant DDI) to be permitted without the need for a substantial amendment were defined.
    13 Jul 2020
    The purpose of this amendment was to update the exclusion criteria and concomitant therapy sections pertaining to new information regarding a DDI of macitentan 75 mg with moderate dual Cytochrome (CYP)3A4 and CYP2C9 inhibitors or co-administration of a combination of moderate CYP3A4 inhibitors and moderate CYP2C9 inhibitors.
    05 Aug 2020
    The purpose of this amendment was to 1. include the changes related to the use of riociguat and the DDI study that were mandated by voluntary harmonisation procedure (VHP), 2. to implement changes due to an urgent safety measure (USM) (that is, exclusion of subjects treated with dual moderate CYP3A4/CYP2C9 inhibitors), 3. to allow the use of subcutaneous (SC) treprostinil as background pulmonary hypertension (PH)-specific therapy, since it had received marketing authorisation in the European Union (EU) in April 2020, 4. to update the statistical section based on European Medicines Agency (EMA) Scientific Advice as well as to make minor updates and corrections and perform editorial document formatting revisions.
    15 Dec 2020
    The purpose of this amendment was to modify the study design for increasing the double-blind (DB) follow-up time. This increase in the DB follow-up time improved the statistical power for the key secondary endpoint (time to clinical worsening). Also, a new substudy was added to provide additional safety data of chronic treatment with macitentan on testicular function in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Specific requirements for Japanese sites were added. Minor corrections and editorial revisions were also being implemented.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Limitations of the trial such as small numbers of participants analysed or technical problems leading to unreliable data.
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