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    Clinical Trial Results:
    Effects of combination of bosentan and sildenafil versus sildenafil monotherapy on morbidity and mortality in symptomatic patients with pulmonary arterial hypertension – A multicenter, double - blind, randomized, placebo - controlled, parallel group, prospective, event driven Phase IV study "Efectos de la combinación de bosentan y sildenafilo frente a sildenafilo en monoterapia sobre la morbimortalidad en pacientes sintomáticos con hipertensión arterial pulmonar – Estudio de fase IV, multicéntrico, en doble ciego, aleatorizado, controlado con placebo, de grupos paralelos, prospectivo y basado en acontecimientos."

    Summary
    EudraCT number
    2005-005068-97
    Trial protocol
    DE   SE   DK   GB   ES   PT   GR   BE   CZ   SK  
    Global end of trial date
    05 Dec 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Dec 2016
    First version publication date
    10 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-052-414
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00303459
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Loic Perchenet, Actelion Pharmaceuticals Ltd, loic.perchenet@actelion.com
    Scientific contact
    Loic Perchenet, Actelion Pharmaceuticals Ltd, loic.perchenet@actelion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To demonstrate that the combination of bosentan and sildenafil prolongs the time to the first adjudicated morbidity/mortality event compared with sildenafil monotherapy in symptomatic patients with pulmonary arterial hypertension (PAH)
    Protection of trial subjects
    The clinical trial was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, the US CFR Title 21 (adapt to the countries where the trial was conducted), and with the ethical principles laid down in the Declaration of Helsinki
    Background therapy
    PDE5-i at stable dose for 3 months prior to randomization
    Evidence for comparator
    -
    Actual start date of recruitment
    17 May 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 71
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United States: 156
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Saudi Arabia: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    Greece: 9
    Worldwide total number of subjects
    334
    EEA total number of subjects
    106
    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)
    242
    From 65 to 84 years
    91
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    First subject, first visit was 17 May 2006 and last subject, last visit was 05 Dec 2013.

    Pre-assignment
    Screening details
    There was a screening period of up to 14 days to assess eligibility. A total of 377 patients were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bosentan
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Bosentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    62.5 mg BID for 4 weeks followed by 125 mg BID maintenance dose

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    62.5 mg BID for 4 weeks followed by 125 mg BID maintenance dose

    Number of subjects in period 1
    Bosentan Placebo
    Started
    159
    175
    Completed
    76
    86
    Not completed
    83
    89
         Decision by the investigator
    5
    7
         Administrative reason
    7
    7
         Withdrawal of consent
    32
    26
         Lung transplantation
    1
    1
         Adverse event, serious fatal
    33
    44
         Lost to follow-up
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bosentan
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Bosentan Placebo Total
    Number of subjects
    159 175
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    52.9 ± 15.44 54.7 ± 15.73 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    125 128 253
        Male
    34 47 81
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian/White
    147 149 296
        Black
    7 12 19
        Hispanic
    5 6 11
        Other
    0 8 8
    Region of Enrollment
    Units: Subjects
        Brazil
    36 35 71
        Czech Republic
    12 15 27
        Denmark
    3 4 7
        Germany
    19 22 41
        Greece
    4 5 9
        Portugal
    3 0 3
        Saudi Arabia
    0 1 1
        Slovakia
    4 3 7
        Spain
    1 1 2
        Sweden
    4 5 9
        United Kingdom
    0 1 1
        United States
    73 83 156

    End points

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    End points reporting groups
    Reporting group title
    Bosentan
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Time to first confirmed morbidity/mortality event up to the end of study

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    End point title
    Time to first confirmed morbidity/mortality event up to the end of study
    End point description
    Kaplan-Meier estimate of percentage of participants without a morbidity/mortality event. A morbidity/mortality event is defined as the occurrence of a) death, b) hospitalization for worsening or complication of PAH or intravenous prostanoid initiation, c) atrial septostomy, d) lung transplantation, or e) worsening PAH, defined as "moderately" or "markedly" worsened PAH symptoms using a patient global self-assessment (PGSA) scale AND initiation of inhaled or subcutaneous prostanoids or the disease progression package (open-label bosentan). If a patient replied "no change" or "mildly worse" on the PGSA, a decrease in 6MWT of 20% versus last visit or 30% versus baseline is also required to confirm the event.
    End point type
    Primary
    End point timeframe
    From baseline to end of study, approximately 86 months
    End point values
    Bosentan Placebo
    Number of subjects analysed
    159
    175
    Units: percentage of participants-Kaplan Meier
    number (not applicable)
        Kaplan-Meier estimate at Month 4
    96.1
    90.6
        Kaplan-Meier estimate at Month 8
    90.5
    83
        Kaplan-Meier estimate at Month 12
    82.7
    74
        Kaplan-Meier estimate at Month 16
    74.7
    71
        Kaplan-Meier estimate at Month 20
    71.8
    66.1
        Kaplan-Meier estimate at Month 24
    66.6
    61.5
        Kaplan-Meier estimate at Month 28
    65.8
    55
        Kaplan-Meier estimate at Month 32
    62.4
    52.7
        Kaplan-Meier estimate at Month 34
    57.5
    48.8
        Kaplan-Meier estimate at Month 40
    56.4
    48
        Kaplan-Meier estimate at Month 44
    50.6
    46.2
        Kaplan-Meier estimate at Month 48
    46.7
    45.2
        Kaplan-Meier estimate at Month 52
    45.1
    45.2
        Kaplan-Meier estimate at Month 56
    45.1
    42.6
        Kaplan-Meier estimate at Month 60
    45.1
    39.7
        Kaplan-Meier estimate at Month 64
    45.1
    39.7
        Kaplan-Meier estimate at Month 68
    40.1
    39.7
        Kaplan-Meier estimate at Month 72
    40.1
    39.7
        Kaplan-Meier estimate at Month 76
    40.1
    36.1
        Kaplan-Meier estimate at Month 80
    40.1
    36.1
        Kaplan-Meier estimate at Month 84
    40.1
    36.1
        Kaplan-Meier estimate at End of Study
    40.1
    36.1
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.2508
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.831
    Confidence interval
         level
    97.31%
         sides
    2-sided
         lower limit
    0.582
         upper limit
    1.187

    Secondary: Time to first confirmed death, hospitalization for worsening or complication of PAH or initiation of intravenous prostanoids, atrial septostomy, or lung transplantation

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    End point title
    Time to first confirmed death, hospitalization for worsening or complication of PAH or initiation of intravenous prostanoids, atrial septostomy, or lung transplantation
    End point description
    Kaplan-Meier estimate of percentage of participants without an event of death, hospitalization (for worsening or complication of PAH or initiation of intravenous prostanoids), atrial septostomy or lung transplantation. Time to first confirmed death, hospitalization (for worsening or complication of PAH or initiation of intravenous prostanoids), atrial septostomy or lung transplantation from baseline to end of study was confirmed by an independent Clinical Endpoint Committee.
    End point type
    Secondary
    End point timeframe
    Baseline to end of study, approximately 86 months
    End point values
    Bosentan Placebo
    Number of subjects analysed
    159
    175
    Units: percentage of participants-Kaplan Meier
    number (not applicable)
        Kaplan-Meier estimate at Month 4
    97.4
    95.3
        Kaplan-Meier estimate at Month 8
    94.6
    91.8
        Kaplan-Meier estimate at Month 12
    89.6
    88.8
        Kaplan-Meier estimate at Month 16
    85.3
    86.9
        Kaplan-Meier estimate at Month 20
    82.3
    83.8
        Kaplan-Meier estimate at Month 24
    76.9
    79.8
        Kaplan-Meier estimate at Month 28
    76.1
    74.7
        Kaplan-Meier estimate at Month 32
    75.2
    73.1
        Kaplan-Meier estimate at Month 36
    72.2
    64.4
        Kaplan-Meier estimate at Month 40
    72.2
    61.9
        Kaplan-Meier estimate at Month 44
    64.2
    60.1
        Kaplan-Meier estimate at Month 48
    60.3
    58.1
        Kaplan-Meier estimate at Month 52
    57.4
    56.8
        Kaplan-Meier estimate at Month 56
    53.8
    52.7
        Kaplan-Meier estimate at Month 60
    53.8
    51.3
        Kaplan-Meier estimate at Month 64
    53.8
    51.3
        Kaplan-Meier estimate at Month 68
    39.8
    49.2
        Kaplan-Meier estimate at Month 72
    39.8
    49.2
        Kaplan-Meier estimate at Month 76
    39.8
    45.1
        Kaplan-Meier estimate at Month 80
    39.8
    45.1
        Kaplan-Meier estimate at Month 84
    39.8
    45.1
        Kaplan-Meier estimate at End of Study
    39.8
    45.1
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.8385
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.963
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.673
         upper limit
    1.38

    Secondary: Change from baseline to Week 16 in 6 minute walk test (6MWT)

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    End point title
    Change from baseline to Week 16 in 6 minute walk test (6MWT)
    End point description
    The 6MWT is a non-encouraged test, which measures the distance covered over a 6 minute walk; the patient is instructed to walk as far as possible in a 30 m long flat corridor, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Areas were to be well ventilated with air temperature controlled between 20 °C and 23 °C (68 °F to 76 °F). The test was to be administered at the same time of day and by the same tester throughout the study. The tester measured the distance walked by non-encouraged patients during the timed 6 minute period.
    End point type
    Secondary
    End point timeframe
    From baseline to week 16
    End point values
    Bosentan Placebo
    Number of subjects analysed
    159
    175
    Units: Meters
    arithmetic mean (standard deviation)
        Baseline
    363 ± 78.5
    358 ± 73.1
        Week 16
    370 ± 98.3
    343 ± 107.3
        Change from baseline
    7.2 ± 66.01
    -14.6 ± 80.42
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0106
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Mean difference (net)
    Point estimate
    21.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.9
         upper limit
    37.8

    Secondary: Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16

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    End point title
    Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16
    End point description
    Class I: no limitation of usual physical activity (PA) which does not increase dyspnea, fatigue, chest pain, or presyncope. Class II: mild limitation of PA. No discomfort at rest. Normal PA increases dyspnea, fatigue, chest pain, or presyncope. Class III: marked limitation of PA. No discomfort at rest. Less than ordinary activity increases dyspnea, fatigue, chest pain, or presyncope. Class IV: unable to perform any PA and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any PA.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 16
    End point values
    Bosentan Placebo
    Number of subjects analysed
    159
    175
    Units: participants
        Improved
    25
    28
        No change
    121
    130
        Worsened
    13
    17
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Bosentan
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 1
    Method
    Fisher exact
    Parameter type
    Relative risk of improvement
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.61

    Secondary: Time to death of all causes from baseline to end of study

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    End point title
    Time to death of all causes from baseline to end of study
    End point description
    Kaplan-Meier estimate of percentage of participants without a mortality event.Time to death due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study, approximately 86 months
    End point values
    Bosentan Placebo
    Number of subjects analysed
    159
    175
    Units: percentage of participants-Kaplan Meier
    number (not applicable)
        Kaplan-Meier estimate at Month 4
    99.4
    98.2
        Kaplan-Meier estimate at Month 8
    98.7
    95.8
        Kaplan-Meier estimate at Month 12
    96.5
    94
        Kaplan-Meier estimate at Month 16
    92.8
    92.8
        Kaplan-Meier estimate at Month 20
    90.6
    89.5
        Kaplan-Meier estimate at Month 24
    89.1
    88.2
        Kaplan-Meier estimate at Month 28
    85.8
    85.9
        Kaplan-Meier estimate at Month 32
    85.8
    84.3
        Kaplan-Meier estimate at Month 36
    85.8
    78.5
        Kaplan-Meier estimate at Month 40
    85.8
    76.8
        Kaplan-Meier estimate at Month 44
    81.4
    74.9
        Kaplan-Meier estimate at Month 48
    77.7
    71.8
        Kaplan-Meier estimate at Month 52
    75
    70.5
        Kaplan-Meier estimate at Month 56
    70.1
    66.4
        Kaplan-Meier estimate at Month 60
    67.8
    64.9
        Kaplan-Meier estimate at Month 64
    67.8
    64.9
        Kaplan-Meier estimate at Month 68
    67.8
    64.9
        Kaplan-Meier estimate at Month 72
    67.8
    64.9
        Kaplan-Meier estimate at Month 76
    67.8
    60.3
        Kaplan-Meier estimate at Month 80
    58.1
    60.3
        Kaplan-Meier estimate at Month 84
    58.1
    60.3
        Kaplan-Meier estimate at End of Study
    58.1
    60.3
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.4974
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.855
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.544
         upper limit
    1.344

    Secondary: Adjusted Percentage Ratio from Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP)

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    End point title
    Adjusted Percentage Ratio from Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP)
    End point description
    Blood sampling for the measurement of NT-pro-BNP was performed and the plasma concentrations of NT-pro-BNP were determined by a certified centralized laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 20
    End point values
    Bosentan Placebo
    Number of subjects analysed
    109
    117
    Units: Adjusted percentage ratio from baseline
    geometric mean (confidence interval 95%)
        Month 1 to Baseline
    87.46 (77.12 to 99.18)
    110.02 (97.56 to 124.06)
        Month 4 to Baseline
    92.65 (81.2 to 105.72)
    113.2 (99.61 to 128.65)
        Month 8 to Baseline
    85.21 (72.58 to 100.05)
    122.87 (104.82 to 144.02)
        Month 12 to Baseline
    84.48 (71.48 to 99.83)
    132.11 (111.95 to 155.89)
        Month 16 to Baseline
    92.69 (75.75 to 113.42)
    129.92 (106.69 to 158.2)
        Month 20 to Baseline
    98.36 (79.46 to 121.75)
    143.17 (115.86 to 176.91)
        Treatment effect over 20 months
    92.54 (82.72 to 103.52)
    121 (108.42 to 135.05)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Bosentan
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0003
    Method
    Repeated measures analysis
    Parameter type
    Percentage change over placebo
    Point estimate
    -23.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.69
         upper limit
    -11.79

    Secondary: Change from baseline to Week 16 in Borg dyspnea index

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    End point title
    Change from baseline to Week 16 in Borg dyspnea index
    End point description
    The Borg dyspnea index was evaluated immediately after the 6MWT to obtain a rating of dyspnea at the end of the exercise using a scale from 0 (‘Nothing at all’) to 10 (‘Very, very severe – maximal’).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Bosentan Placebo
    Number of subjects analysed
    159
    175
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    3.5 ± 1.99
    3.7 ± 2.18
        Week 16
    3.4 ± 2.12
    3.6 ± 2.24
        Change from baseline
    -0.09 ± 1.693
    -0.08 ± 2.035
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.9566
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.42
         upper limit
    0.39

    Secondary: Change from baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) questionnaire calculated score

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    End point title
    Change from baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) questionnaire calculated score
    End point description
    The EQ-5D questionnaire is a patient-reported outcome consisting of a 5 dimensional descriptive system and a visual analog scale (VAS). The descriptive system asks respondents to describe their health status. Health is defined in 5 dimensions: (1) mobility, (2) self care, (3) usual activities, (4) pain or discomfort, and (5) anxiety or depression. Each dimension is divided into 3 levels, indicating (a) no problem, (b) some or moderate problems, or (c) extreme problems. Respondents record their problem(s) in each of the 5 dimensions. Combinations of these levels define a total of 243 health states. A health state defined by the descriptive system of EQ-5D can be described by a 5-digit number with full health is indicated by 11111 and poorest health state by 33333. The EQ-5D calculated score was derived by re-assigning local scores for answers to each question and combining these local scores into a global score with ranges from 0 (worst possible outcome) to 1 (best possible outcome).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 16
    End point values
    Bosentan Placebo
    Number of subjects analysed
    159
    175
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    0.678 ± 0.2172
    0.681 ± 0.2138
        Week 16
    0.662 ± 0.2807
    0.645 ± 0.3062
        Change from Baseline
    -0.0161 ± 0.25232
    -0.0361 ± 0.26671
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.5571
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Mean difference (net)
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.036
         upper limit
    0.076

    Secondary: Change from baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) visual analogue scale score

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    End point title
    Change from baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) visual analogue scale score
    End point description
    The EQ-5D questionnaire is a patient-reported outcome consisting of a 5 dimensional descriptive system and a visual analog scale (VAS) together with brief demographic questions. EQ-5D VAS asks respondents to rate their perception of their overall health on a vertical visual analogue scale with ‘best imaginable health state’ set at 100 and ‘worst imaginable health state’ set at 0.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Bosentan Placebo
    Number of subjects analysed
    159
    175
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    67 ± 17.4
    64 ± 17.5
        Week 16
    69 ± 19.9
    66 ± 19.9
        Change from Baseline
    2.1 ± 18.83
    2 ± 17.01
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.4086
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Mean difference (net)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    4

    Secondary: Patient Global Self Assessment (PGSA) Status at Week 16

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    End point title
    Patient Global Self Assessment (PGSA) Status at Week 16
    End point description
    The PGSA is a questionnaire that allows the patient to compare his/her PAH status in response to the question “How do you feel about your PAH today compared with your last visit?” asked by the investigator. Patients use a seven-point scale to respond: markedly better, moderately better, mildly better, no change, markedly worse, moderately worse, or mildly worse.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Bosentan Placebo
    Number of subjects analysed
    150
    162
    Units: participants
        Markedly better
    24
    13
        Moderately better
    23
    30
        Mildly better
    32
    36
        No change
    50
    59
        Mildly worse
    16
    15
        Moderately worse
    3
    5
        Markedly worse
    2
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to End of Study and up to 1 day after discontinuation of study treatment, approximately 86 weeks
    Adverse event reporting additional description
    All treated patients. Treatment emergent adverse events.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo placebo: Matching bosentan placebo/b.i.d.

    Reporting group title
    Bosentan
    Reporting group description
    Bosentan bosentan: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.

    Serious adverse events
    Placebo Bosentan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    102 / 174 (58.62%)
    73 / 159 (45.91%)
         number of deaths (all causes)
    22
    9
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EXTREMITY NECROSIS
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL ARTERY OCCLUSION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Surgical and medical procedures
    CHEMOTHERAPY
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY BYPASS
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIURETIC THERAPY
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FINGER AMPUTATION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INCISIONAL HERNIA REPAIR
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KNEE ARTHROPLASTY
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIOTHERAPY
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN CYST EXCISION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN NEOPLASM EXCISION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THYMECTOMY
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACOUSTIC NEUROMA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIAL CARCINOMA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIOLOALVEOLAR CARCINOMA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CERVIX CARCINOMA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIFFUSE LARGE B-CELL LYMPHOMA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLAMMATORY CARCINOMA OF THE BREAST
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALIGNANT MELANOMA IN SITU
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENINGIOMA BENIGN
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTATIC MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    RECTAL CANCER
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    PREGNANCY
         subjects affected / exposed
    3 / 174 (1.72%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ADVERSE DRUG REACTION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASTHENIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    7 / 174 (4.02%)
    5 / 159 (3.14%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    FATIGUE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERALISED OEDEMA
         subjects affected / exposed
    3 / 174 (1.72%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTI-ORGAN FAILURE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    BIPOLAR I DISORDER
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUICIDAL IDEATION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         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
    DYSMENORRHOEA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENORRHAGIA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OVARIAN MASS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UTERINE HAEMORRHAGE
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UTERINE PROLAPSE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (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
    FALL
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FOOT FRACTURE
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FRACTURED SACRUM
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INCISIONAL HERNIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LACERATION
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER LIMB FRACTURE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL COMPLICATION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL HAEMATOMA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (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 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSFUSION-RELATED ACUTE LUNG INJURY
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER FUNCTION TEST ABNORMAL
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR RESISTANCE PULMONARY INCREASED
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RIGHT VENTRICULAR FAILURE
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    3 / 174 (1.72%)
    4 / 159 (2.52%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    1 / 174 (0.57%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYARRHYTHMIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    3 / 174 (1.72%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         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 / 174 (0.57%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COR PULMONALE
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRACARDIAC THROMBUS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    RIGHT VENTRICULAR FAILURE
         subjects affected / exposed
    8 / 174 (4.60%)
    6 / 159 (3.77%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    SICK SINUS SYNDROME
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRIFASCICULAR BLOCK
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         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 PULMONARY OEDEMA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 174 (0.57%)
    4 / 159 (2.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ASTHMA
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATELECTASIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIAL HAEMORRHAGE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIAL HYPERREACTIVITY
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    2 / 174 (1.15%)
    4 / 159 (2.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CHRONIC RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    8 / 174 (4.60%)
    5 / 159 (3.14%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 174 (0.00%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OBLITERATIVE BRONCHIOLITIS
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORTHOPNOEA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURISY
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY ARTERIAL HYPERTENSION
         subjects affected / exposed
    28 / 174 (16.09%)
    25 / 159 (15.72%)
         occurrences causally related to treatment / all
    2 / 31
    1 / 29
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 174 (0.57%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    1 / 174 (0.57%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    3 / 174 (1.72%)
    6 / 159 (3.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 174 (1.15%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA HAEMOLYTIC AUTOIMMUNE
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    HYPERSPLENISM
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPLENOMEGALY
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOTIC THROMBOCYTOPENIC PURPURA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (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
    BRAIN STEM STROKE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CONVULSION
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOAESTHESIA
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBAR RADICULOPATHY
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYASTHENIA GRAVIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCIATICA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    6 / 174 (3.45%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    3 / 174 (1.72%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    EYE SWELLING
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RETINAL DETACHMENT
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    SUDDEN HEARING LOSS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    3 / 174 (1.72%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULUM
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL DISORDER
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         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
    1 / 174 (0.57%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOCHEZIA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE POLYP
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGEAL VARICES HAEMORRHAGE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         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 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILIARY DYSKINESIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLESTASIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CIRRHOSIS
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PORTAL HYPERTENSION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    BLADDER NECK OBSTRUCTION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE ACUTE
         subjects affected / exposed
    4 / 174 (2.30%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL TUBULAR NECROSIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    SKIN ULCER
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URTICARIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLLAGEN DISORDER
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CREST SYNDROME
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DUPUYTREN'S CONTRACTURE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMARTHROSIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEONECROSIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROTATOR CUFF SYNDROME
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC LUPUS ERYTHEMATOSUS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    0 / 174 (0.00%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLUID OVERLOAD
         subjects affected / exposed
    0 / 174 (0.00%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLUID RETENTION
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GOUT
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERVOLAEMIA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL ABSCESS
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    3 / 174 (1.72%)
    6 / 159 (3.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS VIRAL
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHOPNEUMONIA
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CELLULITIS
         subjects affected / exposed
    0 / 174 (0.00%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DENGUE FEVER
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED SEPSIS
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 159 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    5 / 174 (2.87%)
    3 / 159 (1.89%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    GASTROENTERITIS CALICIVIRAL
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS SALMONELLA
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 INFLUENZA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOMA INFECTION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTED DERMAL CYST
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KLEBSIELLA BACTERAEMIA
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCOCCAL SEPSIS
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    6 / 174 (3.45%)
    11 / 159 (6.92%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 16
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PNEUMONIA STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS SYNDROME
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SINUSITIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBERCULOSIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 159 (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
    Placebo Bosentan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    147 / 174 (84.48%)
    135 / 159 (84.91%)
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    6 / 174 (3.45%)
    8 / 159 (5.03%)
         occurrences all number
    12
    8
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    7 / 174 (4.02%)
    16 / 159 (10.06%)
         occurrences all number
    9
    21
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    8 / 174 (4.60%)
    13 / 159 (8.18%)
         occurrences all number
    10
    18
    LIVER FUNCTION TEST ABNORMAL
         subjects affected / exposed
    4 / 174 (2.30%)
    11 / 159 (6.92%)
         occurrences all number
    5
    14
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    3 / 174 (1.72%)
    9 / 159 (5.66%)
         occurrences all number
    3
    11
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    10 / 174 (5.75%)
    15 / 159 (9.43%)
         occurrences all number
    10
    21
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    21 / 174 (12.07%)
    22 / 159 (13.84%)
         occurrences all number
    26
    28
    DYSPNOEA
         subjects affected / exposed
    19 / 174 (10.92%)
    21 / 159 (13.21%)
         occurrences all number
    21
    25
    PULMONARY ARTERIAL HYPERTENSION
         subjects affected / exposed
    35 / 174 (20.11%)
    15 / 159 (9.43%)
         occurrences all number
    36
    16
    EPISTAXIS
         subjects affected / exposed
    6 / 174 (3.45%)
    12 / 159 (7.55%)
         occurrences all number
    6
    15
    NASAL CONGESTION
         subjects affected / exposed
    0 / 174 (0.00%)
    8 / 159 (5.03%)
         occurrences all number
    0
    9
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    24 / 174 (13.79%)
    24 / 159 (15.09%)
         occurrences all number
    29
    26
    DIZZINESS
         subjects affected / exposed
    17 / 174 (9.77%)
    17 / 159 (10.69%)
         occurrences all number
    20
    21
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    26 / 174 (14.94%)
    30 / 159 (18.87%)
         occurrences all number
    29
    37
    CHEST PAIN
         subjects affected / exposed
    10 / 174 (5.75%)
    18 / 159 (11.32%)
         occurrences all number
    12
    26
    FATIGUE
         subjects affected / exposed
    19 / 174 (10.92%)
    13 / 159 (8.18%)
         occurrences all number
    19
    15
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    11 / 174 (6.32%)
    9 / 159 (5.66%)
         occurrences all number
    12
    11
    INSOMNIA
         subjects affected / exposed
    11 / 174 (6.32%)
    8 / 159 (5.03%)
         occurrences all number
    11
    8
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    19 / 174 (10.92%)
    19 / 159 (11.95%)
         occurrences all number
    26
    24
    NAUSEA
         subjects affected / exposed
    22 / 174 (12.64%)
    16 / 159 (10.06%)
         occurrences all number
    28
    22
    ABDOMINAL PAIN
         subjects affected / exposed
    12 / 174 (6.90%)
    11 / 159 (6.92%)
         occurrences all number
    14
    15
    VOMITING
         subjects affected / exposed
    12 / 174 (6.90%)
    8 / 159 (5.03%)
         occurrences all number
    13
    10
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    6 / 174 (3.45%)
    10 / 159 (6.29%)
         occurrences all number
    8
    12
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    22 / 174 (12.64%)
    15 / 159 (9.43%)
         occurrences all number
    27
    18
    ARTHRALGIA
         subjects affected / exposed
    20 / 174 (11.49%)
    13 / 159 (8.18%)
         occurrences all number
    25
    17
    PAIN IN EXTREMITY
         subjects affected / exposed
    15 / 174 (8.62%)
    9 / 159 (5.66%)
         occurrences all number
    16
    13
    MUSCLE SPASMS
         subjects affected / exposed
    6 / 174 (3.45%)
    8 / 159 (5.03%)
         occurrences all number
    6
    8
    Infections and infestations
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    29 / 174 (16.67%)
    21 / 159 (13.21%)
         occurrences all number
    44
    38
    URINARY TRACT INFECTION
         subjects affected / exposed
    13 / 174 (7.47%)
    16 / 159 (10.06%)
         occurrences all number
    17
    34
    BRONCHITIS
         subjects affected / exposed
    18 / 174 (10.34%)
    14 / 159 (8.81%)
         occurrences all number
    32
    24
    NASOPHARYNGITIS
         subjects affected / exposed
    15 / 174 (8.62%)
    11 / 159 (6.92%)
         occurrences all number
    24
    15
    SINUSITIS
         subjects affected / exposed
    12 / 174 (6.90%)
    11 / 159 (6.92%)
         occurrences all number
    20
    21
    PNEUMONIA
         subjects affected / exposed
    8 / 174 (4.60%)
    8 / 159 (5.03%)
         occurrences all number
    8
    10

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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