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    Clinical Trial Results:
    A prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group, 12-week study to evaluate the safety and tolerability of macitentan in subjects with combined pre- and post-capillary pulmonary hypertension (CpcPH) due to left ventricular dysfunction

    Summary
    EudraCT number
    		 2013-003822-96
    Trial protocol
    		 IT   CZ   AT   BE   ES  
    Global end of trial date
    15 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Feb 2017
    First version publication date
    25 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055G201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02070991
    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
    16 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of macitentan 10 mg in subjects with CpcPH
    Protection of trial subjects
    The study was conducted in compliance with International Council for Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines, the principles of the ‘Declaration of Helsinki’ and with the laws and regulations of the country in which the research was conducted. Subjects with LVD and severely reduced ejection fraction (<30%) were not included in the study for safety reasons, since they are more likely to develop complications due to fluid retention. Subjects were required to return to the site for a safety visit after 1 week.
    Background therapy
    		 All subjects were required to be on oral diuretic therapy, and they were allowed to continue their usual heart failure therapy. The dose of diuretic(s) (and other heart failure therapy, if applicable) was required to be stable for at least 1 week prior to baseline RHC and up to Randomization
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    63
    EEA total number of subjects
    46
    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)
    8
    From 65 to 84 years
    54
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 88 patients were screened from 28 sites across Europe and North America in 11 countries. Of these, 63 were randomized.

    Pre-assignment
    Screening details
    		 The screening period had to take place within 30 days prior to enrollment into 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
    		 Investigator, Subject, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Macitentan
    Arm description
    		 Patients were administered macitentan oral tablet, 10 mg 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
    Tablet containing 10mg macitentan, once daily

    Arm title
    		 Placebo
    Arm description
    		 Patients were administered matching placebo once daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet identical to the macitentan tablet, once daily

    Number of subjects in period 1
    		Macitentan Placebo
    Started
    31
    32
    Completed
    28
    32
    Not completed
    3
    0
         Adverse event, serious fatal
    2
    -
         Withdrawal by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    		 Patients were administered macitentan oral tablet, 10 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were administered matching placebo once daily

    Reporting group values
    		 Macitentan Placebo Total
    Number of subjects
    		 31 32 63
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 3 8
        From 65-84 years
    		 26 28 54
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70 ( 5.19 ) 71.5 ( 7.77 ) -
    Gender categorical
    Units:
        Male
    		 6 16 22
        Female
    		 25 16 41
    Race
    Units: Subjects
        Black or African American
    		 0 1 1
        American Indian or Alaska
    		 1 0 1
        White
    		 30 30 60
        Other
    		 0 1 1
    NYHA Functional Class at Baseline
    Units: Subjects
        Class II
    		 5 10 15
        Class III
    		 26 22 48
    Left Ventricular Ejection Fraction at Baseline as Measured by Investigator
    Units: Subjects
        < 50%
    		 6 9 15
        >= 50%
    		 25 23 48
    # of subjects with Atrial Fibrillation at baseline
    Units: Subjects
        Yes
    		 22 24 46
        No
    		 9 8 17
    # of subjects with Systemic Hypertension]
    Units: Subjects
        Yes
    		 30 27 57
        No
    		 1 5 6
    # of subjects with Diabetes Mellitus Type II
    Units: Subjects
        Yes
    		 14 13 27
        No
    		 17 19 36
    # of subjects with Right Ventricular Failure
    Units: Subjects
        Yes
    		 7 11 18
        No
    		 24 21 45
    # of subjects with Chronic Kidney Disease
    Units: Subjects
        Yes
    		 8 6 14
        No
    		 23 26 49
    # of subjects with Obesity - BMI > 30kg/m2
    Units: Subjects
        Yes
    		 20 20 40
        No
    		 11 12 23
    Time from Left Ventricular Dysfunction diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    		 4.6 ( 8.9 ) 3.3 ( 6.5 ) -
    6MWD at baseline
    Units: Meters
        arithmetic mean (standard deviation)
    		 317.2 ( 104.3 ) 299.6 ( 107.4 ) -
    PVR at baseline
    Units: dyn.sec/cm5
        arithmetic mean (standard deviation)
    		 491.2 ( 235.5 ) 549.3 ( 239.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    		 Patients were administered macitentan oral tablet, 10 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were administered matching placebo once daily

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Full analysis set included all subjects from the Screened analysis set allocated to a randomized study treatment

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety analysis set included all subjects from the Full analysis set who received at least one dose of study treatment, based on the actual treatment received

    Primary: Proportion of subjects experiencing significant fluid retention or worsening in NYHA functional class up to end-of-treatment

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    End point title
    		 Proportion of subjects experiencing significant fluid retention or worsening in NYHA functional class up to end-of-treatment
    End point description
    Composite endpoint of significant fluid retention (defined as an increase in body weight due to fluid overload by ≥ 5kg or ≥ 5%, or parenteral administration of diuretics) or a worsening of NYHA functional class from baseline. Subject could have met more than 1 component of the main safety endpoint
    End point type
    Primary
    End point timeframe
    From randomization up to End of Study: treatment period up to Week 12
    End point values
    		 Macitentan Placebo
    Number of subjects analysed
    31
    32
    Units: Number of subjects
        Subjects with at least one condition
    7
    4
        Subjects with significant fluid retention
    7
    3
        Worsening in NYHA Functional Class from baseline
    1
    2
    Statistical analysis title
    		 Treatment difference between macitentan & placebo
    Statistical analysis description
    Difference in % of subjects with at least 1 condition
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.337
    Method
    		 Fisher exact
    Parameter type
    		 Difference in proportion
    Point estimate
    10.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.07
         upper limit
    		 33.26

    Other pre-specified: NT-Pro-BNP at Week 12 Expressed As Percent of Baseline

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    End point title
    		 NT-Pro-BNP at Week 12 Expressed As Percent of Baseline
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From randomization up to end of treatment period (Week 12)
    End point values
    		 Macitentan Placebo
    Number of subjects analysed
    25
    26
    Units: % ratio
        geometric mean (confidence interval 95%)
    91.56 (72.37 to 115.83)
    118.9 (92.53 to 152.78)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Ratio of Geometric Means (Macitentan/Placebo)
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.08

    Other pre-specified: PVR at rest at Week 12 expressed as percent of Baseline PVR at rest

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    End point title
    		 PVR at rest at Week 12 expressed as percent of Baseline PVR at rest
    End point description
    PVR was assessed at rest by right heart catheterization
    End point type
    Other pre-specified
    End point timeframe
    From randomization up to end of treatment period (Week 12)
    End point values
    		 Macitentan Placebo
    Number of subjects analysed
    20
    24
    Units: % ratio
        geometric mean (confidence interval 95%)
    66.31 (56.15 to 78.3)
    71.23 (51.35 to 98.81)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Ratio of Geometric Means (Macitentan/Placebo)
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.36

    Other pre-specified: Mean Pulmonary Arterial Pressure - Absolute change from Baseline to Week 12

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    End point title
    		 Mean Pulmonary Arterial Pressure - Absolute change from Baseline to Week 12
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From randomization up to end of treatment period (Week 12)
    End point values
    		 Macitentan Placebo
    Number of subjects analysed
    21
    25
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    -3.5 (-6.1 to -0.9)
    -3.8 (-7.5 to -0.1)
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 4.9

    Other pre-specified: Mean Right Atrial Pressure - Absolute change from baseline to week 12

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    End point title
    		 Mean Right Atrial Pressure - Absolute change from baseline to week 12
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From randomization up to end of treatment period (Week 12)
    End point values
    		 Macitentan Placebo
    Number of subjects analysed
    21
    25
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    -0.9 (-3.5 to 1.7)
    -1.6 (-3.3 to 0)
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 3.6

    Other pre-specified: Pulmonary Artery Wedge Pressure - Absolute change from Baseline to Week 12

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    End point title
    		 Pulmonary Artery Wedge Pressure - Absolute change from Baseline to Week 12
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From randomization up to end of treatment period (Week 12)
    End point values
    		 Macitentan Placebo
    Number of subjects analysed
    20
    24
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    0.8 (-2.3 to 3.9)
    1.1 (-1.6 to 3.8)
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 3.7

    Other pre-specified: Cardiac Index - Absolute change from Baseline to Week 12

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    End point title
    		 Cardiac Index - Absolute change from Baseline to Week 12
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From randomization up to end of treatment period (Week 12)
    End point values
    		 Macitentan Placebo
    Number of subjects analysed
    20
    24
    Units: L/min/m2
        arithmetic mean (confidence interval 95%)
    0.37 (0.14 to 0.6)
    -0.03 (-0.22 to 0.16)
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 0.68

    Other pre-specified: Diastolic Pulmonary V. Pressure Gradient - Absolute change from Baseline to Week 12

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    End point title
    		 Diastolic Pulmonary V. Pressure Gradient - Absolute change from Baseline to Week 12
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From randomization up to end of treatment period (Week 12)
    End point values
    		 Macitentan Placebo
    Number of subjects analysed
    20
    24
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    -4.8 (-7.2 to -2.3)
    -4.3 (-7.5 to -1.1)
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 3.6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 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
    18
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo once daily for at least 8.0 weeks to a maximum duration of 14.1 weeks

    Reporting group title
    Macitentan_10mg
    Reporting group description
    		 Subjects received macitentan oral tablet, 10 mg once daily for at least 0.3 week to a maximum duration of 14.9 weeks

    Serious adverse events
    		 Placebo Macitentan_10mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 32 (18.75%)
    11 / 31 (35.48%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiorenal syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Mouth haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic respiratory failure
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         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
    		 Placebo Macitentan_10mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 32 (46.88%)
    16 / 31 (51.61%)
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Walking distance test abnormal
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic neoplasm
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    Mitral valve incompetence
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 31 (6.45%)
         occurrences all number
    3
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 31 (9.68%)
         occurrences all number
    1
    3
    Nausea
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    Dyspnoea
         subjects affected / exposed
    4 / 32 (12.50%)
    3 / 31 (9.68%)
         occurrences all number
    5
    4
    Pleural effusion
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    3
    Hypokalaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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