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    Clinical Trial Results:
    Prospective, randomized, placebo-controlled, double-blind, multicenter, parallel-group, 24-week study to assess the efficacy, safety and tolerability of macitentan in subjects with inoperable chronic thromboembolic pulmonary hypertension

    Summary
    EudraCT number
    2013-002950-56
    Trial protocol
    CZ   DE   AT   BE   GB   HU   NL   LT  
    Global end of trial date
    28 Sep 2016

    Results information
    Results version number
    v3(current)
    This version publication date
    11 Jun 2020
    First version publication date
    18 Oct 2017
    Other versions
    v1 , v2
    Version creation reason
    • New data added to full data set
    FDS updated per CSR Addendum-2.

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055E201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02021292
    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@actelion.com
    Scientific contact
    Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@actelion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of macitentan 10 mg on pulmonary vascular resistance (PVR) at rest in comparison with placebo in subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).
    Protection of trial subjects
    Prior to the start of the trial the study center consulted an Independent Ethics Committee (IEC), i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well-being of human patients involved in a clinical investigation. The sponsor ensured that the IEC consulted was adequately constituted to provide assurance of that protection, and maintained a list of committee members and their qualifications. The protocol and any material provided to the patient (such as a subject information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate IEC before the study was started. This study was conducted in full conformance with the principles of the ‘Declaration of Helsinki’ and with the laws and regulations of the country in which the 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 patients’ 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
    49 of 80 randomized subjects (61.3%) received PAH-specific background therapy at baseline (24 or 60% of subjects on macitentan and 25 or 62.5% of subjects on placebo).
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Aug 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    China: 24
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 4
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    80
    EEA total number of subjects
    21
    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)
    52
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 48 sites in 20 countries screened subjects for recruitment. The study was conducted (i.e., randomized subjects) in a total of 36 sites across 16 countries: Belgium, China, Czech Republic, France, Germany, Hungary, Lithuania, Mexico, Poland, Russia, Thailand, Turkey, South Korea, Switzerland, Ukraine, and the United Kingdom.

    Pre-assignment
    Screening details
    The target screening period from Visit 1 up to Randomization was a maximum of 30 days, but a longer period (up to 60 days) was permitted with pre-approval from Actelion. A total of 186 subjects were screened.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Macitentan
    Arm description
    Macitentan 10 mg, oral tablet, to be taken once daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    ACT-064992
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet, once daily

    Arm title
    Placebo
    Arm description
    Matching placebo oral tablet, to be taken once daily.
    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
    Placebo, once-daily

    Number of subjects in period 1
    Macitentan Placebo
    Started
    40
    40
    Completed
    40
    37
    Not completed
    0
    3
         Death
    -
    1
         Physician decision
    -
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    Macitentan 10 mg, oral tablet, to be taken once daily.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo oral tablet, to be taken once daily.

    Reporting group values
    Macitentan Placebo Total
    Number of subjects
    40 40 80
    Age categorical
    Units: Subjects
        Age 18-64 years
    26 26 52
        Age 65-84 years
    14 14 28
    Age continuous
    Units: years
        median (full range (min-max))
    60.0 (20 to 80) 58.0 (23 to 78) -
    Gender categorical
    Units:
        Female
    26 25 51
        Male
    14 15 29
    Region of enrollment
    Units: Subjects
        Asia
    15 14 29
        Eastern Europe
    17 19 36
        Latin America
    1 1 2
        Western Europe
    7 6 13
    WHO functional class
    Units: Subjects
        class II
    12 6 18
        class III
    28 33 61
        class IV
    0 1 1
    Body Mass Index (BMI)
    Units: kg/m2
        median (full range (min-max))
    25.7 (19.8 to 47.5) 26.0 (18.3 to 36.2) -
    6-minute walk distance (6MWD)
    Units: meter
        arithmetic mean (standard deviation)
    353.0 ± 87.90 351.2 ± 73.79 -
    Pulmonary vascular resistance (PVR)
    Units: dyn.sec/cm5
        arithmetic mean (standard deviation)
    929.2 ± 379.65 984.3 ± 487.06 -
    Time since diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)
    Units: years
        arithmetic mean (standard deviation)
    1.7 ± 2.36 1.2 ± 1.95 -
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all subjects assigned to a study treatment. In order to adhere to the intention-to-treat principle as much as possible: 1) subjects were evaluated according to the study treatment they have been assigned to; and 2) all available data were included.

    Subject analysis sets values
    Full analysis set (FAS)
    Number of subjects
    80
    Age categorical
    Units: Subjects
        Age 18-64 years
    52
        Age 65-84 years
    28
    Age continuous
    Units: years
        median (full range (min-max))
    59.0 (20 to 80)
    Gender categorical
    Units:
        Female
    51
        Male
    29
    Region of enrollment
    Units: Subjects
        Asia
    29
        Eastern Europe
    36
        Latin America
    2
        Western Europe
    13
    WHO functional class
    Units: Subjects
        class II
    18
        class III
    61
        class IV
    1
    Body Mass Index (BMI)
    Units: kg/m2
        median (full range (min-max))
    25.7 (18.3 to 47.5)
    6-minute walk distance (6MWD)
    Units: meter
        arithmetic mean (standard deviation)
    352.1 ± 80.64
    Pulmonary vascular resistance (PVR)
    Units: dyn.sec/cm5
        arithmetic mean (standard deviation)
    956.8 ± 434.78
    Time since diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)
    Units: years
        arithmetic mean (standard deviation)
    1.5 ± 2.16

    End points

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    End points reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    Macitentan 10 mg, oral tablet, to be taken once daily.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo oral tablet, to be taken once daily.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all subjects assigned to a study treatment. In order to adhere to the intention-to-treat principle as much as possible: 1) subjects were evaluated according to the study treatment they have been assigned to; and 2) all available data were included.

    Primary: Change from baseline to Week 16 in pulmonary vascular resistance (PVR) at rest.

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    End point title
    Change from baseline to Week 16 in pulmonary vascular resistance (PVR) at rest.
    End point description
    The primary efficacy endpoint is defined as the PVR at rest at Week 16 expressed as percent of baseline PVR at rest. Full analysis set included all subjects assigned to a study treatment.
    End point type
    Primary
    End point timeframe
    From baseline to Week 16
    End point values
    Macitentan Placebo
    Number of subjects analysed
    40
    40
    Units: % of PVR at baseline (=100%)
        geometric mean (confidence interval 95%)
    73.0 (63.6 to 83.8)
    87.2 (78.5 to 96.7)
    Statistical analysis title
    Analysis of change in PVR
    Statistical analysis description
    The null hypothesis (change of PVR at rest in Week 16 in percent 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 % of baseline PVR at rest at Week 16.
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.041
    Method
    ANCOVA
    Parameter type
    ratio of geometric means
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    0.99
    Notes
    [1] - ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate.

    Secondary: Change from baseline to Week 24 in exercise capacity, as measured by the 6-minute walk distance (6MWD).

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    End point title
    Change from baseline to Week 24 in exercise capacity, as measured by the 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. Full analysis set included all subjects assigned to a study treatment.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24
    End point values
    Macitentan Placebo
    Number of subjects analysed
    40
    40
    Units: meter
    arithmetic mean (standard deviation)
        6MWD (m) at baseline
    353.0 ± 87.90
    351.2 ± 73.79
        6MWD (m) at Week 24
    388.0 ± 83.31
    352.2 ± 121.29
        Change from baseline to Week 24
    35.0 ± 52.52
    1.0 ± 83.24
    Statistical analysis title
    Analysis of change in 6MWD
    Statistical analysis description
    Statistical model is ANCOVA including 6MWD at baseline as a covariate, with treatment as factor in the model. The least squares (LS) mean difference of change from baseline to Week 24 (treatment difference: macitentan vs placebo) was 34.04 m (95% confidence limit: 2.9, 65.2, p = 0.0326).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.0326
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    34.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.9
         upper limit
    65.2
    Notes
    [2] - To control for multiplicity across primary and secondary endpoints, all secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons.

    Secondary: Change from baseline to Week 24 in Borg dyspnea index collected at the end of the 6-minute walk test (6MWT).

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    End point title
    Change from baseline to Week 24 in Borg dyspnea index collected at the end of the 6-minute walk test (6MWT).
    End point description
    This outcome measures the difference in the Borg dyspnea index at Week 24 compared to baseline. The index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 (‘Nothing at all’) to 10 (‘Very, very severe – maximal’). Full analysis set included all subjects assigned to a study treatment.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24
    End point values
    Macitentan Placebo
    Number of subjects analysed
    40
    40
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Borg dyspnea index score at baseline
    4.2 ± 2.52
    4.2 ± 2.14
        Borg dyspnea index score at Week 24
    4.1 ± 2.52
    4.4 ± 2.45
        Change from baseline to Week 24
    -0.1 ± 1.86
    0.3 ± 2.04
    Statistical analysis title
    Analysis of change in Borg dyspnea index
    Statistical analysis description
    Statistical model is Analysis of Covariance including Borg dyspnea index at baseline as a covariate, with Treatment as factor in the model. The least squares (LS) mean difference of change from baseline to Week 24 (macitentan vs placebo) was -0.39 (95% confidence limit: –1.21, 0.43; p=0.3492).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.3492
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    -0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.21
         upper limit
    0.43
    Notes
    [3] - To control for multiplicity across primary and secondary endpoints, all secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons.

    Secondary: Proportion of subjects with worsening in WHO functional class from baseline to Week 24.

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    End point title
    Proportion of subjects with worsening in WHO functional class from baseline to Week 24.
    End point description
    WHO functional classes are defined as follows: 1) class I: no symptoms with exercise or at rest. No limitation of activity. 2) 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). 3) class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. 4) class IV: symptoms at rest (such as dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms (e.g. may faint especially while bending over with their heads lowered). Patients in class IV manifest signs of right heart failure. Shifting to a higher class (e.g. from class III to class IV) represents a 'worsening' while shifting to a lower class (e.g. from class III to class II) means an 'improvement'. Full analysis set included all subjects assigned to a study treatment.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24
    End point values
    Macitentan Placebo
    Number of subjects analysed
    40
    40
    Units: Subjects
        WHO functional class I at baseline
    0
    0
        WHO functional class II at baseline
    12
    6
        WHO functional class III at baseline
    28
    33
        WHO functional class IV at baseline
    0
    1
        WHO functional class I at Week 24
    3
    1
        WHO functional class II at Week 24
    15
    10
        WHO functional class III at Week 24
    22
    26
        WHO functional class IV at Week 24
    0
    3
        Worsened
    0
    3
        Not worsened (total)
    40
    37
        Not worsened (unchanged)
    31
    29
        Not worsened (improved)
    9
    8
    Statistical analysis title
    Analysis of worsening in WHO functional class
    Statistical analysis description
    The null hypothesis is odds of worsening are the same in placebo and macitentan group. Logistic regression is used for macitentan vs placebo comparison with treatment and WHO functional class at baseline as factors in the model. The odds ratio for worsening WHO functional class at Week 24 (macitentan vs placebo) was 0.212 (95% confidence limit: < 0.001, 1.464, p = 0.0962).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.0962
    Method
    ANCOVA
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.212
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    1.464
    Notes
    [4] - To control for multiplicity across primary and secondary endpoints, all secondary endpoints were analyzed in sequence using hierarchical approach based on order and significance as pre-specified in protocol eliminating further adjustment for multiple comparisons.

    Post-hoc: Post-hoc analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest including subjects with corrected hemodynamic values

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    End point title
    Post-hoc analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest including subjects with corrected hemodynamic values
    End point description
    The main analysis of the primary efficacy endpoint of PVR was repeated after the voluntary right heart catheterization source data verification (SDV) and independent medical review of hemodynamic data corrected for 13 subjects reported after the clinical database closure. Full analysis set for this post-hoc analysis included all subjects assigned to a study treatment with SDV values.
    End point type
    Post-hoc
    End point timeframe
    From baseline to Week 16
    End point values
    Macitentan Placebo
    Number of subjects analysed
    40
    40
    Units: Percent of baseline PVR
        geometric mean (confidence interval 95%)
    71.5 (63.5 to 80.4)
    87.6 (79.0 to 97.2)
    Statistical analysis title
    Analysis of PVR change with corrected PVR values
    Statistical analysis description
    The same statistical model as for the predefined analysis (ANCOVA) was applied, including 13 subjects with corrected hemodynamic values.
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Post-hoc
    Analysis type
    superiority [5]
    P-value
    = 0.0098 [6]
    Method
    ANCOVA
    Parameter type
    Model-adjusted geometric mean ratio
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    0.95
    Notes
    [5] - ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate.
    [6] - This is the post-hoc analysis and p-value is an exploratory p-value.

    Post-hoc: Post-hoc Analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest Excluding Subjects with Corrected Hemodynamic Values

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    End point title
    Post-hoc Analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest Excluding Subjects with Corrected Hemodynamic Values
    End point description
    The main analysis of the primary efficacy endpoint of PVR was repeated which excluded data for 13 subjects with corrected hemodynamic values. The hemodynamic values were reported after the SDV assessment clinical database closure. Full analysis set excluding subjects with corrected hemodynamic values.
    End point type
    Post-hoc
    End point timeframe
    From baseline to Week 16
    End point values
    Macitentan Placebo
    Number of subjects analysed
    33
    34
    Units: Percent of baseline PVR
        geometric mean (confidence interval 95%)
    68.4 (60.3 to 77.5)
    86.1 (77.3 to 95.7)
    Statistical analysis title
    Post-hoc statistical analysis 1
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Post-hoc
    Analysis type
    superiority [7]
    P-value
    = 0.0061 [8]
    Method
    ANCOVA
    Parameter type
    Model-adjusted geometric mean ratio
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    0.93
    Notes
    [7] - ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate.
    [8] - This is the post-hoc analysis and p-value is an exploratory p-value.

    Post-hoc: Post-hoc Analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest Excluding Subjects with Implausible Hemodynamic Findings

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    End point title
    Post-hoc Analysis of change from baseline to Week 16 in Pulmonary Vascular Resistance (PVR) at rest Excluding Subjects with Implausible Hemodynamic Findings
    End point description
    The main analysis of the primary efficacy endpoint of PVR was repeated which excluded 14 subjects with implausible hemodynamic findings. Full analysis set excluding subjects with implausible hemodynamic findings.
    End point type
    Post-hoc
    End point timeframe
    From baseline to Week 16
    End point values
    Macitentan Placebo
    Number of subjects analysed
    32
    34
    Units: Percent of baseline PVR
        geometric mean (confidence interval 95%)
    73.9 (66.2 to 82.4)
    86.6 (77.9 to 96.4)
    Statistical analysis title
    Post-hoc statistical analysis 1
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Post-hoc
    Analysis type
    superiority [9]
    P-value
    = 0.0414 [10]
    Method
    ANCOVA
    Parameter type
    Geometric mean ratio
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    0.99
    Notes
    [9] - ANCOVA model on log-transformed % of baseline PVR at Week 16 adjusted by treatment as a factor and log transformed PVR at baseline as a covariate.
    [10] - This is the post-hoc analysis and p-value is an exploratory p-value.

    Post-hoc: Post-hoc Analysis of Change from baseline to Week 24 in exercise capacity, as measured by the 6-minute walk distance (6MWD) Excluding subjects with Implausible Hemodynamic Findings

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    End point title
    Post-hoc Analysis of Change from baseline to Week 24 in exercise capacity, as measured by the 6-minute walk distance (6MWD) Excluding subjects with Implausible Hemodynamic Findings
    End point description
    The same analysis for the secondary endpoint, 6MWD, is repeated on the full analysis set excluding 14 subject with implausible hemodynamic findings. Full analysis set excluding subjects with implausible hemodynamic findings.
    End point type
    Post-hoc
    End point timeframe
    From baseline to Week 24
    End point values
    Macitentan Placebo
    Number of subjects analysed
    32
    34
    Units: meter
        least squares mean (confidence interval 95%)
    37.41 (11.12 to 63.71)
    0.23 (-25.28 to 25.74)
    Statistical analysis title
    Post-hoc statistical analysis 1
    Statistical analysis description
    Statistical model is ANCOVA including 6MWD at baseline as a covariate, with treatment as factor in the model.
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0468 [11]
    Method
    ANCOVA
    Parameter type
    least squares (LS) mean difference
    Point estimate
    37.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    73.83
    Notes
    [11] - This is the post-hoc analysis and p-value is an exploratory p-value.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From double-blind study treatment initiation up to 30 days after study treatment discontinuation
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    Macitentan 10 mg, oral tablet, to be taken once daily.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo oral tablet, to be taken once daily.

    Serious adverse events
    Macitentan Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 40 (7.50%)
    7 / 40 (17.50%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Weight increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute right ventricular failure
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         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
    Dyspnoea
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         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
    22 / 40 (55.00%)
    19 / 40 (47.50%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    4
    Haemoglobin decreased
         subjects affected / exposed
    6 / 40 (15.00%)
    0 / 40 (0.00%)
         occurrences all number
    7
    0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Dyspnoea
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Epistaxis
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Pulmonary hypertension
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Syncope
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    8 / 40 (20.00%)
    4 / 40 (10.00%)
         occurrences all number
    10
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
         occurrences all number
    1
    3
    Back pain
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Bone pain
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Pain in extremity
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 40 (10.00%)
         occurrences all number
    1
    4
    Pharyngitis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2015
    Global amendment 1 resulting in Protocol version 2. Changes included: - Number of study countries screening period was prolonged to improve the rate of recruitment. - Modification of the required qualifications for country-specific adjudication committees (CSAC). - Further clarification of guidelines on oxygen use during the 6MWT. - Clarification of use of the PAH-SYMPACT questionnaire. - Update of ICF to reflect changes in country numbers and of clarifications of study procedures in clinical protocol.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/28919201
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