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    Clinical Trial Results:
    Long-term extension, multi-centre, multi-national study to evaluate the safety and tolerability of oral BAY63-2521(1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in patients with symptomatic Pulmonary Arterial Hypertension (PAH).

    Summary
    EudraCT number
    		 2008-003610-94
    Trial protocol
    		 DE   FR   SE   AT   GB   IE   BE   CZ   DK   IT   NL   ES   PT   GR  
    Global end of trial date
    18 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Sep 2020
    First version publication date
    02 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY 63-2521/12935
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00863681
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    18 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the long-term safety and tolerability of BAY63-2521 in treatment naive patients and patients pretreated with an Endothelin Receptor Antagonist or a Prostacycline Analogue with symptomatic Pulmonary Arterial Hypertension (PAH).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects/legal representatives. Participating subjects/legal representatives signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. The assent of a minor was also requested where such a person was able to express his own will. His refusal or the withdrawal of his consent was not to be disregarded. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Mar 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
    Australia: 17
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Singapore: 9
    Country: Number of subjects enrolled
    Thailand: 3
    Country: Number of subjects enrolled
    Taiwan: 10
    Country: Number of subjects enrolled
    China: 73
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Brazil: 26
    Country: Number of subjects enrolled
    Mexico: 16
    Worldwide total number of subjects
    396
    EEA total number of subjects
    160
    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)
    306
    From 65 to 84 years
    90
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 97 centers in 27 countries between 12-MAR-2009 (first subject first visit) and 19-AUG-2019 (last subject last visit);

    Pre-assignment
    Screening details
    		 Of the 405 subjects who completed PATENT-1 study, 396 subjects entered PATENT-2 study. 231 subjects were from the former riociguat 1.0-2.5mg group, 109 were from the former placebo group and 56 were from the former riociguat 1.0-1.5mg group.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Study titration phase was from week 1 to week 8, in titration phase, blinded with respect to the riociguat dose. Study main phase was starting from week 12 to the end of study. In study main phase, unblinded with respect to riociguat dose.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Riociguat-Former Riociguat 1.0–2.5 mg
    Arm description
    		 Subjects from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 (2008-003482-68)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY 63-2521
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects from the riociguat 1.0-2.5 mg individual dose titration group of PATENT-1 entered the extension study on the same dose level as they received on the last day of PATENT-1. These subjects received sham titration during the titration phase of PATENT-2. To maintain the blinding of PATENT-1, the PATENT-2 study medication (open-label riociguat) was blinded with respect to the dose during the titration phase, and investigators did not know at which dose level a subject entered the PATENT-2 study. The individual dose was not increased above the dose received on the last day of PATENT-1. If the investigator requested a dose increase above that level via the IVRS, the subject received a sham titration. However, if the investigator requested a dose decrease, dose modifications were possible.

    Arm title
    		 Riociguat-Former Placebo
    Arm description
    		 ‌Subjects were from the former placebo group of PATENT-1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY 63-2521
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects from the placebo group of the PATENT-1 study started at Visit 1 of the PATENT-2 study with a riociguat dose of 1.0 mg tid and were up-titrated in a blinded manner. The individual riociguat dose was titrated every 2weeks according to the peripheral SBP measured at trough before intake of the next morning dose. At the end of the titration phase, subjects reached riociguat doses between 0.5mg tid and 2.5mg tid.

    Arm title
    		 Riociguat-Former Riociguat 1.0–1.5 mg
    Arm description
    		 Subjects from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY 63-2521
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects from the PATENT-1 riociguat 1.0-1.5mg group entered the extension study PATENT-2 on the same dose level as they received on the last day of PATENT-1. For subjects with a starting dose of 1.5mg riociguat tid in PATENT-2, the individual optimal riociguat dose was to be determined every 2 weeks according to the peripheral SBP measured at trough before intake of the next morning dose. At the end of the titration phase, subjects reached riociguat doses between 0.5mg tid and 2.5mg tid. For subjects with a starting dose of 1.0mg or 0.5mg riociguat tid in PATENT-2, the dose was not to be further increased until Visit5. If the investigator requested a dose increase above that level via the IVRS, the subject underwent a sham titration. However, if the investigator requested a dose decrease, dose modifications were possible, but without a subsequent re-increase before Visit5. Subjects who did not tolerate the lowest riociguat dose (0.5mg tid) were to be withdrawn from the study.

    Number of subjects in period 1
    		Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Started
    231
    109
    56
    Completed
    140
    66
    38
    Not completed
    91
    43
    18
         Consent withdrawn by subject
    12
    5
    2
         Adverse event, non-fatal
    28
    10
    6
         Other
    2
    -
    -
         Death
    40
    23
    6
         Non-compliance with study drug
    1
    3
    -
         Lost to follow-up
    3
    -
    3
         Missing
    1
    -
    -
         Protocol deviation
    2
    -
    -
         Lack of efficacy
    2
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Riociguat-Former Riociguat 1.0–2.5 mg
    Reporting group description
    		 Subjects from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 (2008-003482-68)

    Reporting group title
    Riociguat-Former Placebo
    Reporting group description
    		 ‌Subjects were from the former placebo group of PATENT-1

    Reporting group title
    Riociguat-Former Riociguat 1.0–1.5 mg
    Reporting group description
    		 Subjects from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1

    Reporting group values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg Total
    Number of subjects
    		 231 109 56 396
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 174 87 45 306
        From 65-84 years
    		 57 22 11 90
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.4 ± 16.4 48.8 ± 15.9 48.2 ± 16.3 -
    Gender Categorical
    Units: Subjects
        Female
    		 186 87 44 317
        Male
    		 45 22 12 79
    Race / Ethnicity
    Units: Subjects
        White
    		 148 66 28 242
        Black or African American
    		 2 1 1 4
        Asian
    		 74 33 20 127
        Hispanic or Latino
    		 7 8 7 22
        Multiple
    		 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Riociguat-Former Riociguat 1.0–2.5 mg
    Reporting group description
    		 Subjects from the former riociguat (BAY 63-2521) 1.0 - 2.5 mg treatment group in PATENT-1 (2008-003482-68)

    Reporting group title
    Riociguat-Former Placebo
    Reporting group description
    		 ‌Subjects were from the former placebo group of PATENT-1

    Reporting group title
    Riociguat-Former Riociguat 1.0–1.5 mg
    Reporting group description
    		 Subjects from the former riociguat (BAY 63-2521) 1.0 - 1.5 mg treatment group in PATENT-1

    Subject analysis set title
    long-term safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All 396 subjects who received 1 of 3 blinded treatments for 12 weeks in the double-blind PATENT-1 study entered long term extension PATENT-2 study. Baseline of PATENT-2 was Week 0 of PATENT-1. All 396 subjects were included in the long-term safety set

    Primary: Number of subjects with treatment-emergent adverse events (TEAE)

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    End point title
    		 Number of subjects with treatment-emergent adverse events (TEAE) [1]
    End point description
    Analyses of drug-related TEAEs were based on the assessment of causal relationship to study medication.
    End point type
    Primary
    End point timeframe
    From administration of first dose of study medication in PATENT-2 up to 2 days after end of treatment with study medication.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231
    109
    56
    Units: Subjects
        Any TEAE
    229
    108
    56
        Any drug-related TEAE
    138
    74
    30
        Any serious TEAE
    161
    76
    39
        Any drug-related serious TEAE
    25
    16
    3
        Any TEAE leading to death
    42
    25
    6
    No statistical analyses for this end point

    Primary: Number of subject with death

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    End point title
    		 Number of subject with death [2]
    End point description
    Analyses of deaths were based on the assessment of causal relationship to study medication. The safety follow-up visit was to be performed 30 days after the last dose of riociguat.
    End point type
    Primary
    End point timeframe
    From baseline to end of safety follow-up visit
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231
    109
    56
    Units: Subjects
        Death
    48
    30
    7
    No statistical analyses for this end point

    Secondary: Percentage of subjects with treatment-emergent high laboratory abnormalities in Hematology and Coagulation

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    End point title
    		 Percentage of subjects with treatment-emergent high laboratory abnormalities in Hematology and Coagulation
    End point description
    Percentage of subjects with a treatment-emergent shift in hematology and coagulation parameters from normal or low at baseline to a high value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of subjects with a normal or low value at baseline who had at least one high value after the start of treatment with the number of subjects with a normal or low value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Secondary
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231
    109
    56
    Units: Percentage
    number (not applicable)
        aPTT (Sec)
    68.1
    80.0
    79.2
        Basophils (Giga/L)
    1.0
    1.1
    2.0
        Basophils/Leukocytes (%)
    16.4
    12.1
    10.4
        Eosinophils (Giga/L)
    1.9
    2.2
    2.0
        Eosinophils/Leukocytes (%)
    8.7
    3.4
    10.4
        Erythrocytes (T/L)
    13.7
    21.8
    35.0
        Hematocrit (%)
    35.6
    37.7
    48.6
        Hemoglobin (g/dL)
    8.9
    16.5
    24.4
        Leukocytes (Giga/L)
    10.9
    13.6
    22.2
        Lymphocytes (Giga/L)
    1.4
    3.4
    0.0
        Lymphocytes/Leukocytes (%)
    11.4
    19.5
    6.5
        Monocytes (Giga/L)
    6.3
    3.3
    0.0
        Monocytes/Leukocytes (%)
    20.0
    18.0
    22.2
        Neutrophils (Giga/L)
    14.2
    18.8
    28.3
        Neutrophils/Leukocytes (%)
    42.5
    38.3
    52.3
        Platelets (Giga/L)
    14.9
    9.7
    15.6
        Prothrombin INR
    56.3
    74.0
    58.6
    No statistical analyses for this end point

    Secondary: Percentage of subjects with treatment-emergent low laboratory abnormalities in Hematology and Coagulation

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    End point title
    		 Percentage of subjects with treatment-emergent low laboratory abnormalities in Hematology and Coagulation
    End point description
    Percentage of subjects with a treatment-emergent shift in hematology and coagulation parameters from normal or high at baseline to a low value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of subjects with a normal or high value at baseline who had at least one low value after the start of treatment with the number of subjects with a normal or high value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Secondary
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231
    109
    56
    Units: Percentage
    number (not applicable)
        aPTT (Sec)
    12.8
    13.5
    8.5
        Erythrocytes (T/L)
    31.0
    22.8
    25.0
        Hematocrit (%)
    22.1
    23.3
    26.7
        Hemoglobin (g/dL)
    48.2
    38.0
    46.2
        Leukocytes (Giga/L)
    25.7
    23.6
    25.6
        Lymphocytes (Giga/L)
    29.3
    29.3
    32.6
        Lymphocytes/Leukocytes (%)
    50.3
    44.6
    64.3
        Monocytes (Giga/L)
    0.5
    1.1
    2.0
        Monocytes/Leukocytes (%)
    2.4
    3.3
    14.3
        Neutrophils (Giga/L)
    9.4
    4.4
    8.5
        Neutrophils/Leukocytes (%)
    6.9
    4.5
    6.5
        Platelets (Giga/L)
    23.8
    29.5
    26.8
        Prothrombin INR
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of subjects with treatment-emergent high laboratory abnormalities in Clinical chemistry

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    End point title
    		 Percentage of subjects with treatment-emergent high laboratory abnormalities in Clinical chemistry
    End point description
    Percentage of subjects per treatment group with a treatment-emergent shift in clinical chemistry parameters from normal or low at baseline to a high value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of subjects with a normal or low value at baseline who had at least one high value after the start of treatment with the number of subjects with a normal or low value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Secondary
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231
    109
    56
    Units: Percentage
    number (not applicable)
        Alanine Aminotransferase (U/L)
    13.4
    12.0
    8.7
        Albumin (g/dL)
    0.5
    1.0
    0.0
        Alkaline Phosphatase (U/L)
    15.7
    23.4
    15.6
        Aspartate Aminotransferase (U/L)
    11.6
    11.5
    10.6
        Bilirubin (mg/dL)
    14.5
    11.8
    28.9
        Calcium(mg/dL)
    2.5
    0.0
    0.0
        Creatine Kinase (U/L)
    23.8
    24.7
    19.1
        Creatinine (mg/dL)
    29.4
    39.7
    45.5
        Gamma Glutamyl Transferase(U/L)
    18.2
    17.1
    25.0
        Glutamate Dehydrogenase (U/L)
    40.0
    37.7
    56.8
        Phosphate (mg/dL)
    2.6
    0.0
    0.0
        Potassium (mmol/L)
    4.6
    4.9
    8.0
        Protein (g/dL)
    2.3
    4.9
    3.8
        Pseudocholinesterase (U/mL)
    0.5
    0.0
    0.0
        Sodium (mmol/L)
    0.5
    1.9
    3.8
        Triacylglycerol Lipase (U/L)
    22.6
    19.3
    12.2
        Urate (mg/dL)
    24.3
    25.3
    29.3
        Urea (mg/dL)
    20.1
    18.9
    30.4
        eGFR - MDRD Method (mL/min/1.73 m*2)
    0.0
    0.0
    0.0
        Creatinine Clearance (mL/min)
    12.1
    15.4
    13.3
    No statistical analyses for this end point

    Secondary: Percentage of subjects with treatment-emergent low laboratory abnormalities in Clinical chemistry

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    End point title
    		 Percentage of subjects with treatment-emergent low laboratory abnormalities in Clinical chemistry
    End point description
    Percentage of subjects per treatment group with a treatment-emergent shift in clinical chemistry parameters from normal or high at baseline to a low value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of subjects with a normal or high value at baseline who had at least one low value after the start of treatment with the number of subjects with a normal or high value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Secondary
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231
    109
    56
    Units: Percentage
    number (not applicable)
        Alanine Aminotransferase (U/L)
    0.0
    0.0
    0.0
        Albumin (g/dL)
    4.1
    4.0
    0.0
        Alkaline Phosphatase (U/L)
    3.3
    4.0
    0.0
        Bilirubin (mg/dL)
    0.0
    1.0
    0.0
        Calcium (mg/dL)
    25.0
    10.0
    20.0
        Creatine Kinase (U/L)
    8.7
    5.1
    12.2
        Creatinine (mg/dL)
    4.5
    6.9
    5.8
        Gamma Glutamyl Transferase (U/L)
    0.0
    0.0
    0.0
        Phosphate (mg/dL)
    5.3
    15.4
    33.3
        Potassium (mmol/L)
    24.9
    32.6
    29.8
        Protein (g/dL)
    9.0
    10.3
    8.5
        Pseudocholinesterase (U/mL)
    11.0
    11.1
    8.0
        Sodium (mmol/L)
    8.5
    13.0
    11.8
        Triacylglycerol Lipase (U/L)
    0.0
    0.0
    0.0
        Urate (mg/dL)
    3.6
    5.0
    3.8
        Urea (mg/dL)
    0.9
    1.0
    0.0
        eGFR - MDRD Method(mL/min/1.73 m*2)
    19.0
    17.4
    23.3
        Creatinine Clearance (mL/min)
    45.7
    30.3
    48.4
    No statistical analyses for this end point

    Other pre-specified: Change of Systolic blood pressure (SBP)

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    End point title
    		 Change of Systolic blood pressure (SBP)
    End point description
    SBP was measured after the participant had been at rest for 10 minutes in a supine position. Low SBP was defined as SBP <95 mmHg, normal SBP as SBP 95–140mmHg, and high SBP as SBP >140 mmHg. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [3]
    109 [4]
    56 [5]
    Units: millimetre(s) of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    114.36 ± 14.78
    113.75 ± 12.76
    110.88 ± 12.49
        Change from baseline to Termination visit
    -0.88 ± 15.82
    -1.30 ± 15.62
    -0.99 ± 16.12
    Notes
    [3] - Baseline: N=231 Termination visit: N=169
    [4] - Baseline: N=109 Termination visit: N=80
    [5] - Baseline: N=56 Termination visit: N=41
    No statistical analyses for this end point

    Other pre-specified: Change of Diastolic blood pressure (DBP)

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    End point title
    		 Change of Diastolic blood pressure (DBP)
    End point description
    DBP was measured after the participants had been at rest for 10 minutes in a supine position. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [6]
    109 [7]
    56 [8]
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    72.03 ± 10.53
    71.84 ± 9.06
    69.61 ± 9.89
        Change from baseline to Termination visit
    -3.33 ± 12.90
    -4.00 ± 11.72
    -2.13 ± 9.65
    Notes
    [6] - Baseline: N=231 Termination visit: N=169
    [7] - Baseline: N=109 Termination visit: N=80
    [8] - Baseline: N=56 Termination visit: N=41
    No statistical analyses for this end point

    Other pre-specified: Change of Heart rate

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    End point title
    		 Change of Heart rate
    End point description
    Heart rate was measured after the participant had been at rest for 10 minutes in a supine position. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [9]
    109 [10]
    56 [11]
    Units: beats/minute (BPM)
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    76.47 ± 11.04
    77.30 ± 12.53
    76.04 ± 10.83
        Change from baseline to Termination visit
    0.75 ± 13.92
    0.18 ± 14.07
    -1.10 ± 14.74
    Notes
    [9] - Baseline: N=231 Termination visit: N=169
    [10] - Baseline: N=109 Termination visit: N=80
    [11] - Baseline: N=56 Termination visit: N=41
    No statistical analyses for this end point

    Other pre-specified: Change of Weight

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    End point title
    		 Change of Weight
    End point description
    Weight was evaluated for safety. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [12]
    109 [13]
    56 [14]
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    68.24 ± 18.25
    69.03 ± 16.94
    69.62 ± 15.01
        From baseline to Termination visit
    -1.67 ± 6.45
    0.04 ± 6.04
    -1.79 ± 8.08
    Notes
    [12] - Baseline: N=231 Termination visit: N=169
    [13] - Baseline: N=109 Termination visit: N=81
    [14] - Baseline: N=56 Termination visit: N=41
    No statistical analyses for this end point

    Other pre-specified: Change of oxygen saturation (SaO2)

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    End point title
    		 Change of oxygen saturation (SaO2)
    End point description
    SaO2 is one parameters of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to termination visit, up to 10 years
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [15]
    109 [16]
    56 [17]
    Units: Percentage
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    95.10 ± 2.61
    94.32 ± 3.18
    94.00 ± 2.95
        From baseline to Termination visit
    -1.14 ± 3.48
    -0.56 ± 4.45
    -4.30 ± 5.23
    Notes
    [15] - Baseline: N=227 Termination visit: N=15
    [16] - Baseline: N=109 Termination visit: N=9
    [17] - Baseline: N=56 Termination visit: N=2
    No statistical analyses for this end point

    Other pre-specified: Change of arterial partial oxygen pressure (PaO2)

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    End point title
    		 Change of arterial partial oxygen pressure (PaO2)
    End point description
    PaO2 is one parameter of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [18]
    109 [19]
    56 [20]
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    76.99 ± 17.60
    74.54 ± 17.84
    72.12 ± 13.63
        From baseline to Termination visit
    -4.77 ± 17.42
    7.14 ± 58.00
    -8.05 ± 2.76
    Notes
    [18] - Baseline: N=227 Termination visit: N=15
    [19] - Baseline: N=109 Termination visit: N=9
    [20] - Baseline: N=56 Termination visit: N=2
    No statistical analyses for this end point

    Other pre-specified: Change of arterial partial pressure of carbon dioxide (PaCO2)

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    End point title
    		 Change of arterial partial pressure of carbon dioxide (PaCO2)
    End point description
    PaCO2 is one parameter of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to termination visit, up to 10 years.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [21]
    109 [22]
    56 [23]
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    32.94 ± 4.62
    32.46 ± 4.63
    33.40 ± 4.41
        From baseline to Termination visit
    -1.87 ± 3.72
    -0.68 ± 5.70
    2.00 ± 4.24
    Notes
    [21] - Baseline: N=227 Termination visit: N=15
    [22] - Baseline: N=109 Termination visit: N=9
    [23] - Baseline: N=56 Termination visit: N=2
    No statistical analyses for this end point

    Other pre-specified: Change of RR duration from Electrocardiogram (ECG)

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    End point title
    		 Change of RR duration from Electrocardiogram (ECG)
    End point description
    Heart rate from ECG is derived from the RR duration, unless arrhythmias such as atrial fibrillation or ventricular extra beats require additional calculations. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Month 48.
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [24]
    109 [25]
    56 [26]
    Units: millisecond (msec)
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    817.69 ± 125.61
    828.96 ± 146.32
    822.33 ± 130.27
        Change rom baseline to Month 48
    59.07 ± 109.89
    75.69 ± 181.94
    89.61 ± 113.25
    Notes
    [24] - Baseline: N=218 Month 48: N=15
    [25] - Baseline: N=103 Month 48: N=7
    [26] - Baseline: N=53 Month 48: N=6
    No statistical analyses for this end point

    Other pre-specified: Change of PR duration from ECG

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    End point title
    		 Change of PR duration from ECG
    End point description
    PR duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Month 48
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [27]
    109 [28]
    56 [29]
    Units: msec
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    171.07 ± 27.76
    173.97 ± 32.90
    171.74 ± 25.77
        Change from baseline to Month 48
    7.51 ± 16.29
    16.50 ± 19.41
    -3.22 ± 17.18
    Notes
    [27] - Baseline: N=211 Month 48: N=15
    [28] - Baseline: N=102 Month 48: N=6
    [29] - Baseline: N=53 Month 48: N=6
    No statistical analyses for this end point

    Other pre-specified: Change of QRS duration from ECG

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    End point title
    		 Change of QRS duration from ECG
    End point description
    QRS duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Month 48
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [30]
    109 [31]
    56 [32]
    Units: msec
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    99.59 ± 17.38
    100.09 ± 16.15
    103.22 ± 19.82
        Change from baseline to Month 48
    5.07 ± 8.56
    11.14 ± 18.69
    -0.44 ± 7.52
    Notes
    [30] - Baseline: N=213 Month 48: N=15
    [31] - Baseline: N=103 Month 48: N=7
    [32] - Baseline: N=53 Month 48: N=6
    No statistical analyses for this end point

    Other pre-specified: Change of QT duration in ECG

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    End point title
    		 Change of QT duration in ECG
    End point description
    QT duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Month 48
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [33]
    109 [34]
    56 [35]
    Units: msec
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    401.56 ± 31.35
    406.67 ± 35.44
    405.10 ± 30.52
        Change from baseline to Month 48
    10.93 ± 27.58
    16.89 ± 16.78
    27.34 ± 28.61
    Notes
    [33] - Baseline: N=177 Month 48: N=9
    [34] - Baseline: N=76 Month 48: N=3
    [35] - Baseline: N=40 Month 48: N=4
    No statistical analyses for this end point

    Other pre-specified: Change in Six-minute walking distance (6MWD) test

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    End point title
    		 Change in Six-minute walking distance (6MWD) test
    End point description
    6MWD is exercise testing and is one of efficacy evaluation
    End point type
    Other pre-specified
    End point timeframe
    From baseline to End of study visit
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [36]
    109 [37]
    56 [38]
    Units: meters
    median (full range (min-max))
        Baseline (Week 0)
    375.0 (160 to 468)
    395.0 (174 to 450)
    376.0 (158 to 448)
        Change from baseline to End of study visit
    19.0 (-448 to 309)
    9.0 (-446 to 275)
    1.5 (-448 to 492)
    Notes
    [36] - Baseline: N=231 End of study visit: N=231
    [37] - Baseline: N=109 End of study visit: N=109
    [38] - Baseline: N=56 End of study visit: N=56
    No statistical analyses for this end point

    Other pre-specified: Change in Pulmonary vascular resistance (PVR)

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    End point title
    		 Change in Pulmonary vascular resistance (PVR)
    End point description
    Pulmonary vascular resistance (PVR) was measured only if right-heart catheterization was performed as part of a regular diagnostic work-up. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Termination visit
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [39]
    109 [40]
    56 [41]
    Units: dyn*s*cm-5
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    802.40 ± 452.97
    835.45 ± 476.52
    855.70 ± 552.92
        Change from baseline to Termination Visit
    34.25 ± 104.83
    0 ± 0
    0 ± 0
    Notes
    [39] - Baseline: N=228 Termination Visit: N=2
    [40] - Baseline: N=103 Termination Visit: N=0
    [41] - Baseline: N=56 Termination Visit: N=0
    No statistical analyses for this end point

    Other pre-specified: Change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)

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    End point title
    		 Change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
    End point description
    NT-proBNP levels in the blood are used for diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure
    End point type
    Other pre-specified
    End point timeframe
    From baseline to End of study visit
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [42]
    109 [43]
    56 [44]
    Units: picograms/millilitre (pg/mL)
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    996.30 ± 1627.48
    1135.68 ± 1533.20
    1220.11 ± 1457.90
        Change from baseline to End of study visit
    82.52 ± 2253.30
    202.42 ± 3466.94
    115.77 ± 1918.81
    Notes
    [42] - Baseline: N=210 End of study visit: N=210
    [43] - Baseline: N=97 End of study visit: N=97
    [44] - Baseline: N=47 End of study visit: N=47
    No statistical analyses for this end point

    Other pre-specified: Change in World Health Organization (WHO) functional class

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    End point title
    		 Change in World Health Organization (WHO) functional class
    End point description
    The subject's functional class was determined according to the WHO classification: I: Subjects with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. II: Subjects with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. III: Subjects with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. IV: Subjects with PH with inability to carry out any physical activity without symptoms. These participants manifest signs of right-heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to End of study (EOS) visit
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [45]
    109 [46]
    56 [47]
    Units: Subjects
        Baseline (Week 0)-class I
    5
    3
    4
        Baseline (Week 0)-class II
    98
    54
    17
        Baseline (Week 0)-class III
    128
    49
    35
        Baseline (Week 0)-class IV
    0
    2
    0
        Baseline (Week 0)-Missing
    0
    1
    0
        Change from baseline to EOS visit- -2
    5
    0
    1
        Change from baseline to EOS visit- -1
    50
    16
    13
        Change from baseline to EOS visit- 0
    101
    52
    28
        Change from baseline to EOS visit- +1
    23
    15
    6
        Change from baseline to EOS visit- +2
    33
    17
    5
        Change from baseline to EOS visit- +3
    19
    8
    3
    Notes
    [45] - Baseline: N=231 End of study visit: N=231
    [46] - Baseline: N=109 End of study visit: N=108
    [47] - Baseline: N=56 End of study visit: N=56
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with clinical worsening

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    End point title
    		 Number of subjects with clinical worsening
    End point description
    Time to clinical worsening was a parameter that combined death and events reflective of persistent clinical worsening of the participant's underlying diagnosis of pulmonary hypertension (PH)
    End point type
    Other pre-specified
    End point timeframe
    From baseline to End of study visit
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231
    109
    56
    Units: Subjects
        Any clinical worsening
    87
    41
    18
        Heart/lung transplantation
    3
    0
    2
        Atrial septostomy
    1
    1
    0
        Hospitalization due to pulmonary hypertension
    29
    12
    8
        Start of new pulmonary hypertension treatment
    52
    20
    14
        Decrease in 6MWD due to pulmonary hypertension
    7
    6
    2
        Persistent worsening of functional class due to PH
    8
    2
    1
        Death
    48
    30
    7
    No statistical analyses for this end point

    Other pre-specified: Incidence of clinical worsening events

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    End point title
    		 Incidence of clinical worsening events
    End point description
    Time to clinical worsening was a parameter that combined death and events reflective of persistent clinical worsening of the participant's underlying diagnosis of pulmonary hypertension (PH)
    End point type
    Other pre-specified
    End point timeframe
    From baseline to End of study visit
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231
    109
    56
    Units: Percentage per 100 person-years
    number (not applicable)
        Any clinical worsening event
    193
    87
    43
        Heart/Lung Transplantation
    3
    0
    2
        Atrial Septostomy
    1
    1
    0
        Hospitalization due to PH
    39
    15
    13
        Start of new PH treatment
    85
    32
    17
        Decrease in 6MWD due to PH
    9
    7
    2
        Persistent worsening of functional class due to PH
    8
    2
    2
        Death
    48
    30
    7
    No statistical analyses for this end point

    Other pre-specified: Change from baseline in Borg CR 10 Scale

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    End point title
    		 Change from baseline in Borg CR 10 Scale
    End point description
    The Borg CR10 Scale was measured in conjunction with the 6MWD test. The test was explained to the participant before starting the 6MWD test. Participants were asked to rank their exertion at the end of the 6MWD test. Low values indicate low levels of exertion; high values indicate more intense exertion reported by the participant. The score ranges from 0 ("Nothing at all") to 10 (“Extremely strong – Maximal”)
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [48]
    109 [49]
    56 [50]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    3.87 ± 2.24
    3.80 ± 2.26
    3.41 ± 1.77
        Change from baseline to Week 12
    -0.58 ± 1.84
    -0.54 ± 1.91
    -0.52 ± 1.64
    Notes
    [48] - Baseline: N=231 Week 12: N=216
    [49] - Baseline: N=109 Week 12: N=101
    [50] - Baseline: N=56 Week 12: N=54
    No statistical analyses for this end point

    Other pre-specified: Change in score of EQ-5D questionnaire

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    End point title
    		 Change in score of EQ-5D questionnaire
    End point description
    The EQ-5D is a standardized instrument for use as a measure of health outcome. The EQ-5D is a self report questionnaire. The utility score is calculated based on five questions concerning problems with mobility, self-care, usual activities, pain/discomfort and anxiety/depression. An increase in the utility score represents an improvement in quality of life. The score ranges from -0.594 (worst answer in all five questions) to 1 (best answer in all five questions).
    End point type
    Other pre-specified
    End point timeframe
    From baseline to End of study visit
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [51]
    109 [52]
    56 [53]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    0.6883 ± 0.2339
    0.6929 ± 0.2302
    0.6338 ± 0.2744
        Change from baseline to EOS Visit
    -0.2452 ± 0.5894
    -0.2812 ± 0.5944
    -0.0925 ± 0.4376
    Notes
    [51] - Baseline: N=230 End of study visit: N=230
    [52] - Baseline: N=107 End of study visit: N=107
    [53] - Baseline: N=55 End of study visit: N=55
    No statistical analyses for this end point

    Other pre-specified: Change in score of Living with Pulmonary Hypertension (LPH) questionnaire

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    End point title
    		 Change in score of Living with Pulmonary Hypertension (LPH) questionnaire
    End point description
    The LPH questionnaire is designed to measure the effects of PH and PH-specific treatments on an individual’s quality of life. The LPH is a self-report questionnaire and was completed by the participant. The LPH total score can range from 0 (best) to 105 (worst).
    End point type
    Other pre-specified
    End point timeframe
    From baseline to End of study visit
    End point values
    		 Riociguat-Former Riociguat 1.0–2.5 mg Riociguat-Former Placebo Riociguat-Former Riociguat 1.0–1.5 mg
    Number of subjects analysed
    231 [54]
    109 [55]
    56 [56]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline (Week 0)
    41.77 ± 22.18
    41.94 ± 23.34
    45.10 ± 22.08
        Change from baseline to EOS Visit
    4.99 ± 34.04
    12.28 ± 32.76
    -4.07 ± 31.40
    Notes
    [54] - Baseline: N=225 End of study visit: N=225
    [55] - Baseline: N=105 End of study visit: N=105
    [56] - Baseline: N=55 End of study visit: N=55
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From administration of first dose of study medication up to 2 days after end of treatment with study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Former Riociguat 1.0- 2.5 mg
    Reporting group description
    		 Patients from the PATENT-1 1.0 - 2.5 mg Dose Arm will enter the extension trial (PATENT-2)with the same dose which they have received on the last day of PATENT-1 (Visit 6).

    Reporting group title
    Former Riociguat 1.0 - 1.5 mg
    Reporting group description
    		 Patients from the PATENT-1 1.0 - 1.5 mg Dose Arm will enter the extension trial (PATENT-2)with the same dose which they have received on the last day of PATENT-1 (Visit 6).

    Reporting group title
    Former Placebo
    Reporting group description
    		 Patients from the PATENT-1 Placebo Arm will enter the extension trial (PATENT-2)with the starting dose 1 mg Riociguat tid.

    Serious adverse events
    		 Former Riociguat 1.0- 2.5 mg Former Riociguat 1.0 - 1.5 mg Former Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    161 / 231 (69.70%)
    39 / 56 (69.64%)
    76 / 109 (69.72%)
         number of deaths (all causes)
    48
    7
    30
         number of deaths resulting from adverse events
    42
    6
    25
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Renal neoplasm
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lymphatic system neoplasm
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arteriovenous fistula
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    5 / 231 (2.16%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial septal defect repair
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac pacemaker insertion
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel decompression
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric polypectomy
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung transplant
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteotomy
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prophylaxis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Swan ganz catheter placement
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin neoplasm excision
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dental operation
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose vein operation
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder polypectomy
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract operation
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Balloon atrial septostomy
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Trapeziectomy
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
    Injection site pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Sudden cardiac death
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exercise tolerance decreased
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular stent stenosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Social circumstances
    Homicide
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scrotal oedema
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial dysplasia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diaphragm muscle weakness
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    11 / 231 (4.76%)
    1 / 56 (1.79%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    8 / 231 (3.46%)
    2 / 56 (3.57%)
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    5 / 12
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 231 (1.30%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal obstruction
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 231 (0.87%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    3 / 231 (1.30%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    17 / 231 (7.36%)
    6 / 56 (10.71%)
    6 / 109 (5.50%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary veno-occlusive disease
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nasal cavity mass
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    31 / 231 (13.42%)
    11 / 56 (19.64%)
    14 / 109 (12.84%)
         occurrences causally related to treatment / all
    2 / 50
    1 / 13
    0 / 28
         deaths causally related to treatment / all
    2 / 9
    0 / 1
    0 / 7
    Acute interstitial pneumonitis
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lead dislodgement
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Biopsy
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheterisation cardiac
         subjects affected / exposed
    18 / 231 (7.79%)
    3 / 56 (5.36%)
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest X-ray abnormal
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endoscopy
         subjects affected / exposed
    1 / 231 (0.43%)
    2 / 56 (3.57%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endoscopy upper gastrointestinal tract
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transplant evaluation
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Facial bones fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Snake bite
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative hypotension
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Heart disease congenital
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    3 / 231 (1.30%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 231 (0.87%)
    2 / 56 (3.57%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    5 / 231 (2.16%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    8 / 231 (3.46%)
    1 / 56 (1.79%)
    7 / 109 (6.42%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    Cardiac failure acute
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cor pulmonale chronic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    26 / 231 (11.26%)
    7 / 56 (12.50%)
    6 / 109 (5.50%)
         occurrences causally related to treatment / all
    0 / 47
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 6
    0 / 1
    0 / 3
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Acute coronary syndrome
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Acute right ventricular failure
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac dysfunction
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma hepatic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 231 (0.87%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    26 / 231 (11.26%)
    5 / 56 (8.93%)
    15 / 109 (13.76%)
         occurrences causally related to treatment / all
    10 / 43
    0 / 5
    12 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain stem syndrome
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Central nervous system vasculitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 231 (2.16%)
    1 / 56 (1.79%)
    6 / 109 (5.50%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spontaneous haematoma
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Choroidal neovascularisation
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic nerve disorder
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 231 (1.30%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 231 (1.30%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic congestion
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fixed eruption
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 231 (1.73%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture delayed union
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 231 (1.30%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sjogren's syndrome
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    3 / 231 (1.30%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Connective tissue disorder
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint instability
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic scleroderma
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    5 / 231 (2.16%)
    2 / 56 (3.57%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 231 (0.87%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    7 / 231 (3.03%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 56 (1.79%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 56 (3.57%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 231 (0.87%)
    2 / 56 (3.57%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 231 (1.73%)
    6 / 56 (10.71%)
    7 / 109 (6.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pneumonia viral
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 231 (1.73%)
    2 / 56 (3.57%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 231 (0.87%)
    3 / 56 (5.36%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Serratia infection
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial colitis
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    2 / 231 (0.87%)
    1 / 56 (1.79%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 56 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 56 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Former Riociguat 1.0- 2.5 mg Former Riociguat 1.0 - 1.5 mg Former Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    218 / 231 (94.37%)
    54 / 56 (96.43%)
    106 / 109 (97.25%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    7 / 231 (3.03%)
    3 / 56 (5.36%)
    2 / 109 (1.83%)
         occurrences all number
    8
    3
    2
    Hypotension
         subjects affected / exposed
    32 / 231 (13.85%)
    10 / 56 (17.86%)
    10 / 109 (9.17%)
         occurrences all number
    39
    13
    14
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    17 / 231 (7.36%)
    3 / 56 (5.36%)
    6 / 109 (5.50%)
         occurrences all number
    23
    4
    8
    Chest discomfort
         subjects affected / exposed
    15 / 231 (6.49%)
    6 / 56 (10.71%)
    6 / 109 (5.50%)
         occurrences all number
    26
    7
    6
    Chest pain
         subjects affected / exposed
    32 / 231 (13.85%)
    7 / 56 (12.50%)
    16 / 109 (14.68%)
         occurrences all number
    44
    7
    25
    Fatigue
         subjects affected / exposed
    20 / 231 (8.66%)
    4 / 56 (7.14%)
    12 / 109 (11.01%)
         occurrences all number
    23
    6
    20
    Oedema
         subjects affected / exposed
    9 / 231 (3.90%)
    4 / 56 (7.14%)
    9 / 109 (8.26%)
         occurrences all number
    11
    6
    11
    Oedema peripheral
         subjects affected / exposed
    64 / 231 (27.71%)
    17 / 56 (30.36%)
    31 / 109 (28.44%)
         occurrences all number
    108
    26
    51
    Pyrexia
         subjects affected / exposed
    24 / 231 (10.39%)
    3 / 56 (5.36%)
    7 / 109 (6.42%)
         occurrences all number
    45
    3
    8
    Peripheral swelling
         subjects affected / exposed
    7 / 231 (3.03%)
    5 / 56 (8.93%)
    4 / 109 (3.67%)
         occurrences all number
    7
    7
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    66 / 231 (28.57%)
    13 / 56 (23.21%)
    28 / 109 (25.69%)
         occurrences all number
    94
    20
    42
    Dyspnoea
         subjects affected / exposed
    33 / 231 (14.29%)
    12 / 56 (21.43%)
    15 / 109 (13.76%)
         occurrences all number
    54
    15
    21
    Epistaxis
         subjects affected / exposed
    30 / 231 (12.99%)
    12 / 56 (21.43%)
    16 / 109 (14.68%)
         occurrences all number
    42
    18
    20
    Haemoptysis
         subjects affected / exposed
    20 / 231 (8.66%)
    2 / 56 (3.57%)
    9 / 109 (8.26%)
         occurrences all number
    46
    6
    10
    Nasal congestion
         subjects affected / exposed
    8 / 231 (3.46%)
    3 / 56 (5.36%)
    6 / 109 (5.50%)
         occurrences all number
    9
    4
    7
    Productive cough
         subjects affected / exposed
    12 / 231 (5.19%)
    2 / 56 (3.57%)
    8 / 109 (7.34%)
         occurrences all number
    16
    2
    10
    Pulmonary hypertension
         subjects affected / exposed
    6 / 231 (2.60%)
    3 / 56 (5.36%)
    4 / 109 (3.67%)
         occurrences all number
    8
    4
    6
    Pulmonary arterial hypertension
         subjects affected / exposed
    15 / 231 (6.49%)
    2 / 56 (3.57%)
    13 / 109 (11.93%)
         occurrences all number
    20
    2
    20
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 231 (4.33%)
    1 / 56 (1.79%)
    8 / 109 (7.34%)
         occurrences all number
    10
    1
    14
    Depression
         subjects affected / exposed
    13 / 231 (5.63%)
    3 / 56 (5.36%)
    6 / 109 (5.50%)
         occurrences all number
    13
    5
    7
    Insomnia
         subjects affected / exposed
    21 / 231 (9.09%)
    5 / 56 (8.93%)
    10 / 109 (9.17%)
         occurrences all number
    24
    5
    13
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    8 / 231 (3.46%)
    3 / 56 (5.36%)
    4 / 109 (3.67%)
         occurrences all number
    10
    3
    6
    International normalised ratio increased
         subjects affected / exposed
    9 / 231 (3.90%)
    4 / 56 (7.14%)
    4 / 109 (3.67%)
         occurrences all number
    11
    5
    4
    Weight decreased
         subjects affected / exposed
    8 / 231 (3.46%)
    0 / 56 (0.00%)
    6 / 109 (5.50%)
         occurrences all number
    9
    0
    7
    Weight increased
         subjects affected / exposed
    6 / 231 (2.60%)
    5 / 56 (8.93%)
    1 / 109 (0.92%)
         occurrences all number
    8
    7
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 231 (5.19%)
    1 / 56 (1.79%)
    2 / 109 (1.83%)
         occurrences all number
    13
    1
    3
    Contusion
         subjects affected / exposed
    17 / 231 (7.36%)
    1 / 56 (1.79%)
    3 / 109 (2.75%)
         occurrences all number
    24
    1
    4
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    3 / 231 (1.30%)
    3 / 56 (5.36%)
    3 / 109 (2.75%)
         occurrences all number
    3
    3
    3
    Cardiac failure
         subjects affected / exposed
    6 / 231 (2.60%)
    4 / 56 (7.14%)
    2 / 109 (1.83%)
         occurrences all number
    6
    4
    2
    Palpitations
         subjects affected / exposed
    22 / 231 (9.52%)
    5 / 56 (8.93%)
    14 / 109 (12.84%)
         occurrences all number
    27
    9
    14
    Right ventricular failure
         subjects affected / exposed
    7 / 231 (3.03%)
    3 / 56 (5.36%)
    6 / 109 (5.50%)
         occurrences all number
    10
    3
    6
    Tachycardia
         subjects affected / exposed
    9 / 231 (3.90%)
    4 / 56 (7.14%)
    4 / 109 (3.67%)
         occurrences all number
    10
    7
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    67 / 231 (29.00%)
    15 / 56 (26.79%)
    31 / 109 (28.44%)
         occurrences all number
    118
    22
    57
    Headache
         subjects affected / exposed
    46 / 231 (19.91%)
    10 / 56 (17.86%)
    34 / 109 (31.19%)
         occurrences all number
    102
    14
    61
    Hypoaesthesia
         subjects affected / exposed
    9 / 231 (3.90%)
    4 / 56 (7.14%)
    3 / 109 (2.75%)
         occurrences all number
    9
    4
    3
    Presyncope
         subjects affected / exposed
    5 / 231 (2.16%)
    2 / 56 (3.57%)
    8 / 109 (7.34%)
         occurrences all number
    5
    4
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    30 / 231 (12.99%)
    6 / 56 (10.71%)
    14 / 109 (12.84%)
         occurrences all number
    35
    6
    29
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    6 / 231 (2.60%)
    1 / 56 (1.79%)
    6 / 109 (5.50%)
         occurrences all number
    6
    1
    7
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    14 / 231 (6.06%)
    0 / 56 (0.00%)
    6 / 109 (5.50%)
         occurrences all number
    20
    0
    7
    Abdominal pain
         subjects affected / exposed
    17 / 231 (7.36%)
    4 / 56 (7.14%)
    9 / 109 (8.26%)
         occurrences all number
    24
    4
    11
    Abdominal pain upper
         subjects affected / exposed
    18 / 231 (7.79%)
    2 / 56 (3.57%)
    7 / 109 (6.42%)
         occurrences all number
    19
    2
    8
    Constipation
         subjects affected / exposed
    22 / 231 (9.52%)
    2 / 56 (3.57%)
    10 / 109 (9.17%)
         occurrences all number
    26
    2
    11
    Diarrhoea
         subjects affected / exposed
    50 / 231 (21.65%)
    11 / 56 (19.64%)
    34 / 109 (31.19%)
         occurrences all number
    81
    22
    62
    Dyspepsia
         subjects affected / exposed
    34 / 231 (14.72%)
    8 / 56 (14.29%)
    14 / 109 (12.84%)
         occurrences all number
    68
    9
    22
    Gastritis
         subjects affected / exposed
    7 / 231 (3.03%)
    3 / 56 (5.36%)
    10 / 109 (9.17%)
         occurrences all number
    8
    3
    12
    Gastrooesophageal reflux disease
         subjects affected / exposed
    16 / 231 (6.93%)
    6 / 56 (10.71%)
    13 / 109 (11.93%)
         occurrences all number
    19
    6
    16
    Nausea
         subjects affected / exposed
    46 / 231 (19.91%)
    8 / 56 (14.29%)
    26 / 109 (23.85%)
         occurrences all number
    63
    10
    41
    Vomiting
         subjects affected / exposed
    36 / 231 (15.58%)
    9 / 56 (16.07%)
    23 / 109 (21.10%)
         occurrences all number
    47
    19
    34
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 231 (2.16%)
    3 / 56 (5.36%)
    3 / 109 (2.75%)
         occurrences all number
    5
    3
    4
    Erythema
         subjects affected / exposed
    1 / 231 (0.43%)
    4 / 56 (7.14%)
    0 / 109 (0.00%)
         occurrences all number
    1
    4
    0
    Hyperhidrosis
         subjects affected / exposed
    4 / 231 (1.73%)
    4 / 56 (7.14%)
    1 / 109 (0.92%)
         occurrences all number
    4
    5
    1
    Pruritus
         subjects affected / exposed
    10 / 231 (4.33%)
    3 / 56 (5.36%)
    3 / 109 (2.75%)
         occurrences all number
    16
    3
    3
    Rash
         subjects affected / exposed
    13 / 231 (5.63%)
    3 / 56 (5.36%)
    3 / 109 (2.75%)
         occurrences all number
    18
    3
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    28 / 231 (12.12%)
    6 / 56 (10.71%)
    10 / 109 (9.17%)
         occurrences all number
    34
    7
    15
    Arthritis
         subjects affected / exposed
    2 / 231 (0.87%)
    4 / 56 (7.14%)
    3 / 109 (2.75%)
         occurrences all number
    2
    5
    4
    Back pain
         subjects affected / exposed
    36 / 231 (15.58%)
    5 / 56 (8.93%)
    11 / 109 (10.09%)
         occurrences all number
    48
    7
    17
    Joint swelling
         subjects affected / exposed
    4 / 231 (1.73%)
    3 / 56 (5.36%)
    2 / 109 (1.83%)
         occurrences all number
    5
    4
    2
    Muscle spasms
         subjects affected / exposed
    6 / 231 (2.60%)
    3 / 56 (5.36%)
    9 / 109 (8.26%)
         occurrences all number
    8
    4
    11
    Musculoskeletal pain
         subjects affected / exposed
    10 / 231 (4.33%)
    4 / 56 (7.14%)
    6 / 109 (5.50%)
         occurrences all number
    16
    4
    6
    Myalgia
         subjects affected / exposed
    5 / 231 (2.16%)
    4 / 56 (7.14%)
    7 / 109 (6.42%)
         occurrences all number
    6
    4
    10
    Pain in extremity
         subjects affected / exposed
    27 / 231 (11.69%)
    7 / 56 (12.50%)
    12 / 109 (11.01%)
         occurrences all number
    35
    7
    15
    Systemic lupus erythematosus
         subjects affected / exposed
    4 / 231 (1.73%)
    4 / 56 (7.14%)
    0 / 109 (0.00%)
         occurrences all number
    4
    4
    0
    Spinal pain
         subjects affected / exposed
    5 / 231 (2.16%)
    3 / 56 (5.36%)
    1 / 109 (0.92%)
         occurrences all number
    5
    3
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    24 / 231 (10.39%)
    11 / 56 (19.64%)
    14 / 109 (12.84%)
         occurrences all number
    35
    13
    19
    Conjunctivitis
         subjects affected / exposed
    8 / 231 (3.46%)
    3 / 56 (5.36%)
    4 / 109 (3.67%)
         occurrences all number
    10
    5
    4
    Gastroenteritis
         subjects affected / exposed
    14 / 231 (6.06%)
    6 / 56 (10.71%)
    6 / 109 (5.50%)
         occurrences all number
    15
    6
    7
    Gastrointestinal infection
         subjects affected / exposed
    9 / 231 (3.90%)
    3 / 56 (5.36%)
    3 / 109 (2.75%)
         occurrences all number
    11
    5
    3
    Influenza
         subjects affected / exposed
    14 / 231 (6.06%)
    7 / 56 (12.50%)
    4 / 109 (3.67%)
         occurrences all number
    21
    7
    5
    Lower respiratory tract infection
         subjects affected / exposed
    8 / 231 (3.46%)
    3 / 56 (5.36%)
    6 / 109 (5.50%)
         occurrences all number
    11
    5
    17
    Nasopharyngitis
         subjects affected / exposed
    76 / 231 (32.90%)
    21 / 56 (37.50%)
    31 / 109 (28.44%)
         occurrences all number
    160
    44
    81
    Oral candidiasis
         subjects affected / exposed
    2 / 231 (0.87%)
    3 / 56 (5.36%)
    0 / 109 (0.00%)
         occurrences all number
    2
    3
    0
    Pharyngitis
         subjects affected / exposed
    9 / 231 (3.90%)
    4 / 56 (7.14%)
    4 / 109 (3.67%)
         occurrences all number
    13
    8
    4
    Pneumonia
         subjects affected / exposed
    9 / 231 (3.90%)
    7 / 56 (12.50%)
    8 / 109 (7.34%)
         occurrences all number
    9
    7
    10
    Sinusitis
         subjects affected / exposed
    13 / 231 (5.63%)
    1 / 56 (1.79%)
    9 / 109 (8.26%)
         occurrences all number
    25
    1
    11
    Upper respiratory tract infection
         subjects affected / exposed
    39 / 231 (16.88%)
    10 / 56 (17.86%)
    24 / 109 (22.02%)
         occurrences all number
    64
    20
    49
    Urinary tract infection
         subjects affected / exposed
    12 / 231 (5.19%)
    9 / 56 (16.07%)
    12 / 109 (11.01%)
         occurrences all number
    21
    12
    17
    Lung infection
         subjects affected / exposed
    4 / 231 (1.73%)
    3 / 56 (5.36%)
    4 / 109 (3.67%)
         occurrences all number
    5
    4
    4
    Respiratory tract infection
         subjects affected / exposed
    24 / 231 (10.39%)
    5 / 56 (8.93%)
    13 / 109 (11.93%)
         occurrences all number
    53
    10
    19
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    26 / 231 (11.26%)
    9 / 56 (16.07%)
    12 / 109 (11.01%)
         occurrences all number
    34
    14
    16
    Iron deficiency
         subjects affected / exposed
    11 / 231 (4.76%)
    4 / 56 (7.14%)
    7 / 109 (6.42%)
         occurrences all number
    13
    4
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2009
    Amendment 5:This amendment was implemented in response to recommendations from a series of investigator meetings conducted on a global level. The major changes concerned: - Change of initial dose for subjects from the PATENT-1 study’s 1.5mg dose group to remain at 1.5mg riociguat for the first 2weeks of the titration phase of PATENT-2. - Clarifications and additions of exclusion criteria, including mandatory withdrawal from the trial if a subject misses study medication for longer than 3days at a stretch (9 missing doses) during the titration phase - Specification of 6-minute walking distance (6MWD) test - Change of Modified Borg Dyspnoea score to Borg CR10 Scale - Collection of healthcare resource information - Addition of definition of physical training program - Specification of timelines for study medication dosing - Addition of methodology for blood pressure measurement - Addition of dizziness andsyncope as undesirable effects - Visit window from Vn onextendedto 14days - Addition of role of SC and DMC
    21 Mar 2010
    Amendment 6:This amendment was implemented in response to recommendations from the SC and a series of investigator meetings conducted on a global level. The major changes concerned: - Abolishment of mandatory overnight stays at Visit1 - Clarification of contraception methods in exclusion criteria - Clarification of pregnancy testing - Change in assessment periods - Clarification of use of the Modified Borg Dyspnoea Score in subjects who were enrolled before approval of PATENT-1 study protocol amendment4in their country - Collection of smoking status information - Smoking added as interaction Clearance of riociguat was found to be increased in smokers compared to non-smokers in study12166 in subjects with PH. - Addition of vomiting and gastritis as undesirable effects - Visit window for safety follow-up visit extended from 30 (+2) days to 30 (+5) days.
    14 Feb 2011
    Amendment 8:This amendment modified the protocol to correct some typographical errors and to add laboratory measurements for calcium and phosphate for subjects included under study protocol amendment8 of the PATENT-1 study.
    12 Dec 2012
    This amendment was primarily prepared to update the PATENT-2 protocol to consider status and the results of the of the PATENT-1 studyand the overall riociguat development program. Changes of the protocol by the amendment focused on operational aspects of the study execution and facilitated some of the study related activities. - Amongst others central laboratory and ECG collection were stopped and instead performed locally upon decision of the investigator. - Visit procedures at individual visits were reduced, but all other aspects of safety monitoring were mostly unchanged.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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