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    Clinical Trial Results:
    A multicenter, double-blind, placebo-controlled Phase 3 study assessing the safety and efficacy of selexipag on morbidity and mortality in patients with pulmonary arterial hypertension

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2009-014490-41
    Trial protocol
    BE   DK   FR   ES   SE   CZ   GB   IE   HU   AT   SK   DE   GR   NL   IT  
    Global end of trial date
    27 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Mar 2016
    First version publication date
    31 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-065A302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01106014
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com
    Scientific contact
    clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the effect of selexipag (ACT-293987) on time to first morbidity and mortality (MM) event in patients with 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, and with the ethical principles laid down in the Declaration of Helsinki
    Background therapy
    Background PAH therapies ongoing at the time of study entry, except for prostacyclin and prostacyclin analogs, were allowed if patients had been on a stable dose for at least 3 months prior to randomization.
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Dec 2009
    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
    Argentina: 24
    Country: Number of subjects enrolled
    Australia: 62
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belarus: 51
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    Chile: 38
    Country: Number of subjects enrolled
    China: 140
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 47
    Country: Number of subjects enrolled
    Germany: 61
    Country: Number of subjects enrolled
    Greece: 9
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    India: 23
    Country: Number of subjects enrolled
    Ireland: 6
    Country: Number of subjects enrolled
    Israel: 32
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Mexico: 30
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Peru: 15
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    Russian Federation: 91
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    Singapore: 10
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Turkey: 22
    Country: Number of subjects enrolled
    Ukraine: 50
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 155
    Worldwide total number of subjects
    1156
    EEA total number of subjects
    302
    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)
    949
    From 65 to 84 years
    207
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 1351 patients were screened from 181 sites in 39 countries worldwide. Of these, 1156 were randomized.

    Pre-assignment
    Screening details
    Screening assessments were performed up to a maximum of 28 days before baseline

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    The sponsor and all people involved in the study were blinded to the treatment, except for the members of the Data Monitoring Committee (regular review of unblinded efficacy, safety and tolerability data), clinical trial supply manager and people in charge of the pharmacokinetic analyses.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Selexipag
    Arm description
    During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues.
    Arm type
    Experimental

    Investigational medicinal product name
    selexipag
    Investigational medicinal product code
    ACT293987
    Other name
    NS304
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet contained 200 μg of selexipag

    Arm title
    Placebo
    Arm description
    Matching placebo was administered following the same administration schedule as described for selexipag.
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet had the same aspects as selexipag tablet

    Number of subjects in period 1
    Selexipag Placebo
    Started
    574
    582
    Completed
    289
    252
    Not completed
    285
    330
         Morbidity or Mortality Primary Endpoint
             155
             242
         Consent withdrawn by subject
             43
             37
         Administrative
             7
             6
         Adverse Event
             78
             42
         Lost to follow-up
             2
             3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo was administered following the same administration schedule as described for selexipag.

    Reporting group values
    Selexipag Placebo Total
    Number of subjects
    574 582 1156
    Age categorical
    Units: Subjects
        18-64 years old
    475 474 949
        65-84 years old
    99 108 207
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.2 ± 15.19 47.9 ± 15.55 -
    Gender categorical
    Units:
        Female
    457 466 923
        Male
    117 116 233
    Ethnicity
    Number of patients in each ethnic group
    Units: Subjects
        Caucasian/white
    376 375 751
        Asian
    125 120 245
        Hispanic
    51 63 114
        Black
    13 14 27
        Other
    9 10 19
    PAH etiology
    Number of patients in each PAH etiology category
    Units: Subjects
        Idiopathic
    312 337 649
        Heritable
    13 13 26
        Associated with connective tissue disease
    167 167 334
        Assoc. with corrected (>= 12 Mo) congenital shunts
    60 50 110
        Associated with drug or toxin exposure
    17 10 27
        Associated with HIV infection
    5 5 10
    Modified NYHA/WHO Functional class (FC)
    Number of patients in each NYHA/WHO Functional class (FC) at screening. The WHO FC ranges from I to IV, with higher ranges indicating more severe functional restrictions.
    Units: Subjects
        FC I
    4 5 9
        FC II
    274 255 529
        FC III
    293 314 607
        FC IV
    3 8 11
    PAH medications at baseline
    Number of patients receiving PAH background medication at the time of study drug start.
    Units: Subjects
        None
    112 124 236
        Endothelin Receptor Agonists (ERA)
    94 76 170
        Phosphodiesterase type 5 inhibitors (PDE5I)
    189 185 374
        ERA and PDE5I in combination
    179 197 376
    Time since PAH diagnosis
    Units: Years
        median (full range (min-max))
    0.9 (0 to 37.3) 1.1 (0 to 38.9) -
    6-Minute walk distance (6MWD) at baseline
    Units: Meters
        median (full range (min-max))
    376 (90 to 482) 369 (50 to 515) -

    End points

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    End points reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo was administered following the same administration schedule as described for selexipag.

    Subject analysis set title
    Full-analysis set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The full analysis set includes all randomized patients evaluated according to the study drug to which they have been randomized

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set includes all randomized patients who received at least one dose of study drug and were evaluated according to the study drug they have received

    Primary: Time from randomization to the first morbidity event or death (all causes) up to 7 days after the last study drug intake

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    End point title
    Time from randomization to the first morbidity event or death (all causes) up to 7 days after the last study drug intake
    End point description
    Time from randomization to the first occurrence of a morbidity event or death (all causes) was analyzed with the Kaplan-Meier (KM) method (event-free KM estimates at different time points). Morbidity event was defined as any of the following events confirmed by the Critical Event Committee: -Hospitalization for pulmonary arterial hypertension (PAH) worsening, -Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy, -Initiation of parenteral prostanoid therapy or chronic oxygen therapy due to worsening of PAH, -Disease progression which was defined by a decrease in 6-minute walk distance from baseline (>=15%, confirmed by a 2nd test on a different day) combined with worsening of WHO FC for patients belonging to WHO FC II/III at baseline, or combined with the need for additional PAH specific therapy for patients belonging to WHO FC III/IV at baseline. Note: The number of patients at risk decreased over time but this cannot be captured below
    End point type
    Primary
    End point timeframe
    Up to 7 days after end of double-blind treatment (maximum: 4.3 years)
    End point values
    Selexipag Placebo
    Number of subjects analysed
    574 [1]
    582 [2]
    Units: Percentage of patients free of events
    number (confidence interval 95%)
        KM estimate at Month 6
    91.2 (88.5 to 93.4)
    81.7 (78.2 to 84.7)
        KM estimate at Month 12
    83.1 (79.5 to 86.1)
    70.6 (66.6 to 74.3)
        KM estimate at Month 18
    75.5 (71.2 to 79.2)
    61.3 (56.8 to 65.5)
        KM estimate at Month 24
    67.9 (63 to 72.4)
    53.9 (49 to 58.5)
        KM estimate at Month 30
    61.9 (56.3 to 66.9)
    49.3 (44.2 to 54.3)
        KM estimate at Month 36
    58.2 (51.7 to 64.1)
    41.7 (35.2 to 48)
    Notes
    [1] - This is the total number of subjects at start date, not the number at risk at each timepoint
    [2] - This is the total number of subjects at start date, not the number at risk at each timepoint
    Statistical analysis title
    Logrank test and proportional hazard ratio
    Statistical analysis description
    The primary analysis was performed on the Full Analysis Set by a one-sided unstratified log-rank test
    Comparison groups
    Placebo v Selexipag
    Number of subjects included in analysis
    1156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    0.78
    Notes
    [3] - one-sided pvalue

    Secondary: Change from baseline to Week 26 in 6-minute Walk distance (6MWD) at trough

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    End point title
    Change from baseline to Week 26 in 6-minute Walk distance (6MWD) at trough
    End point description
    The 6-minute walk distance test (6MWD) is a non-encouraged test performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. If the patient was used to taking bronchodilators before a walk, he/she was given them 5 to 30 min before the test. Also if the patient was on chronic oxygen therapy, oxygen was given at their standard rate during the test. Absolute change from baseline to Week 26 in 6MWD was measured at trough, i.e., either on the next day after the last study drug administration or at least 12 hours after study drug administration if on the same day.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Selexipag Placebo
    Number of subjects analysed
    574
    582
    Units: Meters
    median (full range (min-max))
        6MWD at baseline - Overall
    376 (90 to 482)
    369 (50 to 515)
        6MWD at Week 26 - Overall
    370 (0 to 617)
    346 (0 to 650)
        6MWD Change from baseline at Week 26
    4 (-448 to 260)
    -9 (-438 to 262)
    Statistical analysis title
    Non-parametric ANCOVA
    Statistical analysis description
    Non-parametric ANCOVA with 6MWD as covariate at baseline. Missing values were imputed based on the following imputation rules: 1) if patient was unable to walk at week 26, 0 meter was imputed, 2) if rule 1 did not apply, the second lowest observed 6MWD value (10 meters) at Week 26 was imputed. Missing values were imputed for 21.6% of the subjects.
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    1156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0027 [4]
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    12
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    1
         upper limit
    24
    Notes
    [4] - One-sided pvalue of the nonparametric ANCOVA, adjusted for 6minute walk distance at baseline

    Secondary: Absence of worsening from baseline to Week 26 in modified NYHA/WHO functional class (WHO FC)

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    End point title
    Absence of worsening from baseline to Week 26 in modified NYHA/WHO functional class (WHO FC)
    End point description
    Patients with WHO FC IV at baseline were excluded from this analysis as they could not shift to a worse category
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Selexipag Placebo
    Number of subjects analysed
    571
    574
    Units: Percentage of patients
        number (not applicable)
    77.8
    74.9
    Statistical analysis title
    Cochran Mantel Haenszel test
    Statistical analysis description
    Cochran-Mantel-Haenszel test stratified by WHO FC at baseline. For patients with missing modified NYHA/WHO FC at Week 26, the modified NYHA/WHO FC is considered as having worsened from baseline at Week 26. Missing values were imputed for 18.3% of the subjects.
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    1145
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [5]
    P-value
    = 0.2843 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.161
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.811
         upper limit
    1.664
    Notes
    [5] - It was assumed that the probabilities for absence of worsening in WHO FC at Week 26 were the same for both treatment groups
    [6] - Two-sided p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to up to 7 days after end of treatment (EOT)
    Adverse event reporting additional description
    Median duration of exposure to study drug was 70.7 weeks (range: 0.3–216.7 weeks) in the selexipag group and 63.7 weeks (range: 0.7–192.0 weeks) in the placebo group.
    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
    This group includes patients who received at least one dose of placebo. Four patients who were randomized to placebo never received the drugs and another patient received selexipag by mistake (see Selexipag group for more details). Therefore, these patients were excluded from the placebo group in the safety analysis set.

    Reporting group title
    Selexipag
    Reporting group description
    This group includes patients who received at least one dose of selexipag. One subject who was randomized to placebo received a single dose of 8 tablets of selexipag due to an error in the dispensation of the medication bottle. Therefore, this patient was assigned to the selexipag group in the safety analysis set.

    Serious adverse events
    Placebo Selexipag
    Total subjects affected by serious adverse events
         subjects affected / exposed
    272 / 577 (47.14%)
    252 / 575 (43.83%)
         number of deaths (all causes)
    41
    49
         number of deaths resulting from adverse events
    Vascular disorders
    CIRCULATORY COLLAPSE
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    EXTREMITY NECROSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLUSHING
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMODYNAMIC INSTABILITY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    3 / 577 (0.52%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HYPOVOLAEMIC SHOCK
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERY THROMBOSIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHLEBITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOPHLEBITIS SUPERFICIAL
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENA CAVA THROMBOSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENOUS INSUFFICIENCY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENOUS THROMBOSIS LIMB
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    BARIATRIC GASTRIC BALLOON INSERTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLADDER NECK SUSPENSION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC PACEMAKER INSERTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIOVERSION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CERVICAL CONISATION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTECTOMY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG THERAPY CHANGED
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GLAUCOMA SURGERY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMODIALYSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG TRANSPLANT
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    MASTECTOMY
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NASAL SEPTAL OPERATION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SALPINGECTOMY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (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
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STEM CELL TRANSPLANT
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    TURBINECTOMY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETHRAL OPERATION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    3 / 577 (0.52%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST CANCER RECURRENT
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL HAEMANGIOMA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLORECTAL CANCER METASTATIC
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    DIFFUSE LARGE B-CELL LYMPHOMA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HEPATIC NEOPLASM
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHANGIOSIS CARCINOMATOSA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG TRANSPLANT REJECTION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SARCOIDOSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SECONDARY IMMUNODEFICIENCY
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    PREGNANCY
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RUPTURED ECTOPIC PREGNANCY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST DISCOMFORT
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    6 / 577 (1.04%)
    6 / 575 (1.04%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    EXERCISE TOLERANCE DECREASED
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (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 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMPAIRED HEALING
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTI-ORGAN FAILURE
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    4 / 577 (0.69%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUDDEN CARDIAC DEATH
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SUDDEN DEATH
         subjects affected / exposed
    4 / 577 (0.69%)
    5 / 575 (0.87%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Psychiatric disorders
    ALCOHOLISM
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCHIZOAFFECTIVE DISORDER
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SOMNAMBULISM
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STRESS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    CERVICAL DYSPLASIA
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTOCELE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENDOMETRIOSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENORRHAGIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OVARIAN CYST
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OVARIAN CYST RUPTURED
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (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
    ACCIDENT
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACETABULUM FRACTURE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN HERNIATION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CRANIOCEREBRAL INJURY
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    FALL
         subjects affected / exposed
    6 / 577 (1.04%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FOOT FRACTURE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GINGIVAL INJURY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INJURY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JAW FRACTURE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JOINT DISLOCATION
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIGAMENT SPRAIN
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIP INJURY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER LIMB FRACTURE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTIPLE INJURIES
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PELVIC FRACTURE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (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 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMATOMA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PUBIS FRACTURE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FUME INHALATION DISORDER
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    2 / 577 (0.35%)
    4 / 575 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRAUMATIC FRACTURE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VACCINATION COMPLICATION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR PROCEDURE COMPLICATION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR PSEUDOANEURYSM
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         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 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN NATRIURETIC PEPTIDE INCREASED
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC INDEX DECREASED
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CATHETERISATION CARDIAC
         subjects affected / exposed
    1 / 577 (0.17%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INVESTIGATION
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER FUNCTION TEST ABNORMAL
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OXYGEN SATURATION DECREASED
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY ARTERIAL PRESSURE INCREASED
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY ARTERIAL WEDGE PRESSURE INCREASED
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RED BLOOD CELL COUNT INCREASED
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSPLANT EVALUATION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WALKING DISTANCE TEST ABNORMAL
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT INCREASED
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (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 / 577 (0.17%)
    0 / 575 (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 / 577 (0.00%)
    1 / 575 (0.17%)
         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
    5 / 577 (0.87%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    ANGINA PECTORIS
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARRHYTHMIA
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    4 / 577 (0.69%)
    7 / 575 (1.22%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    5 / 577 (0.87%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL TACHYCARDIA
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL THROMBOSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK SECOND DEGREE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYARRHYTHMIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARDIAC ARREST
         subjects affected / exposed
    4 / 577 (0.69%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    CARDIAC FAILURE
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    2 / 577 (0.35%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    CARDIOGENIC SHOCK
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    CARDIOPULMONARY FAILURE
         subjects affected / exposed
    1 / 577 (0.17%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    CHRONIC RIGHT VENTRICULAR FAILURE
         subjects affected / exposed
    2 / 577 (0.35%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COR PULMONALE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COR PULMONALE ACUTE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COR PULMONALE CHRONIC
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY INSUFFICIENCY
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CORONARY ARTERY OCCLUSION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CORONARY ARTERY STENOSIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYANOSIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (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
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    PALPITATIONS
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIGHT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIGHT VENTRICULAR FAILURE
         subjects affected / exposed
    41 / 577 (7.11%)
    34 / 575 (5.91%)
         occurrences causally related to treatment / all
    1 / 49
    1 / 42
         deaths causally related to treatment / all
    1 / 6
    0 / 7
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    4 / 577 (0.69%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYCARDIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENTRICULAR FIBRILLATION
         subjects affected / exposed
    0 / 577 (0.00%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    ACUTE LUNG INJURY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASTHMA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         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
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    13 / 577 (2.25%)
    17 / 575 (2.96%)
         occurrences causally related to treatment / all
    2 / 17
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    4 / 577 (0.69%)
    4 / 575 (0.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    5 / 577 (0.87%)
    5 / 575 (0.87%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HYPOXIA
         subjects affected / exposed
    3 / 577 (0.52%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ORGANISING PNEUMONIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORTHOPNOEA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY ARTERIAL HYPERTENSION
         subjects affected / exposed
    127 / 577 (22.01%)
    83 / 575 (14.43%)
         occurrences causally related to treatment / all
    2 / 183
    2 / 106
         deaths causally related to treatment / all
    1 / 16
    0 / 19
    PULMONARY ARTERY DILATATION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    3 / 577 (0.52%)
    4 / 575 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY HAEMORRHAGE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY HYPERTENSION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY INFARCTION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY VENO-OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    3 / 577 (0.52%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    RESPIRATORY GAS EXCHANGE DISORDER
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SLEEP APNOEA SYNDROME
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYPNOEA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    3 / 577 (0.52%)
    5 / 575 (0.87%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGIC ANAEMIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IDIOPATHIC THROMBOCYTOPENIC PURPURA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    AGEUSIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APHASIA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATAXIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AUTONOMIC NERVOUS SYSTEM IMBALANCE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBELLAR SYNDROME
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL INFARCTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEMYELINATION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HEADACHE
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIC UNCONSCIOUSNESS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL IMPAIRMENT
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MIGRAINE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARKINSON'S DISEASE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST HERPETIC NEURALGIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         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 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    20 / 577 (3.47%)
    10 / 575 (1.74%)
         occurrences causally related to treatment / all
    3 / 23
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THALAMIC INFARCTION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOCAL CORD PARALYSIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    CATARACT
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOROIDITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MACULOPATHY
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VISION BLURRED
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL HERNIA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    4 / 577 (0.69%)
    5 / 575 (0.87%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAL HAEMORRHAGE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS ISCHAEMIC
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    3 / 577 (0.52%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DUODENAL ULCER
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPEPSIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCELE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL ANGIODYSPLASIA HAEMORRHAGIC
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    3 / 577 (0.52%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOCHEZIA
         subjects affected / exposed
    2 / 577 (0.35%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE POLYP
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MELAENA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NECROTISING COLITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    OESOPHAGEAL OBSTRUCTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGEAL VARICES HAEMORRHAGE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SIGMOIDITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 577 (0.35%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    ACUTE HEPATIC FAILURE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLANGITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CIRRHOSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CYST
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC MASS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATORENAL SYNDROME
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NODULAR REGENERATIVE HYPERPLASIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE PRERENAL FAILURE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANURIA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUPUS NEPHRITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OLIGURIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE ACUTE
         subjects affected / exposed
    6 / 577 (1.04%)
    6 / 575 (1.04%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 6
         deaths causally related to treatment / all
    1 / 3
    0 / 2
    URETHRAL STENOSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS CONTACT
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DERMATOMYOSITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN OF SKIN
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCLERODERMA ASSOCIATED DIGITAL ULCER
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN ULCER
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TELANGIECTASIA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHONDROCALCINOSIS PYROPHOSPHATE
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (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 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CRYSTAL ARTHROPATHY
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (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 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MIXED CONNECTIVE TISSUE DISEASE
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYALGIA
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOPOROSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOPOROTIC FRACTURE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYMYOSITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    2 / 577 (0.35%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STILL'S DISEASE ADULT ONSET
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC LUPUS ERYTHEMATOSUS
         subjects affected / exposed
    1 / 577 (0.17%)
    5 / 575 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC SCLEROSIS
         subjects affected / exposed
    2 / 577 (0.35%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endocrine disorders
    AUTOIMMUNE THYROIDITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASEDOW'S DISEASE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTHYROIDISM
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTHYROIDISM
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    2 / 577 (0.35%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DIABETES MELLITUS INADEQUATE CONTROL
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSLIPIDAEMIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ELECTROLYTE IMBALANCE
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    FLUID OVERLOAD
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLUID RETENTION
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GOUT
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 577 (0.17%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HYPONATRAEMIC SYNDROME
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL INFECTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABSCESS INTESTINAL
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABSCESS LIMB
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABSCESS ORAL
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS PERFORATED
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    4 / 577 (0.69%)
    6 / 575 (1.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHOPNEUMONIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CATHETER SITE INFECTION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    3 / 577 (0.52%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTITIS ESCHERICHIA
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC GANGRENE
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         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 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCOLITIS VIRAL
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    3 / 577 (0.52%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS C
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 577 (0.00%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOBAR PNEUMONIA
         subjects affected / exposed
    2 / 577 (0.35%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOCALISED INFECTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    4 / 577 (0.69%)
    4 / 575 (0.70%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ABSCESS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    2 / 577 (0.35%)
    4 / 575 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHANGITIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NASOPHARYNGITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAINFLUENZAE VIRUS INFECTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAROTITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    2 / 577 (0.35%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PILONIDAL CYST
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    25 / 577 (4.33%)
    17 / 575 (2.96%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 18
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL INFECTION
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL SEPSIS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    0 / 577 (0.00%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS CHRONIC
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 577 (0.52%)
    4 / 575 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 577 (0.17%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 577 (0.17%)
    3 / 575 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOOTH ABSCESS
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOOTH INFECTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRACHEOBRONCHITIS
         subjects affected / exposed
    1 / 577 (0.17%)
    0 / 575 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 577 (0.52%)
    4 / 575 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 577 (0.17%)
    2 / 575 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 577 (0.00%)
    1 / 575 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Selexipag
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    486 / 577 (84.23%)
    544 / 575 (94.61%)
    Vascular disorders
    FLUSHING
         subjects affected / exposed
    29 / 577 (5.03%)
    69 / 575 (12.00%)
         occurrences all number
    31
    80
    Cardiac disorders
    PALPITATIONS
         subjects affected / exposed
    31 / 577 (5.37%)
    32 / 575 (5.57%)
         occurrences all number
    41
    40
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    67 / 577 (11.61%)
    56 / 575 (9.74%)
         occurrences all number
    87
    67
    DYSPNOEA
         subjects affected / exposed
    110 / 577 (19.06%)
    79 / 575 (13.74%)
         occurrences all number
    143
    100
    PULMONARY ARTERIAL HYPERTENSION
         subjects affected / exposed
    84 / 577 (14.56%)
    46 / 575 (8.00%)
         occurrences all number
    141
    64
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    28 / 577 (4.85%)
    43 / 575 (7.48%)
         occurrences all number
    37
    53
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    85 / 577 (14.73%)
    85 / 575 (14.78%)
         occurrences all number
    106
    111
    HEADACHE
         subjects affected / exposed
    189 / 577 (32.76%)
    374 / 575 (65.04%)
         occurrences all number
    261
    649
    SYNCOPE
         subjects affected / exposed
    34 / 577 (5.89%)
    30 / 575 (5.22%)
         occurrences all number
    42
    35
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    24 / 577 (4.16%)
    29 / 575 (5.04%)
         occurrences all number
    27
    33
    CHEST PAIN
         subjects affected / exposed
    39 / 577 (6.76%)
    34 / 575 (5.91%)
         occurrences all number
    54
    37
    FATIGUE
         subjects affected / exposed
    58 / 577 (10.05%)
    46 / 575 (8.00%)
         occurrences all number
    72
    54
    OEDEMA PERIPHERAL
         subjects affected / exposed
    100 / 577 (17.33%)
    77 / 575 (13.39%)
         occurrences all number
    138
    90
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    29 / 577 (5.03%)
    44 / 575 (7.65%)
         occurrences all number
    37
    54
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    32 / 577 (5.55%)
    34 / 575 (5.91%)
         occurrences all number
    38
    39
    DIARRHOEA
         subjects affected / exposed
    109 / 577 (18.89%)
    242 / 575 (42.09%)
         occurrences all number
    137
    375
    NAUSEA
         subjects affected / exposed
    107 / 577 (18.54%)
    192 / 575 (33.39%)
         occurrences all number
    136
    265
    VOMITING
         subjects affected / exposed
    48 / 577 (8.32%)
    103 / 575 (17.91%)
         occurrences all number
    53
    143
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    44 / 577 (7.63%)
    62 / 575 (10.78%)
         occurrences all number
    57
    82
    BACK PAIN
         subjects affected / exposed
    35 / 577 (6.07%)
    34 / 575 (5.91%)
         occurrences all number
    38
    36
    MYALGIA
         subjects affected / exposed
    34 / 577 (5.89%)
    90 / 575 (15.65%)
         occurrences all number
    37
    120
    PAIN IN EXTREMITY
         subjects affected / exposed
    46 / 577 (7.97%)
    95 / 575 (16.52%)
         occurrences all number
    62
    142
    PAIN IN JAW
         subjects affected / exposed
    36 / 577 (6.24%)
    148 / 575 (25.74%)
         occurrences all number
    38
    188
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    19 / 577 (3.29%)
    34 / 575 (5.91%)
         occurrences all number
    23
    38
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    41 / 577 (7.11%)
    42 / 575 (7.30%)
         occurrences all number
    49
    46
    NASOPHARYNGITIS
         subjects affected / exposed
    63 / 577 (10.92%)
    75 / 575 (13.04%)
         occurrences all number
    95
    105
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    79 / 577 (13.69%)
    72 / 575 (12.52%)
         occurrences all number
    119
    100
    URINARY TRACT INFECTION
         subjects affected / exposed
    30 / 577 (5.20%)
    24 / 575 (4.17%)
         occurrences all number
    34
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2010
    - Merge of studies AC-065A301 and AC-065A302 into one study (AC-065A302 /GRIPHON) - Two primary endpoints were initially defined: time to clinical worsening (mortality / morbidity events) and change from baseline to week 16 in 6MWD. The latter was moved to the secondary endpoints and the time of assessment was slightly changed (from week 16 to week 26). In addition, for the analysis of the time to clinical worsening, subjects were to be censored 7 days after study treatment discontinuation, in accordance with FDA recommendations
    20 Dec 2010
    - Additional ECGs as recommended by the FDA - Deletion of the inclusion criteria related to “refrain from sun exposure” (phase I study did not indicate phototoxic potential) - Statistical clarification as requested by the FDA
    11 May 2011
    - Addition of thyroid markers monitoring - Addition of a sub-study for ophthalmological evaluations
    14 Dec 2011
    - Increase in the assumed hazard ratio for the primary endpoint (0.5729 to 0.65) and the sample size (670 to 1150) and the sample size (670 to 1150) and increase of the number of MM events (202 to 331) - Addition of a futility and efficacy interim analysis after 202 M/M events - M/M events with onset date up to 16 AUG 11 to be censored for primary endpoint analysis NOTE: All the events, including those < 16AUG11 are reported in the present results summary since the results were virtually identical with and without censoring
    23 Jan 2013
    - Wording of the primary endpoint “clinical worsening event” was changed to “mortality/morbidity event” - Introduction of a post-treatment observation period (PTOP) data collection - Addition of an ophthalmological safety board, an expert medical review committee (PAH etiology) and expansion of the CEC role - Addition of exploratory endpoints including: time to first MM event up to study closure (SC), time to first MM event (excluding disease progression) up to SC, time to death or hospitalization due to PAH up to 7 days after EOT or up to SC - Statistical clarifications and modifications but the primary statistical analysis of the primary efficacy endpoint was not affected

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26699168
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