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    Clinical Trial Results:
    Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Adult and Adolescent Subjects

    Summary
    EudraCT number
    		 2016-003320-23
    Trial protocol
    		 GB   DE   DK   FR   PL   IE   CZ  
    Global end of trial date
    26 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Feb 2022
    First version publication date
    09 Feb 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AC-055H301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03153137
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, CH-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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001032-PIP03-19
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to assess the effect of macitentan on exercise capacity (measured by peak oxygen uptake/consumption [VO2]) in comparison with placebo in Fontan-palliated subjects.
    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 Practices and applicable regulatory requirements. Safety evaluations were based on assessment of treatment-emergent adverse events (AEs) and serious AEs (SAEs), vital signs, and laboratory parameters.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Oct 2017
    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
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    Czechia: 20
    Country: Number of subjects enrolled
    Denmark: 23
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    137
    EEA total number of subjects
    78
    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)
    18
    Adults (18-64 years)
    119
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 137 subjects were randomized and enrolled in the study of which 130 subjects completed the study.

    Period 1
    Period 1 title
    Overall Study (overall 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
    		 Placebo
    Arm description
    		 Subjects received Macitentan matching placebo tablets orally once daily (o.d) with or without food starting Day 1 (Visit 2) up to Week 52.
    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
    Subjects received Macitentan matching placebo tablets with or without food.

    Arm title
    		 Macitentan
    Arm description
    		 Subjects received Macitentan 10 milligrams (mg) tablet o.d orally with or without food starting Day 1 up to Week 52.
    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
    Subjects received Macitentan 10 mg tablets with or without food.

    Number of subjects in period 1
    		Placebo Macitentan
    Started
    69
    68
    Completed
    66
    64
    Not completed
    3
    4
         Consent withdrawn by subject
    2
    1
         Physician decision
    -
    1
         Adverse event, non-fatal
    -
    2
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Macitentan matching placebo tablets orally once daily (o.d) with or without food starting Day 1 (Visit 2) up to Week 52.

    Reporting group title
    Macitentan
    Reporting group description
    		 Subjects received Macitentan 10 milligrams (mg) tablet o.d orally with or without food starting Day 1 up to Week 52.

    Reporting group values
    		 Placebo Macitentan Total
    Number of subjects
    		 69 68 137
    Title for AgeCategorical
    Units: subjects
        Adolescents: 12-<18 yrs
    		 10 8 18
        Adults: >= 18 yrs
    		 59 60 119
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 24.5 ± 7.49 23.2 ± 5.82 -
    Title for Gender
    Units: subjects
        Female
    		 25 23 48
        Male
    		 44 45 89

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Macitentan matching placebo tablets orally once daily (o.d) with or without food starting Day 1 (Visit 2) up to Week 52.

    Reporting group title
    Macitentan
    Reporting group description
    		 Subjects received Macitentan 10 milligrams (mg) tablet o.d orally with or without food starting Day 1 up to Week 52.

    Primary: Change in Peak Oxygen Uptake/Consumption (VO2) from Baseline to Week 16

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    End point title
    		 Change in Peak Oxygen Uptake/Consumption (VO2) from Baseline to Week 16
    End point description
    Change in peak VO2 from baseline to Week 16 was reported. Full analysis set (FAS) included all subjects randomized to the study treatment. (V̇O2 is a flow = a ratio of a volume by unit of time)
    End point type
    Primary
    End point timeframe
    Baseline to Week 16
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: Milliliter/kilogram/minute (mL/kg/min)
        arithmetic mean (standard deviation)
    -0.67 ± 2.657
    -0.16 ± 2.855
    Statistical analysis title
    		 Statistical Analysis Set A
    Statistical analysis description
    Due to adaptive nature of the design, the main analysis was conducted on FAS using the inverse normal combination method with pre-specified weights to combine first and second stage p-values.
    Comparison groups
    Placebo v Macitentan
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.193 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Median unbiased estimate and repeated CI
    Point estimate
    0.62
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 1.85
    Notes
    [1] - For each stage, the p-value from the ANCOVA model including randomized treatment, geographical region, and baseline peak VO2 was used to construct the final adjusted p-value.
    [2] - Final adjusted p-value (from weighted inverse normal combination test)

    Secondary: Change in Peak VO2 from Baseline over 52 Weeks

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    End point title
    		 Change in Peak VO2 from Baseline over 52 Weeks
    End point description
    Change in peak VO2 from baseline over 52 weeks was reported. FAS included all subjects randomized to the study treatment. The results reported disregard the adaptive nature of the design.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: mL/kg/min
        least squares mean (standard error)
    -0.92 ± 0.296
    -0.31 ± 0.293
    No statistical analyses for this end point

    Secondary: Change in Mean Count per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) from Baseline to Week 16

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    End point title
    		 Change in Mean Count per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) from Baseline to Week 16
    End point description
    Change in mean count per minute of daily PA-Ac from baseline to Week 16 was reported. The daily physical activity (counts/min) of the subject is assessed via accelerometer during daytime. FAS included all subjects randomized to the study treatment. N (number of subjects analyzed) is defined as the number of subjects evaluable for this outcome measure. The results reported disregard the adaptive nature of the design.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    58
    61
    Units: counts
        least squares mean (standard error)
    -13.95 ± 13.882
    -3.39 ± 13.536
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-emergent Adverse Events (AEs) and Treatment-emergent Serious AEs (SAEs)

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    End point title
    		 Number of Subjects with Treatment-emergent Adverse Events (AEs) and Treatment-emergent Serious AEs (SAEs)
    End point description
    An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. The Safety analysis set (SS) included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 56 weeks
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: subjects
        Treatment- emergent AEs
    44
    48
        Treatment- emergent SAEs
    9
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects with AEs Leading to Premature Discontinuation of Study Treatment

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    End point title
    		 Number of Subjects with AEs Leading to Premature Discontinuation of Study Treatment
    End point description
    Number of subjects with AEs leading to premature discontinuation of study treatment was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: subjects
    1
    3
    No statistical analyses for this end point

    Secondary: Change in Systolic and Diastolic Arterial Blood Pressure [BP] from Baseline up to Week 56

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    End point title
    		 Change in Systolic and Diastolic Arterial Blood Pressure [BP] from Baseline up to Week 56
    End point description
    Change in systolic and diastolic arterial BP from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Systolic BP: Week 8
    2.5 ± 14.41
    -0.4 ± 11.67
        Systolic BP: Week 16
    0.5 ± 14.68
    -4.6 ± 13.05
        Systolic BP: Week 32
    -6.3 ± 15.09
    -3.1 ± 10.51
        Systolic BP: Week 52
    0.0 ± 12.12
    -4.8 ± 12.08
        Systolic BP: EOT+1 Day
    0.4 ± 12.28
    -4.6 ± 12.21
        Systolic BP: between EOT+1 and EOT+35 Days
    6.5 ± 3.54
    -0.3 ± 8.14
        Diastolic BP: Week 8
    -0.2 ± 5.86
    -0.1 ± 9.57
        Diastolic BP: Week 16
    -0.6 ± 10.06
    -3.1 ± 8.74
        Diastolic BP: Week 32
    1.3 ± 8.64
    -1.4 ± 8.21
        Diastolic BP: Week 52
    1.3 ± 10.84
    -2.8 ± 11.21
        Diastolic BP: EOT+1 Day
    1.7 ± 10.96
    -2.7 ± 10.74
        Diastolic BP: between EOT+1 and EOT+35 Days
    6.5 ± 9.19
    7.2 ± 6.59
    No statistical analyses for this end point

    Secondary: Change in Pulse Rate from Baseline up to Week 56

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    End point title
    		 Change in Pulse Rate from Baseline up to Week 56
    End point description
    Change in pulse rate from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: beats per minute (bpm)
    arithmetic mean (standard deviation)
        Week 8
    -3.9 ± 12.80
    -5.9 ± 12.07
        Week 16
    0.1 ± 14.76
    -0.1 ± 11.57
        Week 32
    0.2 ± 12.37
    1.1 ± 9.10
        Week 52
    -0.7 ± 11.56
    -2.9 ± 10.25
        EOT+1 Day
    -0.4 ± 12.96
    -2.7 ± 11.13
        Between EOT+1 and EOT+35 Days
    -13.0 ± 16.97
    -1.5 ± 8.62
    No statistical analyses for this end point

    Secondary: Change in Oxygen Saturation (SpO2) from Baseline up to Week 56

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    End point title
    		 Change in Oxygen Saturation (SpO2) from Baseline up to Week 56
    End point description
    Change in SpO2 from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: percentage
    arithmetic mean (standard deviation)
        Week 8
    0.0 ± 3.20
    1.2 ± 2.78
        Week 16
    0.5 ± 2.57
    0.8 ± 2.75
        Week 32
    0.8 ± 2.94
    1.4 ± 3.73
        Week 52
    1.4 ± 2.77
    0.9 ± 2.99
        EOT+1 Day
    1.2 ± 2.71
    0.9 ± 2.99
        Between EOT+1 and EOT+35 Days
    3.0 ± 1.41
    2.0 ± 4.29
    No statistical analyses for this end point

    Secondary: Change in Body Weight from Baseline up to Week 56

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    End point title
    		 Change in Body Weight from Baseline up to Week 56
    End point description
    Change in body weight from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: kilograms (kg)
    arithmetic mean (standard deviation)
        Week 8
    -0.38 ± 1.996
    0.43 ± 1.568
        Week 16
    0.21 ± 2.028
    0.58 ± 2.230
        Week 32
    0.73 ± 2.952
    0.77 ± 3.411
        Week 52
    1.44 ± 3.746
    1.30 ± 4.358
        EOT+1 Day
    1.21 ± 3.732
    1.27 ± 4.178
        Between EOT+1 and EOT+35 Days
    0.55 ± 0.778
    2.53 ± 3.753
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-emergent Marked Laboratory Abnormalities

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    End point title
    		 Number of Subjects with Treatment-emergent Marked Laboratory Abnormalities
    End point description
    Number of subjects with treatment-emergent marked laboratory abnormalities was reported. SS includes all subjects who received at least one dose of study treatment. n (number analyzed) is defined as number of subjects evaluable for this specified category.
    End point type
    Secondary
    End point timeframe
    Up to 56 weeks
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: subjects
        Haemoglobin: LLL less than (<) 80 (n=69,67)
    0
    0
        Haemoglobin: LL< 100 (n=69,67)
    0
    0
        Haemoglobin: HH (Increase in > 20 g/L) (n=69,67)
    0
    0
        Haemoglobin: HHH (Increase in > 40 g/L (n=69,67)
    0
    0
        Hematocrit: LLL (< 0.20) (n=69,67)
    0
    0
        Hematocrit: LL (< 0.28 (female) < 0.32 (male))
    0
    0
        Hematocrit: HH (> 0.55 (female) > 0.60 (male))
    0
    0
        Hematocrit: HHH (> 0.65)
    0
    0
        Platelets: LLL (< 50) (n=69,67)
    0
    0
        Platelets: LL (< 75) (n=69,67)
    2
    1
        Platelets: HH (> 600) (n=69,67)
    0
    0
        Platelets: HHH (> 999) (n=69,67)
    0
    0
        Leukocytes: LLL (< 1.9) (n=69,67)
    0
    0
        Leukocytes: HH (> 20.0) (n=69,67)
    0
    0
        Leukocytes: HHH (> 100.0) (n=69,67)
    0
    0
        Lymphocytes: LLL (< 0.2) (n=69,67)
    0
    0
        Lymphocytes: HH (> 4.0) (n=69,67)
    0
    1
        Lymphocytes: HHH (> 20) (n=69,67)
    0
    0
        Neutrophils: LLL (< 1.0) (n=69,67)
    0
    0
        Neutrophils: LL (< 1.5) (n=69,67)
    0
    2
        Eosinophils: HH (> 5.0) (n=69,67)
    0
    0
        Prothrombin Intl. Normalized Ratio: HH (≥ 1.5 ULN)
    3
    5
        Prothrombin Intl. Normalized Ratio: HH (≥ 2.5 ULN)
    1
    1
        Bilirubin: HH (≥ 2 ULN) (n=69,67)
    1
    2
        Bilirubin: HHH (≥ 5 ULN) (n=69,67)
    0
    0
        Alkaline Phosphatase: HH (> 2.5 ULN) (n=69,67)
    1
    0
        Alkaline Phosphatase: HHH (> 5 ULN) (n=69,67)
    0
    0
        Glomerular Filtration Rate: LLL (< 30) (n=68,67)
    0
    0
        Glomerular Filtration Rate: LL (< 60) (n=68,67)
    1
    1
        Glucose: LLL (< 2.2) (n=68,67)
    0
    0
        Glucose: LL (< 3.0) (n=68,67)
    0
    2
        Glucose: HH (> 8.9) (n=68,67)
    0
    2
        Glucose: HHH (> 13.9) (n=68,67)
    0
    0
        Triglycerides: HH (> 3.42) (n=68,67)
    3
    1
        Triglycerides: HHH (> 11.4 (n=68,67)
    0
    0
    No statistical analyses for this end point

    Secondary: Change in Hemoglobin from Baseline up to Week 56

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    End point title
    		 Change in Hemoglobin from Baseline up to Week 56
    End point description
    Change in hemoglobin from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: grams per liter (g/L)
    arithmetic mean (standard deviation)
        Week 8
    0.0 ± 6.59
    -8.7 ± 9.33
        Week 16
    0.0 ± 7.75
    -8.7 ± 8.51
        Week 32
    1.3 ± 8.29
    -7.3 ± 9.84
        Week 52
    -2.9 ± 10.04
    -7.1 ± 10.02
        EOT+1 Day
    -1.6 ± 10.25
    -7.6 ± 10.45
        Between EOT+1 and EOT+35 Days
    -3.7 ± 5.59
    -7.4 ± 16.69
    No statistical analyses for this end point

    Secondary: Change in Hematocrit from Baseline up to Week 56

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    End point title
    		 Change in Hematocrit from Baseline up to Week 56
    End point description
    Change in hematocrit from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: Liter/Liter (L/L)
    arithmetic mean (standard deviation)
        Week 8
    0.002 ± 0.027
    -0.030 ± 0.023
        Week 16
    0.003 ± 0.027
    -0.023 ± 0.026
        Week 32
    0.003 ± 0.031
    -0.009 ± 0.028
        Week 52
    -0.010 ± 0.030
    -0.021 ± 0.028
        EOT+1 Day
    -0.005 ± 0.033
    -0.024 ± 0.028
        Between EOT+1 and EOT+35 Days
    -0.015 ± 0.007
    -0.034 ± 0.055
    No statistical analyses for this end point

    Secondary: Change in Erythrocytes and Reticulocytes from Baseline up to Week 56

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    End point title
    		 Change in Erythrocytes and Reticulocytes from Baseline up to Week 56
    End point description
    Change in erythrocytes and reticulocytes from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: 10^12 per liter
    arithmetic mean (standard deviation)
        Erythrocytes: Week 8
    0.048 ± 0.2461
    -0.297 ± 0.2866
        Erythrocytes: Week 16
    0.012 ± 0.2521
    -0.264 ± 0.2790
        Erythrocytes: Week 32
    -0.031 ± 0.2442
    -0.090 ± 0.2337
        Erythrocytes: Week 52
    -0.096 ± 0.2515
    -0.184 ± 0.2671
        Erythrocytes: EOT+1 Day
    -0.051 ± 0.2895
    -0.241 ± 0.2980
        Erythrocytes: between EOT+1 and EOT+35 Days
    -0.100 ± 0.0000
    -0.228 ± 0.5364
        Reticulocytes: Week 8
    -0.006 ± 0.017
    -0.006 ± 0.016
        Reticulocytes: Week 16
    -0.003 ± 0.026
    -0.001 ± 0.021
        Reticulocytes: Week 32
    -0.003 ± 0.028
    -0.008 ± 0.027
        Reticulocytes: Week 52
    -0.012 ± 0.033
    -0.011 ± 0.023
        Reticulocytes: EOT+1 Day
    -0.010 ± 0.031
    -0.008 ± 0.023
        Reticulocytes: between EOT+1 and EOT+35 Days
    -0.016 ± 0.007
    0.021 ± 0.030
    No statistical analyses for this end point

    Secondary: Change in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets from Baseline up to Week 56

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    End point title
    		 Change in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets from Baseline up to Week 56
    End point description
    Change in leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Leukocytes: Week 8
    -0.242 ± 1.7651
    -1.001 ± 1.2096
        Leukocytes: Week 16
    -0.199 ± 1.5490
    -0.378 ± 1.3908
        Leukocytes: Week 32
    0.417 ± 1.1782
    -0.237 ± 1.7224
        Leukocytes: Week 52
    -0.554 ± 1.4050
    -0.715 ± 1.6433
        Leukocytes: EOT+1 Day
    -0.442 ± 1.3504
    -0.594 ± 1.6208
        Leukocytes: between EOT+1 and EOT+35 Days
    -3.535 ± 0.4596
    -0.653 ± 0.9841
        Neutrophils: Week 8
    -0.133 ± 1.3604
    -0.743 ± 0.9864
        Neutrophils: Week 16
    -0.291 ± 1.3547
    -0.373 ± 1.0896
        Neutrophils: Week 32
    0.494 ± 0.9719
    -0.254 ± 1.2012
        Neutrophils: Week 52
    -0.384 ± 1.1619
    -0.627 ± 1.2475
        Neutrophils: EOT+1 Day
    -0.308 ± 1.1214
    -0.536 ± 1.2369
        Neutrophils: between EOT+1 and EOT+35 Days
    -3.560 ± 0.1414
    -0.353 ± 1.2918
        Lymphocytes: Week 8
    -0.113 ± 0.4770
    -0.165 ± 0.2886
        Lymphocytes: Week 16
    0.073 ± 0.4756
    0.042 ± 0.6164
        Lymphocytes: Week 32
    0.047 ± 0.3341
    0.126 ± 0.2269
        Lymphocytes: Week 52
    -0.082 ± 0.4740
    -0.033 ± 0.3890
        Lymphocytes: EOT+1 Day
    -0.060 ± 0.4553
    -0.054 ± 0.3731
        Lymphocytes: between EOT+1 and EOT+35 Days
    0.025 ± 0.2758
    0.098 ± 0.2641
        Monocytes: Week 8
    -0.017 ± 0.1645
    -0.081 ± 0.1400
        Monocytes: Week 16
    0.002 ± 0.1703
    -0.050 ± 0.1202
        Monocytes: Week 32
    -0.018 ± 0.1209
    -0.071 ± 0.1162
        Monocytes: Week 52
    -0.039 ± 0.1380
    -0.077 ± 0.1257
        Monocytes: EOT+1 Day
    -0.034 ± 0.1321
    -0.065 ± 0.1221
        Monocytes: between EOT+1 and EOT+35 Days
    -0.005 ± 0.2333
    -0.053 ± 0.1706
        Eosinophils: Week 8
    -0.003 ± 0.5146
    0.014 ± 0.0816
        Eosinophils: Week 16
    0.016 ± 0.3056
    0.002 ± 0.0755
        Eosinophils: Week 32
    -0.100 ± 0.5447
    0.029 ± 0.1951
        Eosinophils: Week 52
    -0.046 ± 0.3597
    0.015 ± 0.1935
        Eosinophils: EOT+1 day
    -0.041 ± 0.3334
    0.023 ± 0.1758
        Eosinophils: between EOT+1 and EOT+35 Days
    0.005 ± 0.0919
    -0.093 ± 0.1548
        Basophils: Week 8
    -0.002 ± 0.0255
    -0.002 ± 0.0233
        Basophils: Week 16
    0.004 ± 0.0394
    0.000 ± 0.0363
        Basophils: Week 32
    -0.003 ± 0.0354
    0.016 ± 0.0313
        Basophils: Week 52
    -0.003 ± 0.0389
    0.006 ± 0.0281
        Basophils: EOT+1 Day
    0.001 ± 0.0391
    0.004 ± 0.0290
        Basophils: between EOT+1 and EOT+35 Days
    0.000 ± 0.0000
    0.000 ± 0.0316
        Platelets: Week 8
    -5.9 ± 32.85
    -9.1 ± 35.38
        Platelets: Week 16
    -5.4 ± 30.33
    -3.0 ± 28.77
        Platelets: Week 32
    -7.8 ± 33.46
    8.2 ± 33.76
        Platelets: Week 52
    -11.2 ± 29.94
    -5.7 ± 31.75
        Platelets: EOT+1 Day
    -8.8 ± 28.90
    -7.7 ± 30.35
        Platelets: between EOT+1 and EOT+35 Days
    -28.5 ± 3.54
    3.8 ± 7.97
    No statistical analyses for this end point

    Secondary: Change in Prothrombin Time from Baseline up to Week 56

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    End point title
    		 Change in Prothrombin Time from Baseline up to Week 56
    End point description
    Change in prothrombin time from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: Seconds (sec)
    arithmetic mean (standard deviation)
        Week 8
    -0.23 ± 3.265
    -0.53 ± 4.567
        Week 16
    0.04 ± 3.921
    0.36 ± 10.868
        Week 32
    1.45 ± 8.261
    0.03 ± 4.135
        Week 52
    -0.64 ± 3.167
    -1.20 ± 3.567
        EOT+1 Day
    -0.99 ± 4.005
    -1.70 ± 5.953
        Between EOT+1 and EOT+35 Days
    0.75 ± 3.041
    1.12 ± 3.699
    No statistical analyses for this end point

    Secondary: Change in Prothrombin Intl. Normalized Ratio from Baseline up to Week 56

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    End point title
    		 Change in Prothrombin Intl. Normalized Ratio from Baseline up to Week 56
    End point description
    Change in prothrombin intl. normalized ratio from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: Ratio
    arithmetic mean (standard deviation)
        Week 8
    -0.009 ± 0.3216
    -0.054 ± 0.4652
        Week 16
    0.015 ± 0.3806
    0.049 ± 1.1653
        Week 32
    0.171 ± 0.9204
    0.033 ± 0.4597
        Week 52
    -0.044 ± 0.3265
    -0.120 ± 0.3889
        EOT+1 day
    -0.093 ± 0.4460
    -0.168 ± 0.6244
        Between EOT+1 and EOT+35 days
    0.250 ± 0.4950
    -0.020 ± 0.0800
    No statistical analyses for this end point

    Secondary: Change in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP) from Baseline up to Week 56

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    End point title
    		 Change in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP) from Baseline up to Week 56
    End point description
    Change in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: Units per liter (U/L)
    arithmetic mean (standard deviation)
        ALT: Week 8
    -0.8 ± 5.57
    -1.8 ± 9.99
        ALT: Week 16
    -0.2 ± 6.86
    -1.6 ± 7.94
        ALT: Week 32
    -0.4 ± 5.62
    -2.1 ± 12.53
        ALT: Week 52
    -0.2 ± 8.11
    -0.3 ± 14.04
        ALT: EOT+1 day
    -0.1 ± 7.72
    1.1 ± 17.41
        ALT: Between EOT+1 and EOT+35 Days
    -4.1 ± 6.12
    8.3 ± 25.48
        AST: Week 8
    -0.7 ± 4.92
    -4.4 ± 2.37
        AST: Week 16
    -0.5 ± 6.13
    -3.9 ± 20.25
        AST: Week 32
    0.9 ± 4.14
    -4.7 ± 22.46
        AST: Week 52
    -0.6 ± 6.83
    -3.2 ± 24.16
        AST: EOT+1 day
    -0.5 ± 6.53
    -0.7 ± 26.60
        AST: Between EOT+1 and EOT+35 days
    -5.0 ± 4.36
    4.5 ± 15.38
        AP: Week 8
    -7.6 ± 19.82
    -8.5 ± 18.14
        AP: Week 16
    -4.7 ± 19.20
    -7.1 ± 22.54
        AP: Week 32
    -10.1 ± 32.43
    -1.1 ± 26.30
        AP: Week 52
    -12.9 ± 34.81
    -7.0 ± 27.63
        AP: EOT+1 Day
    -11.8 ± 32.47
    -9.3 ± 30.51
        AP: Between EOT+1 and EOT+35 days
    -13.0 ± 14.14
    0.3 ± 10.97
    No statistical analyses for this end point

    Secondary: Change in Bilirubin and Direct Bilirubin from Baseline up to Week 56

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    End point title
    		 Change in Bilirubin and Direct Bilirubin from Baseline up to Week 56
    End point description
    Change in bilirubin and direct bilirubin from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: umol/L
    arithmetic mean (standard deviation)
        Bilirubin: Week 8
    0.62 ± 5.985
    -1.08 ± 5.693
        Bilirubin: Week 16
    1.98 ± 5.799
    -1.76 ± 7.075
        Bilirubin: Week 32
    1.47 ± 5.285
    0.29 ± 5.052
        Bilirubin: Week 52
    0.69 ± 5.778
    -1.02 ± 5.778
        Bilirubin: EOT+1 Day
    1.13 ± 6.059
    -1.47 ± 7.657
        Bilirubin: Between EOT+1 and EOT+35 Days
    -1.00 ± 1.414
    -0.83 ± 5.115
        Direct Bilirubin: Week 8
    -0.06 ± 1.105
    -0.22 ± 1.149
        Direct Bilirubin: Week 16
    0.24 ± 1.088
    -0.28 ± 1.227
        Direct Bilirubin: Week 32
    0.00 ± 1.029
    -0.04 ± 1.147
        Direct Bilirubin: Week 52
    0.28 ± 1.280
    -0.24 ± 1.228
        Direct Bilirubin: EOT+1 Day
    0.31 ± 1.435
    -0.24 ± 1.138
        Direct Bilirubin: between EOT+1 and EOT+35 days)
    0.50 ± 0.707
    0.17 ± 1.329
    No statistical analyses for this end point

    Secondary: Change in Gamma Glutamyl Transferase from Baseline up to Week 56

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    End point title
    		 Change in Gamma Glutamyl Transferase from Baseline up to Week 56
    End point description
    Change in gamma glutamyl transferase from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: Units per liter (U/L)
    arithmetic mean (standard deviation)
        Week 8
    -4.8 ± 13.22
    -5.5 ± 12.56
        Week 16
    -4.4 ± 13.79
    0.7 ± 27.43
        Week 32
    -1.3 ± 13.39
    -5.3 ± 23.29
        Week 52
    -3.2 ± 22.40
    -6.7 ± 21.31
        EOT+1 Day
    -1.0 ± 15.98
    -6.4 ± 19.98
        Between EOT+1 and EOT+35 Days
    -58.0 ± 82.02
    -7.2 ± 30.81
    No statistical analyses for this end point

    Secondary: Change in Creatinine from Baseline up to Week 56

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    End point title
    		 Change in Creatinine from Baseline up to Week 56
    End point description
    Change in creatinine from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: umol/L
    arithmetic mean (standard deviation)
        Week 8
    -2.0 ± 7.49
    -6.2 ± 7.49
        Week 16
    -1.1 ± 10.72
    -0.3 ± 12.46
        Week 32
    2.2 ± 10.81
    -1.8 ± 13.46
        Week 52
    -1.5 ± 9.52
    0.4 ± 10.00
        EOT+1 Day
    -1.5 ± 9.01
    0.4 ± 10.28
        Between EOT+1 and EOT+35 Days
    3.5 ± 2.12
    -0.8 ± 7.73
    No statistical analyses for this end point

    Secondary: Change in Urea Nitrogen from Baseline up to Week 56

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    End point title
    		 Change in Urea Nitrogen from Baseline up to Week 56
    End point description
    Change in urea nitrogen from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Week 8
    -0.30 ± 0.989
    -0.09 ± 1.217
        Week 16
    -0.04 ± 1.043
    0.06 ± 1.278
        Week 32
    0.02 ± 0.955
    -0.25 ± 1.274
        Week 52
    -0.06 ± 1.251
    0.04 ± 1.101
        EOT+1 Day
    -0.02 ± 1.186
    0.02 ± 1.141
        Between EOT+1 and EOT+35 days)
    -1.70 ± 1.414
    -0.17 ± 0.582
    No statistical analyses for this end point

    Secondary: Change in Urate from Baseline up to Week 56

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    End point title
    		 Change in Urate from Baseline up to Week 56
    End point description
    Change in urate from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: umol/L
    arithmetic mean (standard deviation)
        Week 8
    -0.8 ± 40.76
    -53.6 ± 40.17
        Week 16
    2.8 ± 40.13
    -37.8 ± 40.01
        Week 32
    16.0 ± 39.35
    -56.7 ± 53.18
        Week 52
    1.1 ± 49.36
    -25.8 ± 54.39
        EOT+1 Day
    0.4 ± 46.38
    -27.8 ± 54.24
        Between EOT+1 and EOT+35 Days
    -38.0 ± 4.24
    -10.2 ± 27.26
    No statistical analyses for this end point

    Secondary: Change in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium from Baseline up to Week 56

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    End point title
    		 Change in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium from Baseline up to Week 56
    End point description
    Change in glucose, cholesterol, triglycerides, sodium, potassium, chloride and calcium from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Glucose: Week 8
    0.00 ± 1.028
    -0.46 ± 0.914
        Glucose: Week 16
    0.17 ± 1.153
    -0.04 ± 1.022
        Glucose: Week 32
    0.24 ± 0.911
    -0.12 ± 0.850
        Glucose: Week 52
    -0.03 ± 0.883
    -0.28 ± 1.193
        Glucose: EOT+1 Day
    0.03 ± 0.919
    -0.25 ± 1.156
        Glucose: Between EOT+1 and EOT+35 Days
    -0.25 ± 1.202
    -0.28 ± 0.796
        Cholesterol: Week 8
    -0.182 ± 0.3808
    -0.238 ± 0.3807
        Cholesterol: Week 16
    -0.065 ± 0.3994
    -0.190 ± 0.5139
        Cholesterol: Week 32
    0.060 ± 0.5185
    -0.059 ± 0.5364
        Cholesterol: Week 52
    -0.065 ± 0.4308
    -0.093 ± 0.4243
        Cholesterol: EOT+1 Day
    -0.080 ± 0.4273
    -0.126 ± 0.4450
        Cholesterol: Between EOT+1 and EOT+35 Days
    -0.355 ± 0.2616
    -0.042 ± 0.4820
        Triglycerides: Week 8
    -0.061 ± 0.5950
    -0.071 ± 0.3755
        Triglycerides: Week 16
    -0.099 ± 0.3946
    -0.004 ± 0.4244
        Triglycerides: Week 32
    0.123 ± 0.4749
    0.024 ± 0.5126
        Triglycerides: Week 52
    -0.067 ± 0.5191
    -0.020 ± 0.4703
        Triglycerides: EOT+1 Day
    -0.092 ± 0.5069
    -0.010 ± 0.4449
        Triglycerides: Between EOT+1 and EOT+35 Days
    0.160 ± 0.0990
    0.002 ± 0.1848
        Sodium: Week 8
    -0.5 ± 2.02
    -0.2 ± 2.52
        Sodium: Week 16
    -1.1 ± 2.74
    -0.6 ± 2.94
        Sodium: Week 32
    -0.7 ± 3.23
    -0.3 ± 2.44
        Sodium: Week 52
    -1.1 ± 2.28
    -1.0 ± 2.35
        Sodium: EOT+1 Day
    -1.0 ± 2.25
    -0.8 ± 2.36
        Sodium: Between EOT+1 and EOT+35 Days
    2.0 ± 2.83
    0.2 ± 3.71
        Potassium: Week 8
    -0.074 ± 0.3476
    -0.030 ± 0.2876
        Potassium: Week 16
    -0.013 ± 0.3684
    0.030 ± 0.3783
        Potassium: Week 32
    -0.011 ± 0.3957
    -0.033 ± 0.2599
        Potassium: Week 52
    -0.031 ± 0.3354
    -0.003 ± 0.3356
        Potassium: EOT+1 Day
    -0.050 ± 0.3787
    -0.014 ± 0.3464
        Potassium: Between EOT+1 and EOT+35 Days
    0.200 ± 0.1414
    -0.145 ± 0.3062
        Chloride: Week 8
    0.2 ± 1.71
    1.3 ± 2.33
        Chloride: Week 16
    -0.4 ± 2.88
    0.3 ± 2.75
        Chloride: Week 32
    -0.1 ± 2.37
    0.3 ± 2.28
        Chloride: Week 52
    0.4 ± 2.44
    0.4 ± 2.89
        Chloride: EOT+1 Day
    0.3 ± 2.47
    0.5 ± 2.78
        Chloride: Between EOT+1 and EOT+35 Days
    2.5 ± 2.12
    0.3 ± 3.56
        Calcium: Week 8
    -0.006 ± 0.1096
    -0.062 ± 0.0999
        Calcium: Week 16
    -0.002 ± 0.0929
    -0.050 ± 0.0943
        Calcium: Week 32
    0.035 ± 0.0987
    -0.004 ± 0.1271
        Calcium: Week 52
    -0.021 ± 0.1083
    -0.035 ± 0.1093
        Calcium: EOT+1 Day
    -0.017 ± 0.1046
    -0.037 ± 0.1065
        Calcium: Between EOT+1 and EOT+35 Days
    -0.100 ± 0.0990
    0.003 ± 0.1104
    No statistical analyses for this end point

    Secondary: Change in Albumin and Protein from Baseline up to Week 56

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    End point title
    		 Change in Albumin and Protein from Baseline up to Week 56
    End point description
    Change in albumin and protein from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: grams per liter (g/L)
    arithmetic mean (standard deviation)
        Albumin: Week 8
    -0.74 ± 2.789
    -1.73 ± 2.922
        Albumin: Week 16
    0.61 ± 2.821
    -0.82 ± 3.274
        Albumin: Week 32
    0.79 ± 3.276
    0.38 ± 3.462
        Albumin: Week 52
    -0.08 ± 3.426
    -0.53 ± 3.339
        Albumin: EOT+1 Day
    -0.07 ± 3.248
    -0.80 ± 3.548
        Albumin: Between EOT+1 and EOT+35 Days
    -2.50 ± 3.536
    -2.98 ± 7.443
        Protein: Week 8
    -1.5 ± 4.28
    -3.8 ± 4.38
        Protein: Week 16
    -0.3 ± 4.62
    -1.9 ± 4.51
        Protein: Week 32
    -0.2 ± 4.38
    -0.3 ± 4.60
        Protein: Week 52
    -1.8 ± 5.42
    -2.5 ± 5.56
        Protein: EOT+1 Day
    -1.6 ± 5.10
    -2.7 ± 5.57
        Protein: Between EOT+1 and EOT+35 Days
    -3.5 ± 9.19
    -2.3 ± 3.14
    No statistical analyses for this end point

    Secondary: Change in Alpha Fetoprotein from Baseline up to Week 56

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    End point title
    		 Change in Alpha Fetoprotein from Baseline up to Week 56
    End point description
    Change in alpha fetoprotein from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: micrograms per milliliter (ug/L)
    arithmetic mean (standard deviation)
        Week 8
    0.006 ± 0.5537
    -0.061 ± 0.6314
        Week 16
    0.055 ± 0.4373
    0.160 ± 0.5667
        Week 32
    0.033 ± 0.3911
    0.191 ± 0.5959
        Week 52
    0.068 ± 0.5003
    0.240 ± 0.6349
        EOT+1 Day
    0.120 ± 0.6147
    0.236 ± 0.6976
        Between EOT+1 and EOT+35 Days
    -0.050 ± 0.2121
    0.360 ± 0.4879
    No statistical analyses for this end point

    Secondary: Change in Cystatin C from Baseline up to Week 56

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    End point title
    		 Change in Cystatin C from Baseline up to Week 56
    End point description
    Change in cystatin C from baseline up to week 56 was reported. SS included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 56
    End point values
    		 Placebo Macitentan
    Number of subjects analysed
    69
    68
    Units: milligrams per liter (mg/L)
    arithmetic mean (standard deviation)
        Week 8
    -0.026 ± 0.0563
    -0.019 ± 0.0782
        Week 16
    -0.017 ± 0.1464
    -0.019 ± 0.0964
        Week 32
    -0.038 ± 0.0659
    -0.021 ± 0.0701
        Week 52
    -0.001 ± 0.0723
    0.010 ± 0.0927
        EOT+1 Day
    -0.009 ± 0.0730
    0.006 ± 0.0865
        Between EOT+1 and EOT+35 Days
    0.035 ± 0.0495
    0.014 ± 0.0991
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 56 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    		 Subjects received Macitentan 10 milligrams (mg) tablet o.d orally with or without food starting Day 1 up to Week 52.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Macitentan matching placebo tablets orally once daily (o.d) with or without food starting Day 1 (Visit 2) up to Week 52.

    Serious adverse events
    		 Macitentan Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 68 (19.12%)
    9 / 69 (13.04%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neuroendocrine Tumour
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical Device Removal
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Haemorrhagic Ovarian Cyst
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental Status Changes
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polydipsia Psychogenic
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart Rate Increased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Back Injury
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle Fracture
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia Supraventricular
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Tachycardia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive Hepatopathy
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr Virus Infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Tonsillitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Macitentan Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 68 (22.06%)
    18 / 69 (26.09%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 68 (10.29%)
    6 / 69 (8.70%)
         occurrences all number
    14
    10
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 69 (4.35%)
         occurrences all number
    4
    3
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 69 (5.80%)
         occurrences all number
    2
    4
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 68 (1.47%)
    4 / 69 (5.80%)
         occurrences all number
    1
    6
    Nasopharyngitis
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 69 (4.35%)
         occurrences all number
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Aug 2018
    The overall reason for the amendment was to address concerns from BfArM, regarding the new protocol template by reverting to initial safety monitoring modalities. Clarification of participants’ medical care after study completion by confirming that the proposed open-label extension will be accessible to all participants who complete the study, including those who were in the PTOP.
    19 Nov 2018
    The overall reason for the amendment was implementation of Advisory Board recommendations to make the protocol more patient-centric by converting 2 site visits to phone calls; reducing the number of monthly safety labs; introducing a flying nurse service to reduce the time commitment for the study; updating contraception requirements for new markets.
    18 Dec 2019
    The overall reason for the amendment was replacing the blinded SSRE with an IA/unblinded SSRE; formal testing of secondary endpoints; introducing additional exploratory cardiopulmonary exercise testing (CPET) endpoints; adding clarifications for contraceptive use and study completion; introducing use of estimands for the primary endpoint analyses.
    15 Jul 2020
    The overall reason for the amendment was updates to forbidden medication and concomitant therapy sections based on newly identified drug-drug interactions.
    19 Nov 2020
    The overall reason for the amendment was to make global safety updates. Align the protocol with Janssen processes as part of the Actelion and Janssen integration. Simplify study-treatment supply and storage information. Add an appendix to facilitate evaluation of exclusion criterion 6.3.

    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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