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    Clinical Trial Results:
    A prospective, randomized, international, multicenter, double arm, controlled, open label study of Riociguat in patients with pulmonary arterial hypertension (PAH) who are on a stable dose of phosphodiesterase 5 inhibitors (PDE 5i) with or without endothelin receptor antagonist (ERA), but not at treatment goal

    Summary
    EudraCT number
    		 2016-001067-36
    Trial protocol
    		 ES   PT   AT   CZ   GB   DE   BE   NL   DK   GR   PL   IT  
    Global end of trial date
    02 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jan 2021
    First version publication date
    07 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY63-2521/18588
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02891850
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    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
    16 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the proportion of subjects in each treatment arm with a satisfactory clinical response as defined by a composite primary endpoint at Week 24.
    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. Participating subjects 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. 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
    10 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Brazil: 42
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czechia: 25
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Japan: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Poland: 2
    Worldwide total number of subjects
    225
    EEA total number of subjects
    106
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    173
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at multiple centers in 21 countries between 11-JAN-2017 (first participant first visit) and 03-MAR-2020 (last participant last visit).

    Pre-assignment
    Screening details
    		 293 participants were screened in this study. Of these, 67 participants did not enter the treatment period (60 screening failures; 2 withdraw during screening; 2 withdraw following physician decision; 3 withdraw due to other reasons). 226 participants were randomized, of which 1 participant withdraw before treated.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Riociguat
    Arm description
    		 Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adempas
    Investigational medicinal product code
    BAY63-2521
    Other name
    Adempas
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg administered three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks, tablets administrated orally

    Arm title
    		 PDE-5i
    Arm description
    		 Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    ADCIRCA
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 to 40 mg/day for 24 weeks as per the investigator’s discretion, tablets administrated orally

    Investigational medicinal product name
    Sildenafil citrate
    Investigational medicinal product code
    Other name
    REVATIO
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At least 60 mg/day for 24 weeks as per the investigator’s discretion, tablets administrated orally

    Number of subjects in period 1
    		Riociguat PDE-5i
    Started
    111
    114
    Completed
    104
    107
    Not completed
    7
    7
         Adverse event, serious fatal
    -
    4
         Consent withdrawn by subject
    2
    3
         Physician decision
    1
    -
         Adverse event, non-fatal
    3
    -
         Pregnancy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Riociguat
    Reporting group description
    		 Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.

    Reporting group title
    PDE-5i
    Reporting group description
    		 Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.

    Reporting group values
    		 Riociguat PDE-5i Total
    Number of subjects
    		 111 114 225
    Age Categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.4 ( 16.16 ) 49.2 ( 15.64 ) -
    Gender Categorical
    Units: participants
        Female
    		 82 95 177
        Male
    		 29 19 48
    Race
    Units: Subjects
        White
    		 86 89 175
        Black or African American
    		 4 5 9
        Asian
    		 17 19 36
        American Indian or Alaska Native
    		 1 0 1
        Not Reported
    		 3 1 4
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 32 31 63
        Not Hispanic or Latino
    		 75 80 155
        Not Reported
    		 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    Riociguat
    Reporting group description
    		 Participants received BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.

    Reporting group title
    PDE-5i
    Reporting group description
    		 Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The participants who were randomized and took at least 1 medication were considered for the FAS. Participants were analyzed as randomized.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The population for safety analysis comprised all participants who received at least 1 dose of study drug. Participants in the SAF were analyzed as treated.

    Primary: Number of Participants with Satisfactory Clinical Response at Week 24

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    End point title
    		 Number of Participants with Satisfactory Clinical Response at Week 24
    End point description
    The treatment is assessed as efficient (participants with satisfactory clinical response) in case at least 2 out of the following 3 criteria were fulfilled • 6 Minute Walking Distance increase by ≥ 10% or ≥ 30 m from baseline to Week 24 • World Health Organization Functional Class (WHO FC) I or II at Week 24 • N-terminal pro-brain natriuretic peptide (NT-proBNP) reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7) and in absence of the defined criteria of clinical worsening.
    End point type
    Primary
    End point timeframe
    At Week 24
    End point values
    		 Riociguat PDE-5i
    Number of subjects analysed
    111 [1]
    113 [2]
    Units: participants
        With satisfactory clinical response
    45
    23
        Without satisfactory clinical response
    66
    90
    Notes
    [1] - Full Analysis Set (FAS) with evaluable participants
    [2] - Full Analysis Set (FAS) with evaluable participants
    Statistical analysis title
    		 OR for satisfactory clinical response at Week 24
    Comparison groups
    PDE-5i v Riociguat
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.0007
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.526
         upper limit
    		 5.06
    Notes
    [3] - Stratified by PAH category at baseline

    Secondary: Change in 6 Minute Walking Distance (6MWD) with Last Observation Carried Forward from baseline to 24 weeks

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    End point title
    		 Change in 6 Minute Walking Distance (6MWD) with Last Observation Carried Forward from baseline to 24 weeks
    End point description
    Six-minute walk distance (6MWD) was conducted to test the physical limitations of the participant by assessing the participant's exercise capacity. The distance walked by the participant in 6 minutes was measured.
    End point type
    Secondary
    End point timeframe
    From baseline and up to 24 weeks
    End point values
    		 Riociguat PDE-5i
    Number of subjects analysed
    111 [4]
    113 [5]
    Units: meters (m)
        arithmetic mean (standard deviation)
    36.448 ( 65.9748 )
    13.884 ( 67.1552 )
    Notes
    [4] - Full Analysis Set (FAS) with evaluable participants
    [5] - Full Analysis Set (FAS) with evaluable participants
    Statistical analysis title
    		 Mean difference of 6MWD at Week 24
    Comparison groups
    Riociguat v PDE-5i
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 = 0.0542
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    22.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.03
         upper limit
    		 40.1
    Notes
    [6] - Stratified by PAH category at baseline

    Secondary: Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) with Last Observation Carried Forward at Week 24

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    End point title
    		 Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) with Last Observation Carried Forward at Week 24
    End point description
    N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.
    End point type
    Secondary
    End point timeframe
    From baseline and up to 24 weeks
    End point values
    		 Riociguat PDE-5i
    Number of subjects analysed
    108 [7]
    113 [8]
    Units: picograms per milliliter (pg/mL)
        arithmetic mean (standard deviation)
    -88.234 ( 533.9179 )
    81.414 ( 1267.6142 )
    Notes
    [7] - Full Analysis Set (FAS) with evaluable participants
    [8] - Full Analysis Set (FAS) with evaluable participants
    Statistical analysis title
    		 Mean difference of NT-proBNP at Week 24
    Comparison groups
    Riociguat v PDE-5i
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    P-value
    		 = 0.1067
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -169.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -426.18
         upper limit
    		 86.88
    Notes
    [9] - Stratified by PAH category at baseline

    Secondary: Change in World Health Organization Functional Class (WHO FC) with Last Observation Carried Forward at Week 24

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    End point title
    		 Change in World Health Organization Functional Class (WHO FC) with Last Observation Carried Forward at Week 24
    End point description
    The participant’s functional class was determined by using the WHO classification. Possible classes range from I (patients with pulmonary hypertension (PH) but without resulting limitation of physical activity) to IV (patients with PH with inability to carry out any physical activity without symptoms).
    End point type
    Secondary
    End point timeframe
    From baseline and up to 24 weeks
    End point values
    		 Riociguat PDE-5i
    Number of subjects analysed
    111 [10]
    113 [11]
    Units: class
        arithmetic mean (standard deviation)
    -0.5 ( 0.58 )
    -0.2 ( 0.62 )
    Notes
    [10] - Full Analysis Set (FAS) with evaluable participants
    [11] - Full Analysis Set (FAS) with evaluable participants
    Statistical analysis title
    		 Mean difference in WHO FC from baseline to Week 24
    Comparison groups
    Riociguat v PDE-5i
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [12]
    P-value
    		 = 0.0007
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 -0.11
    Notes
    [12] - Stratified by PAH category at baseline

    Secondary: Number of Participants with Adjudicated Clinical Worsening at Week 24

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    End point title
    		 Number of Participants with Adjudicated Clinical Worsening at Week 24
    End point description
    Clinical worsening was defined as death of any cause, hospitalization due to worsening pulmonary arterial hypertension (PAH) (adjudicated) or disease progression (adjudicated).
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Riociguat PDE-5i
    Number of subjects analysed
    111 [13]
    113 [14]
    Units: participants
        Yes
    1
    10
    Notes
    [13] - Full Analysis Set (FAS) with evaluable participants
    [14] - Full Analysis Set (FAS) with evaluable participants
    Statistical analysis title
    		 OR for the clinical worsening at Week 24
    Comparison groups
    Riociguat v PDE-5i
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [15]
    P-value
    		 = 0.0047
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.013
         upper limit
    		 0.725
    Notes
    [15] - Stratified by PAH category at baseline

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events were considered to be treatment emergent if they had started or worsened after the first treatment administration up to 2 days after end of treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Riociguat
    Reporting group description
    		 Participants received riociguat/BAY63-2521 tablets at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg three times a day (TID) for 24 weeks, started with 1.0 mg TID, followed by a dose adjustment period of 8 weeks, then stayed at the optimal dose period of 16 weeks.

    Reporting group title
    PDE-5i
    Reporting group description
    		 Participants remained on their current pulmonary arterial hypertension (PAH) treatment on tadalafil (20 to 40 mg/day) or sildenafil (at least 60 mg/day) for 24 weeks at the discretion of the investigator.

    Serious adverse events
    		 Riociguat PDE-5i
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 111 (7.21%)
    19 / 114 (16.67%)
         number of deaths (all causes)
    0
    4
         number of deaths resulting from adverse events
    0
    3
    Investigations
    Pulmonary arterial pressure increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Drug therapy enhancement
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Riociguat PDE-5i
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 111 (69.37%)
    72 / 114 (63.16%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Flushing
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 114 (0.88%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    13 / 111 (11.71%)
    6 / 114 (5.26%)
         occurrences all number
    19
    11
    Orthostatic hypotension
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Jugular vein distension
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences all number
    0
    2
    Chest discomfort
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    5 / 111 (4.50%)
    5 / 114 (4.39%)
         occurrences all number
    8
    5
    Drug ineffective
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    6 / 111 (5.41%)
    2 / 114 (1.75%)
         occurrences all number
    7
    2
    Malaise
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    2 / 111 (1.80%)
    2 / 114 (1.75%)
         occurrences all number
    2
    2
    Oedema mucosal
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 111 (2.70%)
    4 / 114 (3.51%)
         occurrences all number
    4
    4
    Pyrexia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Menometrorrhagia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Adnexa uteri cyst
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 111 (0.00%)
    7 / 114 (6.14%)
         occurrences all number
    0
    7
    Dry throat
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    3 / 111 (2.70%)
    5 / 114 (4.39%)
         occurrences all number
    4
    6
    Dyspnoea exertional
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 114 (0.00%)
         occurrences all number
    3
    0
    Epistaxis
         subjects affected / exposed
    3 / 111 (2.70%)
    3 / 114 (2.63%)
         occurrences all number
    3
    4
    Hypoxia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Lung disorder
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 114 (0.88%)
         occurrences all number
    1
    1
    Nasal polyps
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 114 (0.00%)
         occurrences all number
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    3
    Depression
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 114 (0.00%)
         occurrences all number
    2
    0
    Insomnia
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 114 (2.63%)
         occurrences all number
    0
    3
    Sleep disorder
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Stress
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood pressure decreased
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Catheterisation cardiac
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Bone contusion
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 114 (0.88%)
         occurrences all number
    1
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Cardiac failure chronic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    3 / 111 (2.70%)
    4 / 114 (3.51%)
         occurrences all number
    4
    4
    Sinus tachycardia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences all number
    0
    2
    Nervous system disorders
    Diabetic neuropathy
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    5 / 111 (4.50%)
    2 / 114 (1.75%)
         occurrences all number
    5
    2
    Headache
         subjects affected / exposed
    14 / 111 (12.61%)
    8 / 114 (7.02%)
         occurrences all number
    16
    8
    Hypoaesthesia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 114 (1.75%)
         occurrences all number
    1
    2
    Syncope
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Anaemia megaloblastic
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 114 (0.00%)
         occurrences all number
    2
    0
    Leukopenia
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences all number
    0
    2
    Lymphopenia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 114 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Astigmatism
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Cataract
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Glaucoma
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Retinal disorder
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Ocular discomfort
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 111 (2.70%)
    0 / 114 (0.00%)
         occurrences all number
    3
    0
    Abdominal distension
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    3 / 111 (2.70%)
    0 / 114 (0.00%)
         occurrences all number
    3
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    3 / 111 (2.70%)
    1 / 114 (0.88%)
         occurrences all number
    3
    1
    Constipation
         subjects affected / exposed
    4 / 111 (3.60%)
    0 / 114 (0.00%)
         occurrences all number
    5
    0
    Diarrhoea
         subjects affected / exposed
    6 / 111 (5.41%)
    3 / 114 (2.63%)
         occurrences all number
    6
    3
    Dyspepsia
         subjects affected / exposed
    10 / 111 (9.01%)
    0 / 114 (0.00%)
         occurrences all number
    10
    0
    Flatulence
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 111 (7.21%)
    1 / 114 (0.88%)
         occurrences all number
    10
    1
    Gingival hypertrophy
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    5 / 111 (4.50%)
    3 / 114 (2.63%)
         occurrences all number
    6
    3
    Toothache
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    3 / 111 (2.70%)
    0 / 114 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal hypermotility
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Reflux gastritis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 114 (0.88%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 114 (2.63%)
         occurrences all number
    1
    3
    Arthritis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 111 (0.90%)
    6 / 114 (5.26%)
         occurrences all number
    1
    6
    Muscle spasms
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 114 (0.88%)
         occurrences all number
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 114 (0.88%)
         occurrences all number
    1
    1
    Neck pain
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 114 (0.88%)
         occurrences all number
    2
    1
    Pain in extremity
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    2
    Pain in jaw
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Body tinea
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 114 (1.75%)
         occurrences all number
    1
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Diverticulitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Enterobiasis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Eye infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Fungal infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Hepatitis E
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 114 (1.75%)
         occurrences all number
    1
    2
    Laryngitis
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 114 (1.75%)
         occurrences all number
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    8 / 111 (7.21%)
    5 / 114 (4.39%)
         occurrences all number
    8
    5
    Otitis media
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 114 (0.88%)
         occurrences all number
    2
    1
    Rhinitis
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 114 (3.51%)
         occurrences all number
    0
    4
    Sinusitis
         subjects affected / exposed
    2 / 111 (1.80%)
    6 / 114 (5.26%)
         occurrences all number
    2
    8
    Tonsillitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 111 (3.60%)
    7 / 114 (6.14%)
         occurrences all number
    4
    8
    Urinary tract infection
         subjects affected / exposed
    2 / 111 (1.80%)
    3 / 114 (2.63%)
         occurrences all number
    2
    3
    Viral infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Febrile infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Bronchitis viral
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Mycobacterial infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Fluid retention
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 114 (3.51%)
         occurrences all number
    0
    4
    Iron deficiency
         subjects affected / exposed
    2 / 111 (1.80%)
    4 / 114 (3.51%)
         occurrences all number
    2
    4
    Decreased appetite
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jan 2017
    Amendment 4 specified following modifications: 1. Any escalation of PAH therapy including targeted PAH drug was permitted during the study at the discretion of the investigator for the individual subject (independent from and without counting as clinical worsening) in both treatment arms. 2. To reiterate that the benefit risk balance for the population in this study (i.e. PAH, Dana Point Group 1) was positive, despite the potential safety issue in Study 13605 in subjects with pulmonary hypertension associated with idiopathic interstitial pneumonia (Dana Point Group 3) which had led to its early termination. 3. To add the requirement for adequate use of effective contraceptive methods during this study. 4. To include other biomarkers (in addition to NT proBNP), at the request of the advisory committee, to further elucidate the value of selected nitric oxide pathway related biomarkers for treatment decision in this controlled study and in comparison with biomarker results from the previous, uncontrolled RESPITE study. 5. To include details for consistency with the Company Core Data Sheet (e.g. titration rules) and other studies using riociguat (e.g. extending the time for collecting AE information). 6. Subjects with “confirmed obstructive sleep apnea” (Exclusion criterion 13f) was changed to “clinically significant obstructive sleep apnea”, if not effectively treated for at least 90 days; only in US/Canada.

    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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