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    Clinical Trial Results:
    The Efficacy and Safety of Initial Triple Versus Initial Dual Oral combination therapy in patients with newly diagnosed Pulmonary Arterial Hypertension: A Multicenter, Double-Blind, Placebo-controlled, Phase 3b study.

    Summary
    EudraCT number
    		 2015-003438-28
    Trial protocol
    		 DE   NO   FR   DK   AT   GB   ES   BE  
    Global end of trial date
    05 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2021
    First version publication date
    08 Apr 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AC-065A308
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02558231
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to compare the effect on pulmonary vascular resistance (PVR) of an initial triple oral regimen (macitentan, tadalafil, selexipag) versus an initial dual oral regimen (macitentan, tadalafil, placebo) in newly diagnosed, treatment-naïve subjects with pulmonary arterial hypertension (PAH).
    Protection of trial subjects
    The 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 was evaluated based on the following assessments: adverse events (AEs), serious adverse events (SAEs), deaths, clinical laboratory tests (hematology, clinical chemistry, pregnancy tests), vital signs, body weight, and physical examination.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Apr 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United States: 114
    Worldwide total number of subjects
    247
    EEA total number of subjects
    97
    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)
    194
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 247 subjects (123 subjects in Triple therapy and 124 subjects in Double therapy) were enrolled in the study. Out of the 247 subjects, 196 subjects completed the study (98 subjects in each arm).

    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
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)
    Arm description
    		 Subjects received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last subjects was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, subjects received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last subjects was enrolled).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg tablet administered once daily on Day 1.

    Investigational medicinal product name
    Selexipag 200 micrograms (mcg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Selexipag 200 mcg tablet administered twice daily (bid) on Day 15 and dose uptitrated in increments of 200 mcg bid, at weekly intervals until either a maximum dose of 1600 mcg bid was reached or adverse pharmacological effects that could not be tolerated or medically managed were experienced, whichever was first.

    Investigational medicinal product name
    Tadalafil 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tadalafil 20 mg tablet administered once daily on Day 1 and dose increased to 40 mg (2 tablets) once daily on Day 8.

    Arm title
    		 Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Arm description
    		 Subjects received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last subjects was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, subjects received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last subjects was enrolled).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Macitentan 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg tablet administered once daily on Day 1.

    Investigational medicinal product name
    Tadalafil 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tadalafil 20 mg tablet administered once daily on Day 1 and dose increased to 40 mg (2 tablets) once daily on Day 8.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet administered twice daily (bid) from Day 15 to End of treatment (10 months after last subject enrolled).

    Number of subjects in period 1
    		Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Started
    123
    124
    Treated
    123
    123
    Completed
    98
    98
    Not completed
    25
    26
         Adverse event, serious fatal
    4
    12
         Physician decision
    7
    5
         Consent withdrawn by subject
    7
    4
         Lost to follow-up
    7
    4
         Sponsor decision
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)
    Reporting group description
    		 Subjects received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last subjects was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, subjects received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last subjects was enrolled).

    Reporting group title
    Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Reporting group description
    		 Subjects received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last subjects was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, subjects received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last subjects was enrolled).

    Reporting group values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo) Total
    Number of subjects
    		 123 124 247
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 96 98 194
        From 65 to 84 years
    		 27 26 53
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.2 ± 13.48 51.6 ± 13.92 -
    Title for Gender
    Units: subjects
        Female
    		 93 94 187
        Male
    		 30 30 60

    End points

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    End points reporting groups
    Reporting group title
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)
    Reporting group description
    		 Subjects received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last subjects was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, subjects received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last subjects was enrolled).

    Reporting group title
    Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Reporting group description
    		 Subjects received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last subjects was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, subjects received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last subjects was enrolled).

    Primary: Change from Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)

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    End point title
    		 Change from Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)
    End point description
    Change from baseline to Week 26 in PVR was expressed as the ratio of Week 26 to baseline PVR value (Week 26 divided by baseline) using re-calculated PVR. PVR was determined by right heart catheterization (RHC). A geometric least square mean ratio of Week 26 to baseline PVR less than (<) 1 corresponds to a reduction in PVR from baseline. Missing values were imputed using a last observation carried forward (LOCF) approach. Full analysis set (FAS) included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    123
    124
    Units: ratio
        least squares mean (confidence interval 95%)
    0.46 (0.422 to 0.503)
    0.48 (0.441 to 0.526)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects analyzed were 123 and 124 in Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms, respectively.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4239
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of geometric Least Square mean
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.856
         upper limit
    		 1.068

    Secondary: Change from Baseline to Week 26 in 6-minute Walk Distance (6MWD)

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    End point title
    		 Change from Baseline to Week 26 in 6-minute Walk Distance (6MWD)
    End point description
    The change from baseline to Week 26 in 6MWD was calculated as Week 26 minus baseline. 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. Missing values were imputed using a LOCF approach. FAS included all randomized subjects. Here, N (number of subjects analyzed) signifies the number of subjects analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    123
    121
    Units: meter
        least squares mean (confidence interval 95%)
    54.96 (40.419 to 69.501)
    56.39 (41.447 to 71.327)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects analyzed were 123 and 121 in Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms, respectively.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8758
    Method
    		 ANCOVA
    Parameter type
    		 Least Square (LS) Mean difference
    Point estimate
    -1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.393
         upper limit
    		 16.538

    Secondary: Change from Baseline to Week 26 in N-terminal pro B-type Natriuretic Peptide (NT-proBNP) Levels

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    End point title
    		 Change from Baseline to Week 26 in N-terminal pro B-type Natriuretic Peptide (NT-proBNP) Levels
    End point description
    The change from baseline to Week 26 in NT-proBNP was expressed as the ratio of Week 26 to baseline NT-proBNP (Week 26 divided by baseline). A geometric least square mean ratio of Week 26 to baseline NT-proBNP <1 corresponds to a reduction in NT-proBNP from baseline. Missing values were imputed using a LOCF approach. FAS included all randomized subjects. Here, N (number of subjects analyzed) signifies the number of subjects analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    121
    122
    Units: ratio
        least squares mean (confidence interval 95%)
    0.26 (0.206 to 0.328)
    0.25 (0.200 to 0.320)
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Subjects analyzed were 121 and 122 in Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms, respectively.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8529
    Method
    		 ANCOVA
    Parameter type
    		 Ratio of LS mean
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.371

    Secondary: Percentage of Subjects with Absence of Worsening from Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC)

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    End point title
    		 Percentage of Subjects with Absence of Worsening from Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC)
    End point description
    WHO FC is a classification graded from Class I to IV which reflects disease severity based on symptoms. Worsening was defined as death or hospitalization due to PAH. Class I: No limitation of activity; Class II: slight limitation with ordinary activities; Class III: may not have symptoms at rest but greatly limited activities; Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Missing values were imputed using a LOCF approach. FAS included all randomized subjects. Here, N (number of subjects analyzed) signifies number of subjects analyzed for this endpoint. Subjects with WHO FC IV at baseline were excluded from this analysis as they could not shift to a worse category.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    122
    119
    Units: Number
        number (not applicable)
    99.2
    97.5
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP)

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    End point title
    		 Change from Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP)
    End point description
    Change from baseline to Week 26 in mean Pulmonary Arterial Pressure (mPAP) was measured. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Missing values were imputed using a LOCF approach. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    123
    124
    Units: millimeters of mercury (mmHg)
        least squares mean (confidence interval 95%)
    -12.92 (-14.609 to -11.235)
    -12.20 (-13.881 to -10.515)
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Subjects analyzed were 123 and 124 in Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms, respectively.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4998
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.834
         upper limit
    		 1.386

    Secondary: Change from Baseline to Week 26 in Mean Right Atrial Pressure (mRAP)

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    End point title
    		 Change from Baseline to Week 26 in Mean Right Atrial Pressure (mRAP)
    End point description
    Change from baseline to Week 26 in mean Right Atrial Pressure (mRAP) was measured. Missing values were imputed using a LOCF approach. FAS included all randomized subjects. Here, N (number of subjects analyzed) signifies the number of subjects analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    123
    123
    Units: mmHg
        least squares mean (confidence interval 95%)
    -1.78 (-2.512 to -1.045)
    -1.69 (-2.429 to -0.955)
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Subjects analyzed were 123 each in both Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8528
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.003
         upper limit
    		 0.83

    Secondary: Change from Baseline to Week 26 in Total Pulmonary Resistance

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    End point title
    		 Change from Baseline to Week 26 in Total Pulmonary Resistance
    End point description
    Change from baseline to Week 26 in total pulmonary resistance was measured. Total pulmonary resistance was calculated as mPAP/CO*80, where CO is cardiac output. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    123
    124
    Units: dynes*second per centimeter^5
        least squares mean (confidence interval 95%)
    -511.88 (-569.36 to -454.40)
    -514.28 (-571.45 to -457.11)
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Subjects analyzed were 123 and 124 in Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms, respectively.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9474
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -69.368
         upper limit
    		 74.178

    Secondary: Change from Baseline to Week 26 in Cardiac Index

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    End point title
    		 Change from Baseline to Week 26 in Cardiac Index
    End point description
    Change from baseline to Week 26 in cardiac index was measured. Cardiac index is the amount of blood pumped by the heart, per minute, per meter square of body surface area. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    123
    124
    Units: liters per minute per meter square
        least squares mean (confidence interval 95%)
    0.97 (0.814 to 1.130)
    0.84 (0.684 to 0.997)
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Subjects analyzed were 123 and 124 in Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms, respectively.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1902
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.066
         upper limit
    		 0.328

    Secondary: Change from Baseline to Week 26 in Venous Oxygen Saturation (%)

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    End point title
    		 Change from Baseline to Week 26 in Venous Oxygen Saturation (%)
    End point description
    Change from baseline to Week 26 in venous oxygen saturation was measured. Missing values were imputed using a LOCF approach. FAS included all randomized subjects. Here, N (number of subjects analyzed) signifies the number of subjects analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    120
    118
    Units: percentage of oxygen saturation
        least squares mean (confidence interval 95%)
    5.59 (4.370 to 6.801)
    6.79 (5.561 to 8.020)
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Subjects analyzed were 120 and 118 in Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms, respectively.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1227
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.737
         upper limit
    		 0.327

    Secondary: Number of Subjects with Disease Progression Event

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    End point title
    		 Number of Subjects with Disease Progression Event
    End point description
    Number of subjects with disease progression event were reported. Disease progression event as adjudicated by the CEC, defined as any of the following: a. Death (all causes; adjudicated for PAH relationship); b. Hospitalization for worsening PAH; c. Initiation of prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist for worsening PAH; d. Clinical worsening defined as a post-baseline decrease in 6MWD by more than (>) 15 percent (%) from the highest 6MWD obtained at or after baseline, accompanied by WHO FC III or IV (both conditions confirmed at two consecutive post-baseline visits separated by 1–21 days). FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)
    End point values
    		 Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects analysed
    123
    124
    Units: subjects
    number (not applicable)
        Week 26
    8
    13
        Month 12
    13
    20
        Month 18
    15
    23
        Month 24
    15
    25
        Month 30
    16
    27
        End of Analysis Period (up to 40 months)
    16
    27
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Subjects analyzed were 123 and 124 in Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) and Double Oral Therapy (Macitentan, Tadalafil, and Placebo) arms, respectively.
    Comparison groups
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag) v Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0867
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.09

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 42 Months
    Adverse event reporting additional description
    The Safety Set included all subjects who received at least one dose of any of 3 study treatments (macitentan, tadalafil, and selexipag or placebo) (Triple oral therapy=123 subjects and Double oral therapy=123 subjects). Four subjects in triple therapy group did not receive selexipag and were analyzed in the double therapy group for safety analysis.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Double Oral Therapy (Macitentan, Tadalafil, and Placebo)
    Reporting group description
    		 Subjects received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last subjects was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, subjects received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last subjects was enrolled).

    Reporting group title
    Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)
    Reporting group description
    		 Subjects received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last subjects was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, subjects received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last subjects was enrolled).

    Serious adverse events
    		 Double Oral Therapy (Macitentan, Tadalafil, and Placebo) Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 127 (37.80%)
    58 / 119 (48.74%)
         number of deaths (all causes)
    12
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast Cancer
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Carcinoma Cell Type Unspecified Stage I
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma Cell Myeloma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of the Tongue
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 127 (1.57%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paradoxical Embolism
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock Haemorrhagic
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Drug Delivery Device Implantation
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Arthroplasty
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Knee Arthroplasty
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Transplant
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Open Reduction of Fracture
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile Operation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Drainage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Therapy Change
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toe Amputation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (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
    Accidental Death
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    3 / 127 (2.36%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Allergy to Arthropod Sting
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Priapism
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         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
    Acute Respiratory Failure
         subjects affected / exposed
    5 / 127 (3.94%)
    6 / 119 (5.04%)
         occurrences causally related to treatment / all
    0 / 8
    2 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Choking
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 127 (0.00%)
    5 / 119 (4.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Arterial Hypertension
         subjects affected / exposed
    8 / 127 (6.30%)
    8 / 119 (6.72%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pulmonary Embolism
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Mass
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         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 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Veno-Occlusive Disease
         subjects affected / exposed
    3 / 127 (2.36%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory Arrest
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 127 (0.79%)
    6 / 119 (5.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device Dislocation
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Pressure Increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Electrophysiologic Study
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheterisation Cardiac
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin Decreased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A Virus Test Positive
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Function Test Increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotavirus Test Positive
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep Study
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant Evaluation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Waist Circumference Increased
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (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
    Chest Injury
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis Postoperative
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fall
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Procedural Haemorrhage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic Vertebral Fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular Pseudoaneurysm
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Gastrointestinal Arteriovenous Malformation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Left Ventricular Failure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute Right Ventricular Failure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Tachycardia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         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
    2 / 127 (1.57%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         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 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure High Output
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Cardiomyopathy
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Failure
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    3 / 127 (2.36%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    8 / 127 (6.30%)
    6 / 119 (5.04%)
         occurrences causally related to treatment / all
    0 / 11
    1 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Sinus Tachycardia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         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
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (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
    Cerebral Infarction
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic Stroke
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic Stroke
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    6 / 127 (4.72%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 127 (1.57%)
    3 / 119 (2.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Loss Anaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron Deficiency Anaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 119 (2.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcytic Anaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness Neurosensory
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Haemorrhage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Amyloidosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 127 (1.57%)
    3 / 119 (2.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal Polyp Haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated Umbilical Hernia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Ischaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestinal Haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Prolapse
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal Haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune Hepatitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Cirrhosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Disorder
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin Ulcer
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 119 (2.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy Toxic
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal Failure
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Amyloidosis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal Impairment
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroderma Renal Crisis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Wall Haematoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic Scleroderma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis Chronic
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 127 (3.15%)
    8 / 119 (6.72%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Legionella
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pseudomonal
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 127 (2.36%)
    4 / 119 (3.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to Thrive
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid Overload
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 119 (1.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 119 (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
    		 Double Oral Therapy (Macitentan, Tadalafil, and Placebo) Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    119 / 127 (93.70%)
    118 / 119 (99.16%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    22 / 127 (17.32%)
    21 / 119 (17.65%)
         occurrences all number
    25
    27
    Hypotension
         subjects affected / exposed
    8 / 127 (6.30%)
    10 / 119 (8.40%)
         occurrences all number
    9
    11
    General disorders and administration site conditions
    Chest Discomfort
         subjects affected / exposed
    10 / 127 (7.87%)
    7 / 119 (5.88%)
         occurrences all number
    14
    8
    Chest Pain
         subjects affected / exposed
    4 / 127 (3.15%)
    6 / 119 (5.04%)
         occurrences all number
    4
    7
    Chills
         subjects affected / exposed
    2 / 127 (1.57%)
    7 / 119 (5.88%)
         occurrences all number
    2
    7
    Fatigue
         subjects affected / exposed
    22 / 127 (17.32%)
    24 / 119 (20.17%)
         occurrences all number
    26
    30
    Influenza Like Illness
         subjects affected / exposed
    7 / 127 (5.51%)
    6 / 119 (5.04%)
         occurrences all number
    7
    6
    Non-Cardiac Chest Pain
         subjects affected / exposed
    6 / 127 (4.72%)
    10 / 119 (8.40%)
         occurrences all number
    8
    11
    Oedema Peripheral
         subjects affected / exposed
    46 / 127 (36.22%)
    45 / 119 (37.82%)
         occurrences all number
    58
    57
    Pain
         subjects affected / exposed
    9 / 127 (7.09%)
    11 / 119 (9.24%)
         occurrences all number
    10
    14
    Peripheral Swelling
         subjects affected / exposed
    4 / 127 (3.15%)
    11 / 119 (9.24%)
         occurrences all number
    8
    11
    Pyrexia
         subjects affected / exposed
    11 / 127 (8.66%)
    11 / 119 (9.24%)
         occurrences all number
    13
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 127 (18.11%)
    19 / 119 (15.97%)
         occurrences all number
    25
    23
    Dyspnoea
         subjects affected / exposed
    25 / 127 (19.69%)
    20 / 119 (16.81%)
         occurrences all number
    36
    27
    Epistaxis
         subjects affected / exposed
    13 / 127 (10.24%)
    13 / 119 (10.92%)
         occurrences all number
    14
    14
    Hypoxia
         subjects affected / exposed
    7 / 127 (5.51%)
    6 / 119 (5.04%)
         occurrences all number
    7
    6
    Nasal Congestion
         subjects affected / exposed
    23 / 127 (18.11%)
    22 / 119 (18.49%)
         occurrences all number
    24
    23
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 127 (1.57%)
    9 / 119 (7.56%)
         occurrences all number
    2
    11
    Pulmonary Arterial Hypertension
         subjects affected / exposed
    3 / 127 (2.36%)
    8 / 119 (6.72%)
         occurrences all number
    3
    9
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 127 (3.94%)
    9 / 119 (7.56%)
         occurrences all number
    6
    9
    Insomnia
         subjects affected / exposed
    6 / 127 (4.72%)
    8 / 119 (6.72%)
         occurrences all number
    6
    8
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    4 / 127 (3.15%)
    8 / 119 (6.72%)
         occurrences all number
    4
    11
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    4 / 127 (3.15%)
    10 / 119 (8.40%)
         occurrences all number
    4
    13
    Haemoglobin Decreased
         subjects affected / exposed
    6 / 127 (4.72%)
    10 / 119 (8.40%)
         occurrences all number
    7
    12
    Weight Increased
         subjects affected / exposed
    8 / 127 (6.30%)
    5 / 119 (4.20%)
         occurrences all number
    9
    6
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    11 / 127 (8.66%)
    14 / 119 (11.76%)
         occurrences all number
    11
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    27 / 127 (21.26%)
    17 / 119 (14.29%)
         occurrences all number
    30
    18
    Headache
         subjects affected / exposed
    78 / 127 (61.42%)
    83 / 119 (69.75%)
         occurrences all number
    110
    144
    Hypoaesthesia
         subjects affected / exposed
    1 / 127 (0.79%)
    6 / 119 (5.04%)
         occurrences all number
    1
    9
    Paraesthesia
         subjects affected / exposed
    2 / 127 (1.57%)
    8 / 119 (6.72%)
         occurrences all number
    2
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 127 (8.66%)
    14 / 119 (11.76%)
         occurrences all number
    12
    16
    Iron Deficiency Anaemia
         subjects affected / exposed
    5 / 127 (3.94%)
    6 / 119 (5.04%)
         occurrences all number
    6
    7
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    4 / 127 (3.15%)
    6 / 119 (5.04%)
         occurrences all number
    7
    7
    Abdominal Pain
         subjects affected / exposed
    6 / 127 (4.72%)
    7 / 119 (5.88%)
         occurrences all number
    7
    8
    Abdominal Pain Upper
         subjects affected / exposed
    7 / 127 (5.51%)
    8 / 119 (6.72%)
         occurrences all number
    11
    10
    Constipation
         subjects affected / exposed
    9 / 127 (7.09%)
    7 / 119 (5.88%)
         occurrences all number
    11
    8
    Diarrhoea
         subjects affected / exposed
    41 / 127 (32.28%)
    66 / 119 (55.46%)
         occurrences all number
    60
    99
    Dyspepsia
         subjects affected / exposed
    17 / 127 (13.39%)
    27 / 119 (22.69%)
         occurrences all number
    18
    31
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    18 / 127 (14.17%)
    11 / 119 (9.24%)
         occurrences all number
    21
    12
    Nausea
         subjects affected / exposed
    33 / 127 (25.98%)
    56 / 119 (47.06%)
         occurrences all number
    40
    73
    Vomiting
         subjects affected / exposed
    14 / 127 (11.02%)
    30 / 119 (25.21%)
         occurrences all number
    15
    37
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 127 (7.09%)
    6 / 119 (5.04%)
         occurrences all number
    9
    9
    Swelling Face
         subjects affected / exposed
    2 / 127 (1.57%)
    8 / 119 (6.72%)
         occurrences all number
    2
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 127 (14.96%)
    19 / 119 (15.97%)
         occurrences all number
    26
    25
    Back Pain
         subjects affected / exposed
    19 / 127 (14.96%)
    13 / 119 (10.92%)
         occurrences all number
    26
    14
    Muscle Spasms
         subjects affected / exposed
    7 / 127 (5.51%)
    9 / 119 (7.56%)
         occurrences all number
    7
    11
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 127 (0.79%)
    8 / 119 (6.72%)
         occurrences all number
    1
    9
    Myalgia
         subjects affected / exposed
    19 / 127 (14.96%)
    21 / 119 (17.65%)
         occurrences all number
    25
    30
    Pain in Extremity
         subjects affected / exposed
    24 / 127 (18.90%)
    37 / 119 (31.09%)
         occurrences all number
    29
    46
    Pain in Jaw
         subjects affected / exposed
    15 / 127 (11.81%)
    35 / 119 (29.41%)
         occurrences all number
    19
    36
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 127 (4.72%)
    6 / 119 (5.04%)
         occurrences all number
    8
    7
    Influenza
         subjects affected / exposed
    7 / 127 (5.51%)
    6 / 119 (5.04%)
         occurrences all number
    9
    6
    Nasopharyngitis
         subjects affected / exposed
    23 / 127 (18.11%)
    20 / 119 (16.81%)
         occurrences all number
    38
    30
    Sinusitis
         subjects affected / exposed
    8 / 127 (6.30%)
    5 / 119 (4.20%)
         occurrences all number
    10
    6
    Upper Respiratory Tract Infection
         subjects affected / exposed
    21 / 127 (16.54%)
    14 / 119 (11.76%)
         occurrences all number
    30
    17
    Urinary Tract Infection
         subjects affected / exposed
    11 / 127 (8.66%)
    9 / 119 (7.56%)
         occurrences all number
    16
    11
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    4 / 127 (3.15%)
    14 / 119 (11.76%)
         occurrences all number
    4
    14
    Fluid Retention
         subjects affected / exposed
    8 / 127 (6.30%)
    6 / 119 (5.04%)
         occurrences all number
    11
    8
    Hypokalaemia
         subjects affected / exposed
    15 / 127 (11.81%)
    17 / 119 (14.29%)
         occurrences all number
    18
    21
    Iron Deficiency
         subjects affected / exposed
    7 / 127 (5.51%)
    3 / 119 (2.52%)
         occurrences all number
    8
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2016
    This amendment dated 10 Jun 2016 (Protocol Version 2) was considered substantial and included changes based on requests from health authorities or Ethics Committees (ECs)/Institutional Review Boards (IRBs), feedback received from investigators on Protocol Version 1 to improve study feasibility, and an update based on selexipag final prescribing information. The main changes were: exclusion criterion on stroke was modified to include cerebrovascular events (in addition to stroke) and exclusion criterion on interstitial lung disease was clarified to include evidence of the condition based on a computed tomography scan. In addition, local laboratory assessments were allowed for assessing the eligibility of subjects at screening when performed with the central laboratory kit in parallel. Reporting requirement for cardiopulmonary rehabilitation program was added to the allowed and forbidden concomitant therapy lists. For the investigational product (selexipag or placebo), a once-daily regimen was recommended for subjects with moderate hepatic impairment due to increased exposure to selexipag and its active metabolite. Hyper-/hypothyroidism was added to the study-specific criteria on study treatment interruption and/or discontinuation.
    09 Feb 2017
    This amendment dated 9 Feb 2017 (Protocol Version 3) was considered substantial and included the following changes: new information on drug-drug interactions was included for selexipag (concomitant therapy lists [allowed and forbidden]); exclusion criteria, and study-specific treatment discontinuation criteria updated for treatment with strong inhibitors of Cytochrome P450 Family 2 Subfamily C Member 8 (CYP2C8) (example, gemfibrozil) and moderate inducers of CYP2C8 (example, rifampicin); new information on risks of selexipag were added.
    16 Aug 2017
    This amendment dated 16 Aug 2017 (Protocol Version 4) was considered substantial and included the following changes: the statistical assumptions of the study and the estimated sample size (144 increased to 238 subjects) were updated based on newly published data in a patient population similar to that in the study, which showed that the reduction in Pulmonary Vascular Resistance (PVR) with initial dual combination therapy with macitentan and tadalafil was larger than originally anticipated. In addition, to control for multiplicity, the statistical testing section was updated with the implementation of hierarchical testing for selected secondary endpoints.
    01 Mar 2018
    This amendment dated 01 Mar 2018 (Protocol Version 5) was considered non-substantial and included the following changes: monthly testing for liver function was to be performed throughout the study based on a recommendation from the Independent data monitoring committee (IDMC). The order of the hierarchical testing of secondary endpoints was updated (change from baseline to Week 26 in 6-minute walk distance [6MWD] to be tested first) following Food and Drug Administration (FDA) interaction in November 2017.
    04 Dec 2018
    This amendment dated 04 Dec 2018 (Protocol Version 6) was considered substantial and included the following change: the dosing instructions for selexipag or placebo study treatment was updated (reduced to once-daily regimen) in the presence of concomitant administration of a moderate CYP2C8 inhibitor based on a drug-drug interaction study with a moderate CYP2C8 inhibitor (example, clopidogrel).

    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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