Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43857   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Phase II Study to Investigate the Efficacy and Safety of Riociguat in Patients With Diffuse Cutaneous Systemic Sclerosis (dcSSc)

    Summary
    EudraCT number
    		 2014-001353-16
    Trial protocol
    		 GB   DE   NL   BE   ES   CZ   HU   IT  
    Global end of trial date
    28 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2019
    First version publication date
    27 Dec 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY63-2521/16277
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02283762
    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
    28 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy of riociguat administered 3 times a day (TID) compared with placebo in terms of change in the mRSS from baseline to Week 52.
    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
    15 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Japan: 20
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    121
    EEA total number of subjects
    57
    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)
    106
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted between 15 January 2015 (first patient first visit) and 28 March 2019 (last patient last visit). The Main Treatment Phase has been conducted between 15 Jan 2015 (first subject first visit) and 03 Jan 2018 (last subject last visit for the main treatment phase).

    Pre-assignment
    Screening details
    		 139 patients were enrolled in 60 study centers in 15 countries worldwide. 121 patients of 139 patients were randomized and treated with at least one dose of study medication. 88 of the 121 randomized patients completed the treatment phase, of whom 87 entered the long term extension (LTE) phase.

    Period 1
    Period 1 title
    Main treatment phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    52 weeks of double-blind treatment, consisting of: - Dose titration period of up to 10 weeks - Maintenance period of up to 42 weeks

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Riociguat (Adempas, BAY63-2521)
    Arm description
    		 Main treatment phase of 52 weeks: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Adempas
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered 3 times a day (TID); dose titration starting with 0.5 mg (up-titration every 2 weeks), orally

    Arm title
    		 Placebo
    Arm description
    		 Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham-titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets to BAY 63-2521 / Riociguat 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID; dose titration starting with 0.5 mg matching placebo tablet, orally

    Number of subjects in period 1
    		Riociguat (Adempas, BAY63-2521) Placebo
    Started
    60
    61
    Completed
    42
    46
    Not completed
    18
    15
         Consent withdrawn by subject
    7
    4
         Physician decision
    1
    1
         Pregnancy
    -
    1
         Adverse event
    9
    9
         Lack of efficacy
    1
    -
    Period 2
    Period 2 title
    Long-term Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Dose titration period of up to 10 weeks (double-blind); Open-label extension period

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Riociguat-Riociguat
    Arm description
    		 Main treatment phase of 52 weeks: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Adempas
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered 3 times a day (TID); dose titration starting with 0.5 mg (up-titration every 2 weeks), orally

    Arm title
    		 Placebo-Riociguat
    Arm description
    		 Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham-titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets to BAY 63-2521 / Riociguat 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered TID; dose titration starting with 0.5 mg matching placebo tablet, orally

    Number of subjects in period 2 [1]
    		Riociguat-Riociguat Placebo-Riociguat
    Started
    42
    45
    Completed
    32
    31
    Not completed
    10
    14
         Physician decision
    1
    2
         Consent withdrawn by subject
    4
    3
         Study terminated at site
    1
    -
         Adverse event
    2
    6
         Lost to follow-up
    -
    1
         Protocol deviation
    1
    1
         Lack of efficacy
    1
    1
    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: One of the 46 patients from the placebo group did not enter the LTE phase.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 Main treatment phase of 52 weeks: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Reporting group title
    Placebo
    Reporting group description
    		 Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham-titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Reporting group values
    		 Riociguat (Adempas, BAY63-2521) Placebo Total
    Number of subjects
    		 60 61 121
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.9 ( 11.5 ) 49.5 ( 12.9 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 47 45 92
        Male
    		 13 16 29
    Race
    Units: Subjects
        White
    		 43 46 89
        Black
    		 2 3 5
        Asian
    		 12 12 24
        Native Hawaiian or other pacific islander
    		 1 0 1
        Not reported
    		 2 0 2
    Ethnicity
    Units: Subjects
        Not Hispanic or latino
    		 59 58 117
        Hispanic or Latino
    		 1 2 3
        Not reported
    		 0 1 1
    Modified Rodnan skin score (mRSS)
    The mRSS is a validated physical examination method for estimating skin thickness. It correlates with biopsy measures of collagen in the dermis and reflects prognosis and visceral involvement, especially in early disease. It is scored on 0 (normal) to 3+ (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 (higher score means worse situation) and is used to categorize severity of systemic sclerosis (SSc).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 16.9 ( 3.4 ) 16.7 ( 4.1 ) -
    Forced vital capacity (FVC) percent predicted
    Pulmonary function tests included forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO). FVC percent predicted was reported.
    Units: FVC percent predicted
        arithmetic mean (standard deviation)
    		 90.743 ( 18.523 ) 94.823 ( 17.034 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    		 Main treatment phase of 52 weeks: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Reporting group title
    Placebo
    Reporting group description
    		 Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham-titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.
    Reporting group title
    Riociguat-Riociguat
    Reporting group description
    		 Main treatment phase of 52 weeks: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Reporting group title
    Placebo-Riociguat
    Reporting group description
    		 Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham-titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS was defined as all patients randomized and treated with study medication.

    Subject analysis set title
    Per protocol set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients were valid for the per protocol analysis set (PPS), if they met the major inclusion and exclusion criteria at randomization that may affect efficacy, were not taking excluded concomitant medications during the study that effected efficacy (not including rescue medication after Week 26), had the mRSS assessed at baseline and at least once during the main treatment phase and who were at least 80% compliant with study medication or did not have any additional major protocol deviations.

    Primary: Change from baseline in modified Rodnan skin score (mRSS) to Week 52

    		 Close Top of page
    End point title
    		 Change from baseline in modified Rodnan skin score (mRSS) to Week 52
    End point description
    The mRSS is a validated physical examination method for estimating skin thickness. It correlates with biopsy measures of collagen in the dermis and reflects prognosis and visceral involvement, especially in early disease. It is scored on 0 (normal) to 3+ (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 (higher score means worse situation) and is used to categorize severity of SSc. A decrease in the mean change of mRSS shows mRSS improved.
    End point type
    Primary
    End point timeframe
    Baseline to week 52
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    57 [1]
    52 [2]
    Units: score on a scale
        arithmetic mean (standard deviation)
    -2.088 ( 5.658 )
    -0.769 ( 8.243 )
    Notes
    [1] - FAS with evaluable data for this outcome measure.
    [2] - FAS with evaluable data for this outcome measure.
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Placebo v Riociguat (Adempas, BAY63-2521)
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0815
    Method
    		 MMRM (Method 1)
    Parameter type
    		 Difference of LS means
    Point estimate
    -2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.99
         upper limit
    		 0.3

    Secondary: CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 reported as number of participants with a CRISS probability >=0.60 or <0.60 from baseline to Week 52

    		 Close Top of page
    End point title
    		 CRISS (American College of Rheumatology Composite Response Index for Clinical Trials) at Week 52 reported as number of participants with a CRISS probability >=0.60 or <0.60 from baseline to Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    60 [3]
    61 [4]
    Units: Participants
        CRISS probability ≥ 0.60
    11
    11
        CRISS probability < 0.60
    49
    50
    Notes
    [3] - Full analysis set (FAS)
    [4] - Full analysis set (FAS)
    Statistical analysis title
    		 Treatment comparaison
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.977
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percent
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.68
         upper limit
    		 14.09
    Notes
    [5] - The pre-specified test was for superiority but ONLY if the primary endpoint and secondary endpoints were meeting statistical significance (hierarchical testing).

    Secondary: Change from baseline in Health Assessment Questionnaire disability index (HAQ-DI) score to Week 52

    		 Close Top of page
    End point title
    		 Change from baseline in Health Assessment Questionnaire disability index (HAQ-DI) score to Week 52
    End point description
    The HAQ-DI is a composite measure from which a ‘Standard Disability Index’ score can be computed to assess a patient’s disability level. Generally, a score of 0–1 represents mild to moderate difficulty, 1–2 moderate to severe disability and 2–3 severe to very severe disability. The HAQ-DI comprises 20 items that assess patient abilities across 8 functional activities: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. Each item is rated on a 4-point scale: 0=Without ANY difficulty, 1=With SOME difficulty, 2=With MUCH difficulty, 3=UNABLE to do. The 8 scores of the 8 sections are summed and divided by 8. In the event that one section is not completed by a subject then the summed score would be divided by 7. The final overall HAQ-DI score ranges from 0 to 3 and positive change indicates worse health-related quality of life (HRQoL).
    End point type
    Secondary
    End point timeframe
    Baseline to week 52
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    60 [6]
    61 [7]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    0.888 ( 0.665 )
    0.693 ( 0.688 )
        Change from baseline
    0.054 ( 0.381 )
    0.127 ( 0.418 )
    Notes
    [6] - Full analysis set (FAS). Number Analyzed for Change from baseline is 56 participants.
    [7] - Full analysis set (FAS). Number Analyzed for Change from baseline is 52 participants.
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.3529
    Method
    		 MMRM (Method 1)
    Parameter type
    		 Difference in LS means
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.08
    Notes
    [8] - The pre-specified test was for superiority but ONLY if the primary endpoint and secondary endpoints were meeting statistical significance (hierarchical testing).

    Secondary: Change from baseline in patient’s global assessment score to Week 52

    		 Close Top of page
    End point title
    		 Change from baseline in patient’s global assessment score to Week 52
    End point description
    The patient’s global assessments (a self-report) quantified the overall disease activity or severity of SSc, with scores ranging from 0 (good) to 10 (worse). Positive change in the patient’s global assessments score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to week 52
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    60 [9]
    61 [10]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    3.933 ( 2.497 )
    3.770 ( 2.341 )
        Change from baseline
    0.689 ( 2.745 )
    -0.022 ( 2.226 )
    Notes
    [9] - Full analysis set (FAS). Number Analyzed for Change from baseline is 45 participants
    [10] - Full analysis set (FAS). Number Analyzed for Change from baseline is 46 participants
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0887
    Method
    		 MMRM (Method 1)
    Parameter type
    		 Difference in LS means
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 1.69
    Notes
    [11] - The pre-specified test was for superiority but ONLY if the primary endpoint and secondary endpoints were meeting statistical significance (hierarchical testing).

    Secondary: Change from baseline in physician’s global assessment score to Week 52

    		 Close Top of page
    End point title
    		 Change from baseline in physician’s global assessment score to Week 52
    End point description
    The physician’s global assessments (reported by the physician) quantified the overall disease activity or severity of SSc, with scores ranging from 0 (good) to 10 (worse). Positive change in the physician’s global assessments score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to week 52
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    60 [12]
    61 [13]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    4.333 ( 2.105 )
    4.016 ( 2.004 )
        Change from baseline
    -0.067 ( 2.157 )
    -0.745 ( 2.090 )
    Notes
    [12] - Full analysis set (FAS). Number Analyzed for change from baseline is 45 participants.
    [13] - Full analysis set (FAS). Number Analyzed for change from baseline is 47 participants.
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.0241
    Method
    		 MMRM (Method 1)
    Parameter type
    		 Difference in LS means
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 1.54
    Notes
    [14] - The pre-specified test was for superiority but ONLY if the primary endpoint and secondary endpoints were meeting statistical significance (hierarchical testing).

    Secondary: Change from baseline in forced vital capacity (FVC) percent predicted to Week 52

    		 Close Top of page
    End point title
    		 Change from baseline in forced vital capacity (FVC) percent predicted to Week 52
    End point description
    Negative change in FVC percent predicted indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to week 52
    End point values
    		 Riociguat (Adempas, BAY63-2521) Placebo
    Number of subjects analysed
    55 [15]
    51 [16]
    Units: FVC percent predicted
        arithmetic mean (standard deviation)
    -2.376 ( 7.515 )
    -2.945 ( 9.727 )
    Notes
    [15] - FAS with evaluable data for this outcome measure.
    [16] - FAS with evaluable data for this outcome measure.
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Riociguat (Adempas, BAY63-2521) v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.901
    Method
    		 MMRM (Method 1)
    Parameter type
    		 Difference in LS means
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 3
    Notes
    [17] - The pre-specified test was for superiority but ONLY if the primary endpoint and secondary endpoints were meeting statistical significance (hierarchical testing).

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first application of study drug up to 2 days after end of treatment with study drug
    Adverse event reporting additional description
    All 42 patients who completed the main treatment phase from the riociguat group entered the LTE phase and continued to receive riociguat. This group is referred in the LTE phase to “riociguat-riociguat group”. One of the 46 patients from the placebo group did not enter the LTE phase. This group is referred to “placebo-riociguat group”.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Riociguat (main treatment phase)
    Reporting group description
    		 Main treatment phase of 52 weeks: participants received increasing doses of riociguatby 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Reporting group title
    Placebo (main treatment phase)
    Reporting group description
    		 Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham-titration in a dose-titration period up to 10 weeks and a maintenanceperiod of up to 42 weeks. Long-term extension phase: starting after the completion of theMain Treatment Phase in Week 52, participants received increasing doses of riociguat by0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Reporting group title
    Riociguat-Riociguat (LTE phase)
    Reporting group description
    		 Main treatment phase: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting from Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Reporting group title
    Placebo-Riociguat (LTE phase)
    Reporting group description
    		 Main treatment phase: participants received matching placebo tablets to riociguat as sham-titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting from Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.

    Serious adverse events
    		 Riociguat (main treatment phase) Placebo (main treatment phase) Riociguat-Riociguat (LTE phase) Placebo-Riociguat (LTE phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 60 (15.00%)
    15 / 61 (24.59%)
    10 / 42 (23.81%)
    11 / 45 (24.44%)
         number of deaths (all causes)
    1
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Ovarian cancer
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (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
    Hypertension
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Prophylaxis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Rhinoplasty
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Large intestinal polypectomy
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    General disorders and administration site conditions
    Inflammation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (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
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Dyspnoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (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
    Epistaxis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Investigations
    Ultrasound kidney abnormal
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Exposure during pregnancy
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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 disorders
    Angina pectoris
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Left ventricular failure
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Pericarditis
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 61 (3.28%)
    0 / 42 (0.00%)
    0 / 45 (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
    Tachycardia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Ventricular tachycardia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar infarction
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Syncope
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Thrombocytopenia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Abdominal pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Gastric haemorrhage
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Haematemesis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Ileus
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (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
    Nausea
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Vomiting
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Subileus
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Scleroderma renal crisis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Osteolysis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (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
    Scleroderma
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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 discomfort
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondropathy
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Systemic scleroderma
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Gastroenteritis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Infected skin ulcer
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    0 / 45 (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
    Localised infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    1 / 60 (1.67%)
    2 / 61 (3.28%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Salpingitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Sepsis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Staphylococcal infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    0 / 45 (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
    Device related sepsis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Medical device site joint infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (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
    Fluid overload
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    1 / 45 (2.22%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Riociguat (main treatment phase) Placebo (main treatment phase) Riociguat-Riociguat (LTE phase) Placebo-Riociguat (LTE phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 60 (91.67%)
    49 / 61 (80.33%)
    38 / 42 (90.48%)
    39 / 45 (86.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 61 (6.56%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Hypotension
         subjects affected / exposed
    7 / 60 (11.67%)
    4 / 61 (6.56%)
    5 / 42 (11.90%)
    7 / 45 (15.56%)
         occurrences all number
    7
    4
    6
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 61 (4.92%)
    2 / 42 (4.76%)
    1 / 45 (2.22%)
         occurrences all number
    6
    4
    2
    1
    Fatigue
         subjects affected / exposed
    7 / 60 (11.67%)
    6 / 61 (9.84%)
    0 / 42 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    7
    7
    0
    4
    Oedema peripheral
         subjects affected / exposed
    6 / 60 (10.00%)
    2 / 61 (3.28%)
    1 / 42 (2.38%)
    3 / 45 (6.67%)
         occurrences all number
    7
    2
    1
    3
    Pain
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    1 / 45 (2.22%)
         occurrences all number
    4
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 61 (6.56%)
    1 / 42 (2.38%)
    1 / 45 (2.22%)
         occurrences all number
    2
    4
    1
    1
    Peripheral swelling
         subjects affected / exposed
    5 / 60 (8.33%)
    5 / 61 (8.20%)
    0 / 42 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    6
    5
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 60 (15.00%)
    5 / 61 (8.20%)
    6 / 42 (14.29%)
    3 / 45 (6.67%)
         occurrences all number
    9
    5
    6
    4
    Dyspnoea
         subjects affected / exposed
    8 / 60 (13.33%)
    5 / 61 (8.20%)
    3 / 42 (7.14%)
    3 / 45 (6.67%)
         occurrences all number
    9
    6
    3
    4
    Epistaxis
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 61 (3.28%)
    2 / 42 (4.76%)
    1 / 45 (2.22%)
         occurrences all number
    5
    2
    2
    1
    Interstitial lung disease
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 61 (3.28%)
    5 / 42 (11.90%)
    5 / 45 (11.11%)
         occurrences all number
    4
    2
    6
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 61 (3.28%)
    2 / 42 (4.76%)
    0 / 45 (0.00%)
         occurrences all number
    3
    2
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    2 / 42 (4.76%)
    3 / 45 (6.67%)
         occurrences all number
    1
    0
    2
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    8 / 60 (13.33%)
    3 / 61 (4.92%)
    3 / 42 (7.14%)
    1 / 45 (2.22%)
         occurrences all number
    8
    3
    3
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 60 (21.67%)
    7 / 61 (11.48%)
    3 / 42 (7.14%)
    6 / 45 (13.33%)
         occurrences all number
    21
    7
    3
    7
    Headache
         subjects affected / exposed
    11 / 60 (18.33%)
    12 / 61 (19.67%)
    3 / 42 (7.14%)
    4 / 45 (8.89%)
         occurrences all number
    12
    16
    4
    4
    Paraesthesia
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 61 (6.56%)
    0 / 42 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    1
    5
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 61 (4.92%)
    3 / 42 (7.14%)
    4 / 45 (8.89%)
         occurrences all number
    2
    4
    3
    4
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    3 / 42 (7.14%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    5
    1
    0
    6
    Abdominal pain
         subjects affected / exposed
    2 / 60 (3.33%)
    5 / 61 (8.20%)
    3 / 42 (7.14%)
    1 / 45 (2.22%)
         occurrences all number
    2
    5
    3
    3
    Constipation
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 61 (6.56%)
    4 / 42 (9.52%)
    2 / 45 (4.44%)
         occurrences all number
    3
    4
    5
    2
    Diarrhoea
         subjects affected / exposed
    10 / 60 (16.67%)
    8 / 61 (13.11%)
    5 / 42 (11.90%)
    8 / 45 (17.78%)
         occurrences all number
    15
    11
    11
    23
    Dry mouth
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 61 (1.64%)
    1 / 42 (2.38%)
    2 / 45 (4.44%)
         occurrences all number
    4
    1
    1
    2
    Dyspepsia
         subjects affected / exposed
    7 / 60 (11.67%)
    2 / 61 (3.28%)
    1 / 42 (2.38%)
    2 / 45 (4.44%)
         occurrences all number
    7
    2
    1
    3
    Dysphagia
         subjects affected / exposed
    6 / 60 (10.00%)
    1 / 61 (1.64%)
    1 / 42 (2.38%)
    1 / 45 (2.22%)
         occurrences all number
    7
    1
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    15 / 60 (25.00%)
    7 / 61 (11.48%)
    7 / 42 (16.67%)
    8 / 45 (17.78%)
         occurrences all number
    16
    7
    7
    8
    Mouth ulceration
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    3 / 42 (7.14%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Nausea
         subjects affected / exposed
    7 / 60 (11.67%)
    6 / 61 (9.84%)
    2 / 42 (4.76%)
    6 / 45 (13.33%)
         occurrences all number
    9
    6
    5
    7
    Vomiting
         subjects affected / exposed
    8 / 60 (13.33%)
    6 / 61 (9.84%)
    7 / 42 (16.67%)
    4 / 45 (8.89%)
         occurrences all number
    14
    8
    11
    14
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 61 (6.56%)
    2 / 42 (4.76%)
    0 / 45 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Erythema
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Pruritus
         subjects affected / exposed
    5 / 60 (8.33%)
    5 / 61 (8.20%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences all number
    6
    9
    1
    0
    Rash
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 61 (3.28%)
    1 / 42 (2.38%)
    0 / 45 (0.00%)
         occurrences all number
    4
    2
    1
    0
    Skin ulcer
         subjects affected / exposed
    4 / 60 (6.67%)
    7 / 61 (11.48%)
    6 / 42 (14.29%)
    4 / 45 (8.89%)
         occurrences all number
    4
    9
    7
    4
    Urticaria
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 42 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    2
    0
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 60 (20.00%)
    8 / 61 (13.11%)
    4 / 42 (9.52%)
    6 / 45 (13.33%)
         occurrences all number
    14
    9
    5
    6
    Back pain
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 61 (6.56%)
    2 / 42 (4.76%)
    1 / 45 (2.22%)
         occurrences all number
    3
    4
    2
    1
    Bursitis
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    2 / 42 (4.76%)
    3 / 45 (6.67%)
         occurrences all number
    2
    0
    3
    3
    Muscle spasms
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 61 (0.00%)
    2 / 42 (4.76%)
    2 / 45 (4.44%)
         occurrences all number
    6
    0
    3
    2
    Myalgia
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 61 (4.92%)
    4 / 42 (9.52%)
    2 / 45 (4.44%)
         occurrences all number
    1
    3
    5
    2
    Pain in extremity
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 61 (3.28%)
    4 / 42 (9.52%)
    2 / 45 (4.44%)
         occurrences all number
    6
    2
    4
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 61 (1.64%)
    5 / 42 (11.90%)
    0 / 45 (0.00%)
         occurrences all number
    3
    1
    6
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 61 (3.28%)
    2 / 42 (4.76%)
    5 / 45 (11.11%)
         occurrences all number
    1
    2
    2
    6
    Influenza
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    3 / 42 (7.14%)
    4 / 45 (8.89%)
         occurrences all number
    2
    0
    3
    5
    Nasopharyngitis
         subjects affected / exposed
    5 / 60 (8.33%)
    5 / 61 (8.20%)
    11 / 42 (26.19%)
    10 / 45 (22.22%)
         occurrences all number
    7
    8
    13
    10
    Pneumonia
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 61 (3.28%)
    3 / 42 (7.14%)
    0 / 45 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 60 (6.67%)
    8 / 61 (13.11%)
    7 / 42 (16.67%)
    6 / 45 (13.33%)
         occurrences all number
    5
    10
    10
    7
    Urinary tract infection
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 61 (3.28%)
    2 / 42 (4.76%)
    3 / 45 (6.67%)
         occurrences all number
    5
    2
    7
    4
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 42 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    2
    0
    4

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2015
    Due to regulatory feedback, additional safety laboratory monitoring was included for subjects entering the study with elevated liver transaminases or bilirubin, or with an estimated glomerular filtration rate (eGFR) between 15 and 29 mL/min/1.73 m2. These patients were not included in the riociguat pivotal trials in pulmonary hypertension. While there was no evidence of liver or renal toxicity with riociguat, there was an increased risk for adverse events related to the mechanism of action of the drug, such as hypotension, due to a higher plasma concentration caused by impaired riociguat metabolism/elimination by liver and kidneys. The list of immunosuppressant therapies requiring washout before inclusion in the study was also expanded to account for standard of care treatment among the participating countries. Safety laboratory tests were added at Week 26, along with other safety assessments such as ECG and lung function tests to be performed. Measurement of glutamate dehydrogenase (GLDH) was deleted from the list of standard safety parameters because the review of data from previous studies and the ongoing long-term studies did not show any clinically significant changes of this parameter in patients treated with riociguat.
    24 Feb 2016
    The list of secondary endpoints was changed to include a hierarchy of testing. The chosen key secondary endpoint is the (American College of Rheumatology) Composite Response Index for Clinical Trials (CRISS) and the other endpoints in the hierarchy are components of this endpoint. Based on feedback from the Food and Drug Administration (FDA), the protocol was adjusted to clearly differentiate between withdrawal from the study (ie, withdrawal of informed consent) or discontinuation of study treatment (with continued data collection).
    31 Aug 2016
    This amendment was implemented to clarify that the benefit-risk balance for the population in this study (patients with dcSSc) remains positive, despite the potential safety issue that has been reported in a study in patients with pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP) leading to early termination of the concerned study. The benefit-risk assessment for patients with dcSSc was re-evaluated by the data monitoring committee (DMC) in 3 meetings and was confirmed to remain positive.
    02 May 2017
    This amendment was implemented based on the recommendation of the DMC after review of the safety analysis on 01 MAR 2017. Due to increased complaints of both palpitations and dizziness in patients with interstitial lung disease (ILD) noted by the DMC, the assessment of orthostatic changes in blood pressure and heart rate as well as the measurement of oxygen saturation (using forehead pulse oximetry) were added to the protocol assessments for all patients. As recruitment for this study was already completed, the new assessments were not implemented starting with the screening visit, but only for study visits, which was performed after implementation of this amendment. Additionally, an error in the description of the units provided in exclusion criterion 6 was corrected.
    17 Apr 2018
    This protocol amendment was prepared based on the results of the main treatment phase of the study and to better characterize the enrolled patient population. The addition of the anti-centromere was included in the autoantibody screen. A change of responsible Global Clinical Lead was made.

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27746061
    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.

    European Medicines Agency © 1995-Thu Apr 25 07:59:59 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA