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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, prospective, multicenter, parallel group study to assess the safety and efficacy of macitentan in patients with portopulmonary hypertension

    Summary
    EudraCT number
    		 2014-004624-21
    Trial protocol
    		 GB   DE   CZ   ES   FR  
    Global end of trial date
    31 Oct 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Nov 2019
    First version publication date
    09 Nov 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AC-055-404
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02382016
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ACTELION Pharmaceuticals Ltd.
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Trial Disclosure Desk, ACTELION Pharmaceuticals Ltd., clinical-trials-disclosure@its.jnj.com
    Scientific contact
    Clinical Trial Disclosure Desk, ACTELION Pharmaceuticals Ltd., clinical-trials-disclosure@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    31 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of macitentan on pulmonary vascular resistance (PVR) as compared to placebo in patients with portopulmonary hypertension (PoPH).
    Protection of trial subjects
    Prior to the start of the study, each study site consulted an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), i.e., a review panel that was responsible for ensuring the protection of the rights, safety and well-being of human subjects involved in a clinical investigation. The study was conducted in compliance with the principles of the ‘Declaration of Helsinki’, the International Council for Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines, and with the laws and regulations of the country in which the clinical research was conducted. Both Actelion and the investigator had the right to terminate the study at any time, and in such a case, were responsible for protecting the subjects’ interests. Written informed consent was obtained from each individual participating in the study prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study. It was made clear to each patient that he or she was completely free to refuse to enter the study, or to withdraw from it at any time for any reason. A description of any incentives to participate in the study was provided in the informed consent form.
    Background therapy
    		 As per randomization stratification, 63.5% of patients (54 out of 85 patients) were receiving a pulmonary arterial hypertension (PAH)-specific therapy at baseline.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    85
    EEA total number of subjects
    57
    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)
    64
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients at 39 sites in 7 countries were screened and were randomized at 36 sites in these 7 countries (Brazil, Czech Republic, France, Germany, Spain, UK and US).

    Pre-assignment
    Screening details
    		 A total of 119 participants were screened and 85 participants were randomized (43 to macitentan 10 mg once daily and 42 to matching placebo) and received double-blind (DB) study treatment. Overall, 80 participants who completed DB treatment period entered the open-label (OL) treatment period and 33 participants in open-label extension (OLE) period.

    Period 1
    Period 1 title
    Double-blind (DB) treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Macitentan 10 mg
    Arm description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily.

    Arm title
    		 Placebo
    Arm description
    		 Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Macitentan matching placebo film-coated tablets orally once daily.

    Number of subjects in period 1
    		Macitentan 10 mg Placebo
    Started
    43
    42
    Completed
    39
    41
    Not completed
    4
    1
         Physician decision
    3
    -
         Consent withdrawn by subject
    -
    1
         Lack of efficacy
    1
    -
    Period 2
    Period 2 title
    Open-label (OL) treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Macitentan 10 mg
    Arm description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily.

    Number of subjects in period 2
    		Macitentan 10 mg
    Started
    80
    Completed
    71
    Not completed
    9
         Consent withdrawn by subject
    2
         Physician decision
    3
         Death
    4
    Period 3
    Period 3 title
    OL Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Macitentan 10 mg
    Arm description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period . Participants (who were randomized at French sites) who completed the core phase of the study as scheduled and opted to continue receiving OL study treatment continued to receive macitentan 10 mg in OLE period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily.

    Number of subjects in period 3 [1]
    		Macitentan 10 mg
    Started
    33
    Completed
    27
    Not completed
    6
         Consent withdrawn by subject
    1
         Physician decision
    3
         Death
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects are different as randomized subjects only at French sites who completed the core phase of study and opted to continue receiving OL study treatment continued to receive macitentan 10 mg in OLE period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

    Reporting group values
    		 Macitentan 10 mg Placebo Total
    Number of subjects
    		 43 42 85
    Title for AgeCategorical
    Units: subjects
        Adults (18-64 years)
    		 35 29 64
        From 65 to 84 years
    		 8 13 21
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.4 ( 9.05 ) 59.0 ( 9.5 ) -
    Title for Gender
    Units: subjects
        Female
    		 21 20 41
        Male
    		 22 22 44
    Enrollment by geographical region
    Units: Subjects
        United States
    		 12 11 23
        Brazil
    		 2 3 5
        Czech Republic
    		 1 3 4
        France
    		 18 21 39
        Germany
    		 4 4 8
        Spain
    		 4 0 4
        United Kingdom
    		 2 0 2
    Race
    Units: Subjects
        Asian
    		 1 0 1
        White
    		 23 21 44
        Other
    		 1 0 1
        Not Applicable
    		 18 21 39
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 6 12
        Not Hispanic or Latino
    		 19 15 34
        Unknown or Not Reported
    		 18 21 39
    PAH-specific therapy
    Units: Subjects
        Yes-PAH
    		 27 27 54
        No-PAH
    		 16 15 31
    Body Mass Index (BMI) at baseline
    Units: Kilogram per meter^2 (Kg/m^2)
        arithmetic mean (standard deviation)
    		 9.01 ( 4.79 ) 29.33 ( 4.04 ) -
    Time since portal hypertension diagnosis
    Units: Months
        median (inter-quartile range (Q1-Q3))
    		 23 (5 to 80) 31 (4 to 69) -
    Time since PAH diagnosis
    Units: Months
        median (inter-quartile range (Q1-Q3))
    		 7 (2 to 33) 12 (1 to 37) -
    Pulmonary vascular resistance (PVR) at baseline (calculated)
    Units: Dyn*sec/cm^5
        arithmetic mean (standard deviation)
    		 552.4 ( 192.8 ) 521.7 ( 163.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period.
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period . Participants (who were randomized at French sites) who completed the core phase of the study as scheduled and opted to continue receiving OL study treatment continued to receive macitentan 10 mg in OLE period.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) includes all randomized patients who received at least one dose of study treatment in the DB treatment period and have a baseline value for the primary endpoint (pulmonary vascular resistance). Subjects are evaluated according to the treatment to which they were assigned (which may be different from the treatment they have received).

    Primary: Change from baseline to Week 12 in pulmonary vascular resistance (PVR)

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    End point title
    		 Change from baseline to Week 12 in pulmonary vascular resistance (PVR)
    End point description
    The relative change from baseline to Week 12 in PVR is expressed as a ratio of Week 12 to baseline PVR.
    End point type
    Primary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    43
    42
    Units: ratio of baseline PVR
        geometric mean (confidence interval 95%)
    0.63 (0.58 to 0.67)
    0.98 (0.91 to 1.05)
    Statistical analysis title
    		 Analysis of change in PVR
    Statistical analysis description
    The null hypothesis (change of PVR at Week 12 as a ratio of baseline PVR in subjects treated with placebo or macitentan is the same) is tested on the primary endpoint by means of an analysis of covariance (ANCOVA) model on the log(e) transformed ratios of PVR at Week 12 to baseline PVR.
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.72
    Notes
    [1] - ANCOVA model adjusted by treatment, background PAH-specific therapy at baseline and region as factors, and log-transformed PVR at baseline as a covariate.

    Secondary: Change from baseline to Week 12 in 6-minute walk distance (6MWD)

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    End point title
    		 Change from baseline to Week 12 in 6-minute walk distance (6MWD)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    43
    42
    Units: meter
    arithmetic mean (standard deviation)
        6MWD at baseline
    385.8 ( 99.97 )
    383.2 ( 108.90 )
        6MWD at Week 12
    392.2 ( 98.46 )
    380.8 ( 114.98 )
        Change of 6MWD from baseline to Week 12
    6.4 ( 65.74 )
    -2.4 ( 43.65 )
    Statistical analysis title
    		 Analysis of change in 6MWD at Week 12
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.4264 [3]
    Method
    		 mixed-effect model repeated measure
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    9.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.5
         upper limit
    		 33.95
    Notes
    [2] - The main analysis on 6MWD was performed using a mixed-effect model repeated measure (MMRM) adjusted for treatment, visit, region, PAH-specific therapy at baseline, and treatment-by-visit interaction as factors, and baseline 6MWD and WHO functional class (FC) as covariates.
    [3] - No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.

    Secondary: Change from baseline to Week 12 in WHO functional class (FC)

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    End point title
    		 Change from baseline to Week 12 in WHO functional class (FC)
    End point description
    Changes from baseline to Week 12 in WHO FC were dichotomized as worsening (i.e., change > 0) versus no change or improvement (i.e., change ≤ 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure.
    End point type
    Secondary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    43
    42
    Units: subjects
        WHO FC I at baseline
    1
    1
        WHO FC II at baseline
    27
    23
        WHO FC III at baseline
    15
    18
        WHO FC IV at baseline
    0
    0
        WHO FC I at Week 12
    3
    4
        WHO FC II at Week 12
    27
    23
        WHO FC III at Week 12
    13
    15
        WHO FC IV at Week 12
    0
    0
        Improved from baseline to Week 12
    9
    7
        Worsened from baseline to Week 12
    6
    1
        Unchanged from baseline to Week 12
    28
    34
    Statistical analysis title
    		 Analysis of worsening in WHO FC at Week 12
    Statistical analysis description
    A logistic regression model (exact) adjusted for treatment, PAH-specific therapy at baseline, and region as covariates was used to analyze worsening in WHO FC.
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1278 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.253
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.714
         upper limit
    		 298.376
    Notes
    [4] - No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.

    Secondary: Change from baseline to Week 12 in the biomarker N-terminal pro b-type natriuretic peptide (NT-proBNP)

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    End point title
    		 Change from baseline to Week 12 in the biomarker N-terminal pro b-type natriuretic peptide (NT-proBNP)
    End point description
    NT-proBNP functions as a strong indicator of prognosis in patients with pulmonary hypertension (PH). The relative change from baseline to Week 12 in NT-proBNP is expressed as a ratio of Week 12 to baseline NT-proBNP. Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, ‘N’(number of participants analyzed included population included participants with available baseline data.
    End point type
    Secondary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    41
    40
    Units: ratio of baseline NT-proBNP
        geometric mean (confidence interval 95%)
    0.86 (0.67 to 1.11)
    1.04 (0.81 to 1.34)
    Statistical analysis title
    		 Analysis of change in NT-proBNP
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3951 [5]
    Method
    		 ANCOVA
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.874
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.639
         upper limit
    		 1.196
    Notes
    [5] - No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.

    Secondary: Change from baseline to Week 12 in mean right atrial pressure (mRAP)

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    End point title
    		 Change from baseline to Week 12 in mean right atrial pressure (mRAP)
    End point description
    Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, ‘N’(number of participants analyzed included population included participants with available baseline data.
    End point type
    Secondary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    42
    42
    Units: mmHg
    arithmetic mean (standard deviation)
        mRAP at baseline
    7.3 ( 3.74 )
    6.7 ( 3.60 )
        mRAP at Week 12
    9.0 ( 5.32 )
    7.0 ( 2.93 )
        Change in mRAP from baseline to Week 12
    1.6 ( 5.55 )
    0.3 ( 3.29 )
    Statistical analysis title
    		 Analysis of change in mRAP
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0637 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 3.44
    Notes
    [6] - No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.

    Secondary: Change from baseline to Week 12 in mean pulmonary artery pressure (mPAP)

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    End point title
    		 Change from baseline to Week 12 in mean pulmonary artery pressure (mPAP)
    End point description
    End point type
    Secondary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    43
    42
    Units: mmHg
    arithmetic mean (standard deviation)
        mPAP at baseline
    46.4 ( 7.89 )
    43.8 ( 8.52 )
        mPAP at Week 12
    40.0 ( 7.61 )
    44.2 ( 8.26 )
        Change in mPAP at Week 12
    -6.4 ( 4.94 )
    0.4 ( 7.04 )
    Statistical analysis title
    		 Analysis of change in mPAP
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -5.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 -3.57
    Notes
    [7] - No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.

    Secondary: Change from baseline to Week 12 in cardiac index

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    End point title
    		 Change from baseline to Week 12 in cardiac index
    End point description
    End point type
    Secondary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    43
    42
    Units: L/min/m2
    arithmetic mean (standard deviation)
        Cardiac index at baseline
    46.4 ( 7.89 )
    43.8 ( 8.52 )
        Cardiac index at Week 12
    40.0 ( 7.61 )
    44.2 ( 8.26 )
        Change in Cardiac index at Week 12
    -6.4 ( 4.94 )
    0.4 ( 7.04 )
    Statistical analysis title
    		 Analysis of change in cardiac index
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.81
    Notes
    [8] - No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.

    Secondary: Change from baseline to Week 12 in total pulmonary resistance (TPR)

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    End point title
    		 Change from baseline to Week 12 in total pulmonary resistance (TPR)
    End point description
    End point type
    Secondary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    43
    42
    Units: dyn*sec/cm5
    arithmetic mean (standard deviation)
        TPR at baseline
    689.3 ( 228.59 )
    671.5 ( 199.73 )
        TRP at Week 12
    489.4 ( 157.13 )
    653.1 ( 197.88 )
        Change in TPR from baseline to Week 12
    -199.8 ( 163.06 )
    -18.3 ( 135.28 )
    Statistical analysis title
    		 Analysis of change in TPR
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -171.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -223.67
         upper limit
    		 -119.3
    Notes
    [9] - No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.

    Secondary: Change from baseline to Week 12 in mixed venous oxygen saturation (SVO2)

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    End point title
    		 Change from baseline to Week 12 in mixed venous oxygen saturation (SVO2)
    End point description
    Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, ‘N’(number of participants analyzed included population included participants with available baseline data.
    End point type
    Secondary
    End point timeframe
    From enrollment/baseline to Week 12 in the DB treatment period
    End point values
    		 Macitentan 10 mg Placebo
    Number of subjects analysed
    41
    41
    Units: percent
    arithmetic mean (standard deviation)
        SVO2 at baseline
    69.2 ( 9.87 )
    69.9 ( 5.34 )
        SVO2 at Week 12
    70.3 ( 7.07 )
    70.7 ( 8.58 )
        Change in SVO2 from baseline to Week 12
    1.1 ( 6.70 )
    0.8 ( 7.81 )
    Statistical analysis title
    		 Analysis of change in SVO2
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9844 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.85
         upper limit
    		 2.91
    Notes
    [10] - No adjustment was made for multiplicity for secondary endpoints, therefore all corresponding p-values provided are of an exploratory nature.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 3.4 years
    Adverse event reporting additional description
    The Safety Set (SS) included all participants who received at least one dose of study treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Double-Blind (DB) Period: Macitentan 10 mg
    Reporting group description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks during DB treatment period.

    Reporting group title
    DB Period: Placebo
    Reporting group description
    		 Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks during DB treatment period.

    Reporting group title
    Open-Label (OL) Period: Macitentan 10 mg
    Reporting group description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period

    Reporting group title
    OL Extension Period: Macitentan 10 mg
    Reporting group description
    		 Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period . Participants (who were randomized at French sites) who completed the core phase of the study as scheduled and opted to continue receiving OL study treatment continued to receive macitentan 10 mg in OLE period.

    Serious adverse events
    		 Double-Blind (DB) Period: Macitentan 10 mg DB Period: Placebo Open-Label (OL) Period: Macitentan 10 mg OL Extension Period: Macitentan 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 43 (20.93%)
    6 / 42 (14.29%)
    18 / 80 (22.50%)
    11 / 33 (33.33%)
         number of deaths (all causes)
    0
    0
    4
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular Carcinoma
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 42 (4.76%)
    0 / 80 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Malignant Ascites
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Adenocarcinoma
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Testis Cancer
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Surgical and medical procedures
    Aneurysm Repair
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 80 (0.00%)
    0 / 33 (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
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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 / 1
    Localised Oedema
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Oedema Peripheral
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Priapism
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Alveolitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Asthma
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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 Arterial Hypertension
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary Toxicity
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Investigations
    Liver Function Test Increased
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I Increased
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Vascular Procedure Complication
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 80 (0.00%)
    0 / 33 (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
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left Ventricular Failure
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    2 / 43 (4.65%)
    1 / 42 (2.38%)
    2 / 80 (2.50%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic Stroke
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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 / 1
    Hepatic Encephalopathy
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    2 / 80 (2.50%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Syncope
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    2 / 80 (2.50%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal Vascular Ectasia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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 Angiodysplasia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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 Haemorrhage
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Intestinal Obstruction
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Melaena
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    2 / 80 (2.50%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal Hypertensive Gastropathy
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Hepatobiliary disorders
    Hepatic Failure
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 42 (2.38%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Chronic Kidney Disease
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Pyelonephritis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Gastroenteritis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Lung Infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Pneumonia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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
    Localised Infection
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 80 (0.00%)
    0 / 33 (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
    Metabolism and nutrition disorders
    Diabetes Mellitus
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    1 / 33 (3.03%)
         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
    Fluid Overload
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    0 / 33 (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 10 mg DB Period: Placebo Open-Label (OL) Period: Macitentan 10 mg OL Extension Period: Macitentan 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 43 (60.47%)
    23 / 42 (54.76%)
    45 / 80 (56.25%)
    26 / 33 (78.79%)
    Investigations
    Haemoglobin Decreased
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 42 (0.00%)
    3 / 80 (3.75%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    3
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 43 (4.65%)
    2 / 42 (4.76%)
    5 / 80 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    2
    7
    1
    Headache
         subjects affected / exposed
    7 / 43 (16.28%)
    7 / 42 (16.67%)
    10 / 80 (12.50%)
    1 / 33 (3.03%)
         occurrences all number
    10
    8
    11
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 42 (0.00%)
    9 / 80 (11.25%)
    5 / 33 (15.15%)
         occurrences all number
    3
    0
    12
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    4 / 80 (5.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    2
    6
    3
    Influenza Like Illness
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    3 / 80 (3.75%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    3
    3
    Oedema Peripheral
         subjects affected / exposed
    10 / 43 (23.26%)
    5 / 42 (11.90%)
    13 / 80 (16.25%)
    5 / 33 (15.15%)
         occurrences all number
    13
    6
    16
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 42 (9.52%)
    1 / 80 (1.25%)
    1 / 33 (3.03%)
         occurrences all number
    1
    6
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 42 (4.76%)
    3 / 80 (3.75%)
    3 / 33 (9.09%)
         occurrences all number
    1
    2
    3
    4
    Cough
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    1 / 80 (1.25%)
    0 / 33 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 80 (1.25%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    1
    2
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    0
    0
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    5 / 33 (15.15%)
         occurrences all number
    1
    0
    0
    5
    Musculoskeletal and connective tissue disorders
    Pain in Extremity
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 42 (7.14%)
    6 / 80 (7.50%)
    1 / 33 (3.03%)
         occurrences all number
    2
    3
    7
    1
    Back Pain
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 42 (2.38%)
    1 / 80 (1.25%)
    2 / 33 (6.06%)
         occurrences all number
    2
    1
    2
    2
    Muscle Spasms
         subjects affected / exposed
    0 / 43 (0.00%)
    5 / 42 (11.90%)
    3 / 80 (3.75%)
    0 / 33 (0.00%)
         occurrences all number
    0
    6
    3
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 42 (0.00%)
    3 / 80 (3.75%)
    13 / 33 (39.39%)
         occurrences all number
    4
    0
    3
    23
    Nasopharyngitis
         subjects affected / exposed
    2 / 43 (4.65%)
    2 / 42 (4.76%)
    3 / 80 (3.75%)
    2 / 33 (6.06%)
         occurrences all number
    3
    2
    3
    2
    Rhinitis
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 42 (0.00%)
    4 / 80 (5.00%)
    7 / 33 (21.21%)
         occurrences all number
    2
    0
    6
    12
    Sinusitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 80 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    1
    0
    0
    3
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 43 (4.65%)
    6 / 42 (14.29%)
    2 / 80 (2.50%)
    2 / 33 (6.06%)
         occurrences all number
    2
    6
    2
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2015
    Amendment 1, resulting in Global Protocol Version 2: • Visit window was changed to ± 4 days from ± 7 days to ensure patients had enough study treatment until the next visit. • Reference to hepatic event questionnaire was removed as this form was removed from the electronic Case Report Form (eCRF) • Daclatasvir was added as permitted Hepatitis C medication following its approval • Analysis of urea was removed as it was not needed in addition to blood urea nitrogen. • NT-proBNP storage/shipping text was further clarified • It was clarified that laboratory assessments to be used for eligibility assessment were those performed at Visit 1 / Screening (not Visit 2 / Randomization). • A urine dipstick pregnancy test was added to the assessments at Visit 2 / Randomization in order to have the result prior to treatment assignment. • It was clarified that hepatic vein catheterization (HVC) was not mandatory • It was clarified that PAH or PoPH medications stopped within 3 months prior to randomization were required to be documented in the eCRF.
    21 Apr 2016
    Amendment 2, resulting in Global Protocol Version 3: • It was clarified that local laboratory assessments were allowed in order to simplify eligibility assessment and implementation of the stopping rule (i.e., for calculating Model for End-Stage Liver Disease (MELD) score and/or Child-Pugh classification) at Week 12. It was further clarified that the central laboratory kit was required to be used in parallel to the use of local laboratory assessments. • It was clarified that study treatment was allowed to be continued in case of orthotopic liver transplantation (OLT) during the OL period of the study, based on medical consideration. • It was allowed to perform the pharmacokinetic (PK) substudy closer to the patient’s home to ease participation • Certain eligibility criteria were modified based on medical considerations, e.g., exclusion criterion 15: transplant expected within 3 months removed; exclusion 21: calcium channel blockers (CCBs) moved to exclusion 20; beta blockers moved to exclusion 10) • The list of allowed and forbidden medications was updated with newly approved antiviral medications • It was clarified that screening started on the day of ICF signature • The definition of the Full Analysis Set was modified to include patients for whom post-baseline PVR was imputed

    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.
    None reported
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