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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled phase II study to investigate the efficacy and safety of riociguat (0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID) in patients with symptomatic pulmonary hypertension associated with idiopathic interstitial pneumonias (IIP)

    Summary
    EudraCT number
    		 2010-024332-42
    Trial protocol
    		 IT   DE   ES   BE   GB   PT   DK   GR  
    Global end of trial date
    14 Sep 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Nov 2017
    First version publication date
    20 May 2017
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    new data to be added

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY63-2521/13605
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02138825
    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
    14 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of 26-weeks of treatment with riociguat vs. placebo in patients with symptomatic PH (pulmonary hypertension) associated with IIP (idiopathic interstitial pneumonias).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Only after the subject voluntarily signed the informed consent form was he/she able to enter the study. If the subject was not capable of providing a signature, an oral statement of consent could have been given in the presence of a witness. Each subject was assured of the right to 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
    04 Jun 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Italy: 6
    Worldwide total number of subjects
    147
    EEA total number of subjects
    55
    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)
    37
    From 65 to 84 years
    110
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 229 subjects were enrolled into the study centers in 19 countries worldwide, from 04-Jun-2014 (first patient first visit) to 14-Sep-2016 (last patient last visit).

    Pre-assignment
    Screening details
    		 A total of 147 subjects were randomized and entered the main study phase, of whom 73 were assigned to riociguat and 74 to placebo. At the time of study termination, all treated subjects were taken off study drug and started the follow-up period, regardless of whether they were in the Main study treatment or in the Long-term extension.

    Period 1
    Period 1 title
    Main study treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Riociguat (Adempas, BAY63-2521)
    Arm description
    		 In the main study treatment phase subjects received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension (LTE) phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Active drug 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration. The starting dose will be 0.5 mg TID, and the dose will be adjusted every two weeks for ten weeks in 0.5 mg increments up to a maximum dose of 2.5 mg TID based on patient’s systolic blood pressure and well-being.

    Arm title
    		 Placebo
    Arm description
    		 In the main study treatment phase subjects received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension (LTE) phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Inactive dosed at 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration for 26 weeks.

    Number of subjects in period 1
    		Riociguat (Adempas, BAY63-2521) Placebo
    Started
    73
    74
    Completed
    33
    39
    Not completed
    40
    35
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    11
    3
         Death
    1
    2
         Study terminated by sponsor
    10
    9
         Medical decision
    1
    -
         Protocol Violation
    2
    2
         Sponsor decision
    12
    18
    Period 2
    Period 2 title
    Long-term extension
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Riociguat (Adempas, BAY63-2521)
    Arm description
    		 In the main study treatment phase subjects received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Active drug 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration. The starting dose will be 0.5 mg TID, and the dose will be adjusted every two weeks for ten weeks in 0.5 mg increments up to a maximum dose of 2.5 mg TID based on patient’s systolic blood pressure and well-being.

    Arm title
    		 Placebo to Riociguat
    Arm description
    		 In the main study treatment phase subjects received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Active drug 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration. The starting dose will be 0.5 mg TID, and the dose will be adjusted every two weeks for ten weeks in 0.5 mg increments up to a maximum dose of 2.5 mg TID based on patient’s systolic blood pressure and well-being.

    Number of subjects in period 2 [1]
    		Riociguat (Adempas, BAY63-2521) Placebo to Riociguat
    Started
    32
    38
    Completed
    0
    0
    Not completed
    32
    38
         Study termination by sponsor
    32
    38
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all subjects completing the main study treatment period entered long-term extension period.
    Period 3
    Period 3 title
    Safety follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Riociguat (Adempas, BAY63-2521)
    Arm description
    		 In the main study treatment phase subjects received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Active drug 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration. The starting dose will be 0.5 mg TID, and the dose will be adjusted every two weeks for ten weeks in 0.5 mg increments up to a maximum dose of 2.5 mg TID based on patient’s systolic blood pressure and well-being.

    Arm title
    		 Placebo
    Arm description
    		 In the main study treatment phase subjects received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Inactive dosed at 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration for 26 weeks.

    Number of subjects in period 3
    		Riociguat (Adempas, BAY63-2521) Placebo
    Started
    72
    64
    Completed
    50
    47
    Not completed
    22
    17
         Consent withdrawn by subject
    5
    3
         too unwell to attend the visit
    -
    1
         Adverse event, non-fatal
    4
    3
         logistical difficulties
    -
    1
         Death
    11
    5
         progressive disease
    -
    2
         clinic worsening
    1
    -
         treatment unblinded
    -
    1
         withdrawn due to lung transplant
    -
    1
         withdrawal by PI
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 In the main study treatment phase subjects received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension (LTE) phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.

    Reporting group title
    Placebo
    Reporting group description
    		 In the main study treatment phase subjects received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension (LTE) phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.

    Reporting group values
    		 Riociguat (Adempas, BAY63-2521) Placebo Total
    Number of subjects
    		 73 74 147
    Age categorical
    Units: Subjects
        <65 years
    		 20 17 37
        >=65 - <75 years
    		 35 45 80
        >=75 years
    		 18 12 30
    Gender categorical
    Units: Subjects
        Female
    		 23 29 52
        Male
    		 50 45 95
    Pulmonary hypertension (PH) subtype (Nice Clinical Classification)
    Units: Subjects
        PH owing to respiratory disease and /or hypoxia
    		 73 74 147
        Other
    		 0 0 0
    Classification of Idiopathic Interstitial Pneumonia
    Units: Subjects
        Idiopathic pulmonary fibrosis
    		 54 49 103
        Idiopathic nonspecific interstitial pneumonia
    		 9 14 23
        Resp. bronchiolitis-interstitial lung disease
    		 1 0 1
        Cryptogenic organizing pneumonia
    		 0 1 1
        Acute interstitial pneumonia
    		 0 1 1
        Idiopathic lymphoid interstitial pneumonia
    		 0 2 2
        Unclassifiable idiopathic interstitial pneumonias
    		 9 7 16
    World Health Organization (WHO) functional class
    The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (Patients with PH but without resulting limitation of physical activity) to class IV (Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure.). Changes to a lower WHO functional class resemble improvement, changes to a higher functional class resemble deterioration of pulmonary arterial hypertension (PAH).
    Units: Subjects
        Class II
    		 16 22 38
        Class III
    		 50 45 95
        Class IV
    		 7 7 14
    6 minute walking distance (6MWD) category
    The 6MWD test is designed to evaluate a patient’s exercise capacity while performing an everyday activity.
    Units: Subjects
        < 320 m
    		 43 32 75
        >= 320 m and <380m
    		 12 28 40
        >= 380 m
    		 18 14 32

    End points

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    End points reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 In the main study treatment phase subjects received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension (LTE) phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.

    Reporting group title
    Placebo
    Reporting group description
    		 In the main study treatment phase subjects received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension (LTE) phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 In the main study treatment phase subjects received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.

    Reporting group title
    Placebo to Riociguat
    Reporting group description
    		 In the main study treatment phase subjects received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 In the main study treatment phase subjects received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.

    Reporting group title
    Placebo
    Reporting group description
    		 In the main study treatment phase subjects received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor’s global team.

    Subject analysis set title
    Intent to treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized and received at least one dose of study medication.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects randomized and received at least one dose of study medication.

    Primary: Mean change in 6 minute walking distance (6MWD) from baseline to week 26

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    End point title
    		 Mean change in 6 minute walking distance (6MWD) from baseline to week 26
    End point description
    The 6MWD test is designed to evaluate a patient’s exercise capacity while performing an everyday activity.
    End point type
    Primary
    End point timeframe
    Baseline to 26 weeks
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    73 [1]
    74 [2]
    Units: Meter
        arithmetic mean (standard deviation)
    3.63 ± 60.8
    -15.94 ± 63.7
    Notes
    [1] - ITT
    [2] - ITT
    Statistical analysis title
    		 Riociguat vs. Placebo
    Statistical analysis description
    The evaluation of primary efficacy endpoint will be based on change from baseline in 6MWD using analysis of covariance (ANCOVA) with baseline 6MWD, treatment arm and region as factors.
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2074
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    21.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.75
         upper limit
    		 51.71

    Secondary: Number of subjects with clinical worsening

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    End point title
    		 Number of subjects with clinical worsening
    End point description
    The combined endpoint “time to clinical worsening”, made up of the following components, defined by the first occurrence: all-cause mortality; need for hospitalization due to worsening cardiopulmonary (CP) status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling); >15% decrease in the 6MWD test; worsening of WHO functional class.
    End point type
    Secondary
    End point timeframe
    Up to week 26
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    73 [3]
    74 [4]
    Units: Subjects
    number (not applicable)
        No clinical event
    39
    38
        >15% decrease in 6MWD
    9
    17
        All-cause mortality
    1
    0
        Hospitalization due to worsening CP status
    15
    7
        Worsening of WHO functional class
    9
    12
    Notes
    [3] - ITT
    [4] - ITT
    Statistical analysis title
    		 Riociguat vs. Placebo
    Statistical analysis description
    The difference in incidences in clinical worsening and mortality will be analyzed using Mantel-Haenszel weights, stratified by region.
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3437
    Method
    		 Mantel-Haenszel
    Confidence interval

    Post-hoc: Number of deaths per study phase for Riociguat group

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    End point title
    		 Number of deaths per study phase for Riociguat group [5]
    End point description
    In the main study treatment phase subjects received Riociguat until 26 weeks. This phase was followed by a long-term extension (LTE) phase, during which subjects continued with Riociguat treatment. At the time of study termination, all treated subjects were taken off study drug and started the safety follow-up phase, regardless of whether they were in the main phase or in the LTE.
    End point type
    Post-hoc
    End point timeframe
    From start of treatment to end of study
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms were separately reported as subjects received different treatment per study phase.
    End point values
    		 Riociguat (Adempas, BAY63-2521)
    Number of subjects analysed
    73 [6]
    Units: Subjects
    number (not applicable)
        Main study treatment
    8
        Long-term extension
    1
        Safety follow-up
    3
    Notes
    [6] - ITT
    No statistical analyses for this end point

    Post-hoc: Number of deaths per study phase for Placebo group

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    End point title
    		 Number of deaths per study phase for Placebo group [7]
    End point description
    In the main study treatment phase subjects received Placebo until 26 weeks. This phase was followed by a long-term extension (LTE) phase, during which subjects were treated with Riociguat. At the time of study termination, all treated subjects were taken off study drug and started the safety follow-up phase, regardless of whether they were in the main phase or in the LTE.
    End point type
    Post-hoc
    End point timeframe
    From start of treatment to end of study
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms were separately reported as subjects received different treatment per study phase.
    End point values
    		 Placebo
    Number of subjects analysed
    74 [8]
    Units: Subjects
    number (not applicable)
        Main study treatment
    3
        Long-term extension: received Riociguat
    8
        Safety follow-up: only treated with Placebo
    3
        Safety follow-up: received Riociguat in LTE
    1
    Notes
    [8] - ITT
    No statistical analyses for this end point

    Post-hoc: Number of Serious Adverse Events During Safety Follow-up Phase

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    End point title
    		 Number of Serious Adverse Events During Safety Follow-up Phase
    End point description
    At the time of study termination, all subjects entered safety follow-up phase regardless of whether they were in the main phase or in the LTE. Subjects who had the End of Treatment visit prior to the implementation of the 120-day safety follow-up were followed-up for at least 30 days.
    End point type
    Post-hoc
    End point timeframe
    From start of safety follow-up phase until end of study
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    73 [9]
    74 [10]
    Units: Subjects
        number (not applicable)
    18
    14
    Notes
    [9] - SAF
    [10] - SAF
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs were collected from start of study treatment up to 7 days after end of treatment
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Riociguat up to 2.5 mg tid
    Reporting group description
    		 Reporting group 1 (RG 1): All subjects randomized to Riociguat treatment in Main study treatment phase (data until week 26); subjects received Riociguat titrated to optimal dose within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. Note: safety data presented here include subjects in Riociguat Arm of Period 1 in Subject disposition section.

    Reporting group title
    Placebo
    Reporting group description
    		 Reporting group 2 (RG 2): All subjects randomized to Placebo treatment in Main study treatment phase (data until week 26); subjects received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. Note: safety data presented here include subjects in Placebo Arm of Period 1 in Subject disposition section.

    Reporting group title
    Riociguat-Riociguat transition
    Reporting group description
    		 Reporting group 3 (RG 3): All subjects that were initially randomized to Riociguat treatment in Main study treatment phase and later entered Long-term extension (LTE) phase (data starting from week 26 to study termination); subjects received a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until the study was terminated. Note: safety data presented here include subjects in Riociguat Arm of Period 2 in Subject disposition section.

    Reporting group title
    Placebo-Riociguat transition
    Reporting group description
    		 Reporting group 4 (RG 4): All subjects that were initially randomized to Placebo treatment in Main study treatment phase and later entered LTE phase (data starting from week 26 to study termination); subjects received a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase subjects were to be treated with Riociguat until the study was terminated. Note: safety data presented here include subjects in Placebo Arm of Period 2 in Subject disposition section.

    Serious adverse events
    		 Riociguat up to 2.5 mg tid Placebo Riociguat-Riociguat transition Placebo-Riociguat transition
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 73 (36.99%)
    17 / 74 (22.97%)
    12 / 32 (37.50%)
    21 / 38 (55.26%)
         number of deaths (all causes)
    11
    6
    1
    9
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder papilloma
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Inguinal hernia repair
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung transplant
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 74 (2.70%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    4 / 73 (5.48%)
    3 / 74 (4.05%)
    3 / 32 (9.38%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    4 / 38 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 74 (2.70%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute interstitial pneumonitis
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nodal rhythm
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 74 (2.70%)
    1 / 32 (3.13%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral artery thrombosis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choroidal neovascularisation
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neovascular age-related macular degeneration
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 74 (2.70%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Herpes zoster
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    4 / 38 (10.53%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    Pneumonia moraxella
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone abscess
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Riociguat up to 2.5 mg tid Placebo Riociguat-Riociguat transition Placebo-Riociguat transition
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 73 (73.97%)
    52 / 74 (70.27%)
    26 / 32 (81.25%)
    32 / 38 (84.21%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 74 (1.35%)
    3 / 32 (9.38%)
    7 / 38 (18.42%)
         occurrences all number
    4
    1
    3
    7
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 73 (5.48%)
    5 / 74 (6.76%)
    2 / 32 (6.25%)
    1 / 38 (2.63%)
         occurrences all number
    8
    6
    4
    1
    Fatigue
         subjects affected / exposed
    3 / 73 (4.11%)
    7 / 74 (9.46%)
    3 / 32 (9.38%)
    2 / 38 (5.26%)
         occurrences all number
    3
    8
    3
    2
    Oedema peripheral
         subjects affected / exposed
    15 / 73 (20.55%)
    7 / 74 (9.46%)
    5 / 32 (15.63%)
    5 / 38 (13.16%)
         occurrences all number
    15
    7
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 73 (10.96%)
    10 / 74 (13.51%)
    2 / 32 (6.25%)
    2 / 38 (5.26%)
         occurrences all number
    9
    10
    2
    2
    Dyspnoea
         subjects affected / exposed
    8 / 73 (10.96%)
    7 / 74 (9.46%)
    6 / 32 (18.75%)
    11 / 38 (28.95%)
         occurrences all number
    10
    7
    6
    13
    Epistaxis
         subjects affected / exposed
    5 / 73 (6.85%)
    7 / 74 (9.46%)
    1 / 32 (3.13%)
    1 / 38 (2.63%)
         occurrences all number
    7
    8
    1
    1
    Haemoptysis
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 74 (2.70%)
    2 / 32 (6.25%)
    0 / 38 (0.00%)
         occurrences all number
    3
    2
    2
    0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 74 (1.35%)
    3 / 32 (9.38%)
    1 / 38 (2.63%)
         occurrences all number
    2
    1
    3
    1
    Nasal congestion
         subjects affected / exposed
    3 / 73 (4.11%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    3
    1
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 73 (1.37%)
    4 / 74 (5.41%)
    1 / 32 (3.13%)
    0 / 38 (0.00%)
         occurrences all number
    1
    4
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 74 (1.35%)
    1 / 32 (3.13%)
    4 / 38 (10.53%)
         occurrences all number
    2
    1
    1
    4
    Investigations
    Blood glucose increased
         subjects affected / exposed
    3 / 73 (4.11%)
    1 / 74 (1.35%)
    2 / 32 (6.25%)
    0 / 38 (0.00%)
         occurrences all number
    3
    1
    2
    0
    Catheterisation cardiac
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    2 / 32 (6.25%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    2
    1
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    2 / 32 (6.25%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    3
    1
    Atrial fibrillation
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 74 (1.35%)
    2 / 32 (6.25%)
    1 / 38 (2.63%)
         occurrences all number
    2
    1
    2
    1
    Right ventricular failure
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 74 (0.00%)
    2 / 32 (6.25%)
    1 / 38 (2.63%)
         occurrences all number
    4
    0
    2
    1
    Tachycardia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    1
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 73 (9.59%)
    8 / 74 (10.81%)
    5 / 32 (15.63%)
    5 / 38 (13.16%)
         occurrences all number
    9
    10
    5
    7
    Headache
         subjects affected / exposed
    8 / 73 (10.96%)
    9 / 74 (12.16%)
    2 / 32 (6.25%)
    2 / 38 (5.26%)
         occurrences all number
    8
    12
    2
    3
    Paraesthesia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    2 / 32 (6.25%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Presyncope
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 74 (1.35%)
    2 / 32 (6.25%)
    1 / 38 (2.63%)
         occurrences all number
    2
    1
    2
    1
    Syncope
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 74 (2.70%)
    1 / 32 (3.13%)
    4 / 38 (10.53%)
         occurrences all number
    4
    2
    1
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    1 / 32 (3.13%)
    3 / 38 (7.89%)
         occurrences all number
    0
    2
    1
    4
    Abdominal pain upper
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 74 (2.70%)
    2 / 32 (6.25%)
    0 / 38 (0.00%)
         occurrences all number
    3
    3
    2
    0
    Constipation
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 74 (2.70%)
    1 / 32 (3.13%)
    3 / 38 (7.89%)
         occurrences all number
    5
    2
    1
    3
    Diarrhoea
         subjects affected / exposed
    11 / 73 (15.07%)
    7 / 74 (9.46%)
    4 / 32 (12.50%)
    5 / 38 (13.16%)
         occurrences all number
    17
    9
    4
    6
    Dyspepsia
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 74 (2.70%)
    0 / 32 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    5
    2
    0
    3
    Dysphagia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    0 / 32 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    1
    0
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 74 (1.35%)
    1 / 32 (3.13%)
    3 / 38 (7.89%)
         occurrences all number
    4
    1
    1
    4
    Nausea
         subjects affected / exposed
    10 / 73 (13.70%)
    9 / 74 (12.16%)
    4 / 32 (12.50%)
    5 / 38 (13.16%)
         occurrences all number
    11
    12
    4
    6
    Vomiting
         subjects affected / exposed
    8 / 73 (10.96%)
    2 / 74 (2.70%)
    3 / 32 (9.38%)
    4 / 38 (10.53%)
         occurrences all number
    9
    2
    3
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 74 (1.35%)
    2 / 32 (6.25%)
    1 / 38 (2.63%)
         occurrences all number
    1
    1
    4
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    3 / 32 (9.38%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 74 (2.70%)
    1 / 32 (3.13%)
    4 / 38 (10.53%)
         occurrences all number
    3
    2
    1
    4
    Back pain
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 74 (4.05%)
    2 / 32 (6.25%)
    0 / 38 (0.00%)
         occurrences all number
    2
    4
    2
    0
    Muscle spasms
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 74 (1.35%)
    1 / 32 (3.13%)
    2 / 38 (5.26%)
         occurrences all number
    1
    1
    2
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 74 (4.05%)
    2 / 32 (6.25%)
    2 / 38 (5.26%)
         occurrences all number
    3
    4
    2
    2
    Influenza
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 74 (1.35%)
    2 / 32 (6.25%)
    3 / 38 (7.89%)
         occurrences all number
    0
    1
    2
    3
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 74 (1.35%)
    2 / 32 (6.25%)
    2 / 38 (5.26%)
         occurrences all number
    4
    1
    3
    6
    Nasopharyngitis
         subjects affected / exposed
    5 / 73 (6.85%)
    4 / 74 (5.41%)
    1 / 32 (3.13%)
    3 / 38 (7.89%)
         occurrences all number
    6
    5
    1
    3
    Pneumonia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    1
    0
    0
    3
    Rhinitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 74 (0.00%)
    0 / 32 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    0
    0
    0
    3
    Sinusitis
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 74 (2.70%)
    1 / 32 (3.13%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 73 (5.48%)
    4 / 74 (5.41%)
    1 / 32 (3.13%)
    2 / 38 (5.26%)
         occurrences all number
    5
    5
    1
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 74 (2.70%)
    2 / 32 (6.25%)
    0 / 38 (0.00%)
         occurrences all number
    4
    2
    3
    0
    Respiratory tract infection
         subjects affected / exposed
    6 / 73 (8.22%)
    6 / 74 (8.11%)
    1 / 32 (3.13%)
    2 / 38 (5.26%)
         occurrences all number
    7
    10
    5
    3
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 74 (2.70%)
    0 / 32 (0.00%)
    4 / 38 (10.53%)
         occurrences all number
    0
    2
    0
    4
    Decreased appetite
         subjects affected / exposed
    3 / 73 (4.11%)
    7 / 74 (9.46%)
    1 / 32 (3.13%)
    2 / 38 (5.26%)
         occurrences all number
    3
    7
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2014
    1. Adjustment of the blinding period 2. Revision of inclusion and exclusion criteria 3. Revision of time windows 4. Addition of missing visit 5. Modification in SAE reporting 6. Addition of echocardiography assessment for screening
    19 May 2015
    1. Revision of the number of randomized patients 2. Addition of time point for calculating secondary and exploratory variables
    24 May 2016
    1. Extension of safety follow-up period from 1 month to 4 months 2. Addition of assessments to be performed in the safety follow-up.

    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.
    The study was prematurely terminated following a recommendation from the independent Data Monitoring Committee, as patients receiving Riociguat showed an increased risk of mortality and serious adverse events as compared to patients receiving Placebo
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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